Double-Differential FRaGmentation (DDFRG) models for proton and light ion production in high energy nuclear collisions
J. Norbury. Nuclear Instruments and Methods in Physics Research A, vol. 986, p. 164681, 2021.
Summary:
A new set of Double-Differential FRaGmentation (DDFRG) models for proton and light ion production from high energy nucleus-nucleus collisions, relevant to space radiation, is introduced. The proton model employs thermal production from the projectile, central fireball and target sources, as well as quasi-elastic direct knockout production. The light ion model uses a hybrid coalescence model. The data show a prominent quasi-elastic peak at small angles which becomes highly suppressed at large angles. The models are able to describe this wide range of experimental data with only a limited set of model parameters. Closed form analytic formulas for double-differential energy and angle cross-sections as well as single-differential spectral cross-sections are developed. These analytic formulas enable highly efficient computation for radiation transport codes.
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Are Further Cross Section Measurements Necessary for Space Radiation Protection or Ion Therapy Applications? Helium Projectiles
J. Norbury, G. Battistoni, J. Besuglow, L. Bocchini, D. Boscolo, A. Botvina, M. Clowdsley, W. de Wet, M. Durante, M. Giraudo, T. Haberer, L. Heilbronn, F. Horst, M. Krämer, C. La Tessa, F. Luoni, A. Mairani, S. Muraro, R. Norman, V. Patera, G. Santin, C. Schuy, L. Sihver, T. Slaba, N. Sobolevsky, A. Topi, U. Weber, C. Werneth, C. Zeitlin Frontiers in Physics, vol. 8, pp. 1-30, 2020.
Summary:
This work reviews the importance of ⁴He projectiles to space radiation and ion therapy, and outline the present status of neutron and light ion production cross section measurements and modeling, with recommendations for future needs.
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Updated deterministic radiation transport for future deep space missions
Slaba TC, Wilson JW, Werneth CM, Whitman K. Life Sci Space Res. 2020 Nov;27:6-18.
Summary:
NASA's deterministic transport code HZETRN, and its three-dimensional (3D) counterpart, 3DHZETRN, are being used to characterize the space radiation environment over a wide range of scenarios, including future planned missions to the moon or Mars. Combined with available spaceflight measurements, these tools provide the fundamental input for biological risk projection models used to verify astronaut safety and satisfy agency limits in support of exploration initiatives. In this work, significant updates to the deterministic radiation transport models are presented. Charged muons and pions are fully coupled to neutron and light ion (Z < 2) transport solutions in 1D and 3D. A direct comparison of deterministic and Monte Carlo transport methodologies using the same nuclear interaction databases is also provided. It is shown that Geant4 and 3DHZETRN are in excellent agreement when the same cross sections are used. The deterministic codes are also compared to ISS data, and it is found that the updated 3D procedures are within measurement uncertainty (+5%) at cutoff rigidities below 1 GV, which approaches free space conditions.
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2nd-order optical model of the isotopic dependence of heavy ion absorption cross sections for radiation transport studies
Francis A. Cucinotta, Congchong Yan, Premkumar B. Saganti Nuclear Inst, and Methods in Physics Research B 414 (2018) 11-17
Summary:
Heavy ion absorption cross sections play an important role in radiation transport codes used in risk assessment and for shielding studies of galactic cosmic ray (GCR) exposures. Due to the GCR primary nuclei composition and nuclear fragmentation leading to secondary nuclei heavy ions of charge number, Z with 3 ≤ Z ≥ 28 and mass numbers, A with 6 ≤ A ≥ 60 representing about 190 isotopes occur in GCR transport calculations. In this report we describe methods for developing a data-base of isotopic dependent heavy ion absorption cross sections for interactions. Calculations of a 2nd-order optical model solution to coupled-channel solutions to the Eikonal form of the nucleus-nucleus scattering amplitude are compared to 1st-order optical model solutions. The 2nd-order model takes into account two-body correlations in the projectile and target ground-states, which are ignored in the 1st-order optical model. Parameter free predictions are described using one-body and two-body ground state form factors for the isotopes considered and the free nucleon-nucleon scattering amplitude. Root mean square (RMS) matter radii for protons and neutrons are taken from electron and muon scattering data and nuclear structure models. We report on extensive comparisons to experimental data for energy-dependent absorption cross sections for over 100 isotopes of elements from Li to Fe interacting with carbon and aluminum targets. Agreement between model and experiments are generally within 10% for the 1st-order optical model and improved to less than 5% in the 2nd-order optical model in the majority of comparisons. Overall the 2nd-order optical model leads to a reduction in absorption compared to the 1st-order optical model for heavy ion interactions, which influences estimates of nuclear matter radii.
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Physical characteristics at the turnover-points of relative biological effect (RBE) with linear energy transfer (LET).
Jones B, Hill MA. Phys Med Biol. 2019 Oct 30. [Epub ahead of print]
Summary:
This article shows that ions of each lighter element (up to Ferric ions) exert their maximum relative biological effect (RBE) at unique values of ionisation clustering (denoted by a linear energy transfer of LETU). This is the LET value at which RBE (and radiosensitivity) begins to fall with further increases of LET. At LETU the ions are at 0.99 of their fully expressed nuclear charge and share some kinematic properties: a velocity of 3-4 nm.fs-1 per nucleon, or around 6-8 nm.fs-1 per unit Z, dimensions that are relevant to radiochemical changes and to DNA and nucleosome.
These findings differ from conclusions drawn from pooled ionic RBE data, which have previously assumed that the maximum bio-effect of all light ions occured at a LET of around 120 keV per micrometre. There are potential implications for future RBE estimations (based on LET and absorbed dose) in radiotherapy, radioprotection and space travel.
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Enhanced GEANT4 Monte Carlo simulations of the space radiation effects on the International Space Station and Apollo missions using high-performance computing environment.
Lund M, Jevremovic T. Acta Astronaut. 2019 Dec;165:219-28. Epub 2019 Sep 19.
Summary:
This paper introduces a new simulation model and application using GEANT4 with multithreading and Message Passing Interface (MPI) that greatly reduces computational time to hours instead of weeks without any post simulation processing based on high-performance computing. This paper also introduces a new set of GEANT4 computational detectors for calculating dose distribution, besides the historically used International Commission of Radiation Units simulation spheres. The computational detectors include a thermoluminescent detector, tissue equivalent proportional counter, and human phantom, along with additional new scorers to calculate dose equivalence based on the International Commission of Radiation Protection standards. This study presents GEANT4 simulations of the dose deposition for the International Space Station and the Apollo 11 and 14 missions, which replicate well the dose measurements during these missions. The simulations of both Apollo missions show consistent doses from galactic cosmic rays and radiation belts with a small variation in dose distribution across the Apollo capsule. The greatest contributor to radiation dose for both Apollo missions in the simulations came from galactic cosmic rays. Simulations of historical solar particle events during an Apollo missions show a solar particle event would not be fatal and below mission limits. These GEANT4 models also provides the values of the dose deposition and dose equivalent for various organs within a human phantom in the International Space Station and Apollo command module, which are developed for the first time using this GEANT4 based application.
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Evaluating the effectiveness of common aerospace materials at lowering the whole body effective dose equivalent in deep space.
Bond DK, Goddard B, Singleterry RC Jr, Bilbao y Leóna S. Acta Astronaut. 2019 Aug 22. [Article in Press]
Summary:

Materials have a primary purpose in the design of space vehicles, such as fuels, walls, racks, windows, etc. Additionally, each will also affect space radiation protection. The shielding capabilities of 59 materials are evaluated for deep space travel, in terms of whole body effective dose equivalent, ED, and number of nucleons per volume#ofNucleonsVolume. The hydrogen rich materials are evaluated further using the number of Hydrogen Atoms per mass and number of Hydrogen Atoms per volume. All evaluated materials, through density, composition, and shielding ability, can be categorized into three groups: metals, polymers and composites, and fuels, hydrides, and liquid gases. The analyses presented in the article shows that a "magic" material is not possible; however polymers and composites should be used instead of metals, if they can serve their primary purpose. Polyethylene and magnesium borohydride are shown to be the best feasible materials from this sample. Thermal neutron absorbers, ⁶Li and ¹⁰B, do not have a significant effect on ED. Alloying of materials, such as aluminum, for strengthening purposes, do not increase ED. Ultimately, a space vehicle is a system of systems and radiation protection must be one of them.

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Advances in space radiation physics and transport at NASA.
Norbury JW, Slaba TC, Aghara S, Badavi FF, Blattnig SR, Clowdsley MS, Heilbronn LH, Lee K, Maung KM, Mertens CJ, Miller J, Norman RB, Sandridge CA, Singleterry R, Sobolevsky N, Spangler JL, Townsend LW, Werneth CM, Whitman K, Wilson JW, Xu SX, Zeitlin C. Life Sci Space Res. 2019 Jul 10. [Article in Press] Review.
Summary:
This paper describes significant new discoveries and advances made in space radiation physics and transport over the past decade. Some of the most important new developments include the following: 1) The discovery of a minimum in the dose-equivalent versus depth curve; 2) A large contribution to dose from pions; 3) A large contribution of neutrons and light ions to dose equivalent for realistic shield thickness; 4) A realization that there are large and significant gaps in cross section measurements needed for space radiation; 5) Development of 3-dimensional deterministic transport methods; 6) Development of a fully relativistic nuclear fragmentation model; 7) Development of a GCR simulation capability at the NASA Space Radiation Laboratory; 8) Development of an On-Line Tool for the Assessment of Radiation In Space (OLTARIS); 9) Development of a Nowcast of Atmospheric Ionizing Radiation for Aviation Safety (NAIRAS) model. Each of these advances contribute significantly to improving our knowledge of space radiation and will help achieve safer long term space travel. The paper is coauthored by 22 scientists from various NASA centers, universities and commercial companies, and includes work funded by NASA's Human Research Program and Advanced Exploration Systems.
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Thick target neutron yields from 100- and 230- MeV/nucleon helium ions bombarding water, PMMA, and iron
P. Tsai, L. Heilbronn, B. Lai, Y. Iwata, T. Murakami, R. Sheu. Nuclear Instruments and Methods in Physics Research B. 2019;449,62-70.
Summary:
The yields of secondary neutrons produced from 100- and 230-MeV/nucleon 4He ions, respectively, stopping in thick natFe, PMMA and water targets were measured. Double-differential thick target neutron yields, angular distributions, and total neutron yields per ion were benchmarked against model calculations with the PHITS, FLUKA, and MCNP Monte Carlo simulation codes. Our results indicate that significant improvements are needed in the physics models used to describe 4He-induced nuclear reactions for predictions of neutron production.
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Impact of Radiation Quality on Microdosimetry and Chromosome Aberrations for High-Energy (>250 MeV/n) Ions.

Poignant, F.; Plante, I.; Crespo, L.; Slaba, T. Life 2022, 12, 358.

Summary:

Using the models RITRACKS (track structure) and RITCARD (chromosome aberration), we studied how radiation quality impacts two endpoints: single-ion energy deposition spectra (microdosimetry in targets the size of a cell nucleus) and chromosome aberration yields. Calculations were performed for high-energy (> 250 MeV/n) mono-energetic ion beams with linear energy transfer (LET) varying from 0.22 to 149.9 keV/µm, and poly-energetic beams after the transport of the mono-energetic ion beams in a digital mouse model, representing the radiation exposure of a cell in a tissue. To discriminate events from ion tracks directly traversing the nucleus, to events from δ-electrons emitted by distant ion tracks, we categorized ion contributions to both endpoints into direct and indirect contributions, respectively. For microdosimetry, the indirect contribution is largely independent of the beam LET and minimally impacted by the beam interactions in mice. In contrast, the direct contribution is strongly dependent on the beam LET and shows increased probabilities of having low and high-energy deposition events when considering beam transport. Regarding chromosome aberrations, the indirect contribution induces a small number of simple exchanges, and a negligible number of complex exchanges. The direct contribution is responsible for most simple and complex exchanges. The complex exchanges are significantly increased for some low-LET ion beams when considering beam transport.

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Track structure model of microscopic energy deposition by protons and heavy ions in segments of neuronal cell dendrites represented by cylinders or spheres.
Alp M, Cucinotta FA.. Life Sci Space Res. 2017 Apr 2. [Article in Press]
Summary:
The purpose of the present work is to develop computational methods to evaluate microscopic energy deposition (ED) in volumes representative of neuron cell structures, including segments of dendrites and spines, using a stochastic track structure model. We consider cylindrical and spherical microscopic volumes of varying geometric parameters and aspect ratios from 0.5 to 5 irradiated by protons, and 3He and 12C particles at energies corresponding to a distance of 1 cm to the Bragg peak, which represent particles of interest in Hadron therapy as well as space radiation exposure.
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Time-lapse monitoring of DNA damage colocalized with particle tracks in single living cells.
McFadden CH, Hallacy TM, Flint DB, Granville DA, Asaithamby A, Sahoo N, Akselrod MS, Sawakuchi GO. Int J Radiat Oncol Biol Phys. 2016 Sep 1;96(1):221-7.
Summary:
Understanding the DNA damage and repair induced by high-energy charged particles such as protons and heavier ions is crucial for developing novel strategies to maximize the use of particle therapy to treat cancer patients as well as to understand the effects of space radiation in humans. However, spatiotemporal studies of DNA damage and repair for beam energies relevant to particle therapy and radiation protection in space have been challenging. We report a technique that enables spatiotemporal measurement of radiation-induced damage in live cells and colocalization of this damage with charged particle tracks over a broad range of beam energies. The technique uses novel fluorescence nuclear track detectors with a custom-built fluorescence confocal laser scanning microscope to visualize particle track traversals within the subcellular compartments of live cells within seconds after injury. Our custom-built microscope can be shipped and installed in any beam line (horizontal and vertical beams) including particle therapy beams and beam lines used for space radiation research such as the NASA Space Radiation Laboratory. This technique makes possible investigations of DNA damage response processes that happen immediately after DNA damage in high-energy beams that are not available in microbeam facilities.
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Experimental microdosimetry: History, applications and recent technical advances.
Braby LA. Radiat Prot Dosimetry. 2015 Apr 15. [Epub ahead of print]
Summary:
This paper summarizes the 50 year development of microdosimetry detectors from delicate laboratory research instruments to rugged detectors that can be used in a wide variety of radiation environments. The relative biological risk presented by different types of ionizing radiation can be estimated based on the amount of energy each type deposits in small volumes such as a cell nucleus. Radiations which deposit a large amount of energy in a few small volumes tend to be more damaging than radiations that deposit a small amount of energy in a large number of small volumes, even though the total amount of energy deposited in an organ is the same. The characterization of energy deposition in small volumes, known as microdosimetry, has been the basis of a sequence of instruments used to evaluate radiation exposure on the STS and ISS for nearly two decades.
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Description and Verification of an Algorithm for Obtaining Microdosimetric Quantities for High-LET Radiation Using a Single TEPC without Pulse Height Analysis.
Thomas B. Borak and Phillip L. Chapman (2014) Radiation Research: October 2014, Vol. 182, No. 4, pp. 396-407.
Summary:
Microdosimetric spectra of single event distributions have been used to provide estimates of quality factors for radiation protection of high LET radiation. It becomes difficult to measure, record and store energy deposition from single events in situations with high dose rates. An alternative approach is to store random energy deposition events in a sequence of fixed time intervals that does not require recording single events. This can be accomplished with one detector without pulse shaping or pulse height analysis. We present the development of the algorithm using expectation analyses of the statistical estimators for moments of lineal energy. The method can provide prompt real-time information in circumstances that restrict detector configurations in terms of size, mass and power consumption such as personal dosimetry during an EVA It can be adapted for measurements of any quantity that is linearly related to absorbed dose, such as estimation of dose averaged LET.
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Biophysics of NASA Radiation Quality Factors.
Francis A. Cucinotta. Radiat Prot Dosimetry (2015) doi: 10.1093/rpd/ncv144. First published online: April 16, 2015
Summary:
NASA has implemented new radiation quality factors (QFs) for projecting cancer risks from space radiation exposures to astronauts. The NASA QFs are based on particle track structure concepts with parameters derived from available radiobiology data, and NASA introduces distinct QFs for solid cancer and leukaemia risk estimates. A key feature of the NASA QFs is to represent the uncertainty in the QF assessments and evaluate the importance of the QF uncertainty to overall uncertainties in cancer risk projections. In this article, the biophysical basis for the probability distribution functions representing QF uncertainties is reviewed, and approaches needed to reduce uncertainties are discussed.
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Comparison of dose and risk estimates between ISS Partner Agencies for a 30-day Lunar Mission.

Shavers MR, Semones EJ, Shurshakov V, Dobynde M, Sato T, Komiyama T, Tomi L, Chen J, El-Jaby S, Straube U, Li C, Rühm W. Comparison of dose and risk estimates between ISS Partner Agencies for a 30-day Lunar Mission. Z Med Phys. 2023 Nov 28:S0939-3889(23)00121-6. doi: 10.1016/j.zemedi.2023.10.005. Epub ahead of print. PMID: 38030484.

Summary:

The International Partner Agencies of the International Space Station (ISS) present a comparison of the ionizing radiation absorbed dose and risk quantities used to characterize example missions in lunar space. This effort builds on previous collaborative work that characterizes radiation environments in space to support radiation protection for human spaceflight on ISS in low-Earth orbit (LEO) and exploration missions beyond (BLEO). A "shielded" ubiquitous galactic cosmic radiation (GCR) environment combined with--and separate from--the transient challenge of a solar particle event (SPE) was modelled for a simulated 30-day mission period. Simple geometries of relatively thin and uniform shields were chosen to represent the space vehicle and other available shielding, and male or female phantoms were used to represent the body's self-shielding. Absorbed dose in organs and tissues and the effective dose were calculated for males and females. Risk parameters for cancer and other outcomes are presented for selected organs. The results of this intracomparison between ISS Partner Agencies itself provide insights to the level of agreement with which space agencies can perform organ dosimetry and calculate effective dose. This work was performed in collaboration with the advisory and guidance efforts of the International Commission on Radiological Protection (ICRP) Task Group 115 and will be presented in an ICRP Report.

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Investigation of shielding material properties for effective space radiation protection
Naito M, Kodaira S, Ogawara R, Tobita K, Someya Y, Kusumoto T, Kusano H, Kitamura H, Koike M, Uchihori Y, Yamanaka M, Mikoshiba R, Endo T, Kiyono N, Hagiwara Y, Kodama H, Matsuo S, Takami Y, Sato T, Orimo S. Life Sci Space Res. 2020 Aug;26:69-76. Epub 2020 May 23.
Summary:
Geant4 Monte Carlo simulations were carried out to investigate the possible shielding materials of aluminum, polyethylene, hydrides, complex hydrides and composite materials for radiation protection in spacecraft by considering two physical parameters, stopping power and fragmentation cross section. The dose reduction with shielding materials was investigated for Fe ions with energies of 500 MeV/n, 1 GeV/n and 2 GeV/n which are around the peak of the GCR energy spectrum. Fe ions easily stop in materials such as polyethylene and hydrides as opposed to materials such as aluminum and complex hydrides including high Z metals with contain little or no hydrogen. Among hydrogenous materials, 6Li10BH4 was one of the more effective shielding materials as a function of mass providing a 20% greater dose reduction compared to polyethylene. Composite materials such as carbon fiber reinforced plastic and SiC composite plastic offer 1.9 times the dose reduction compared to aluminum as well as high mechanical strength. Composite materials have been found to be promising for spacecraft shielding, where both mass and volume are constrained.
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Shielding effectiveness: A weighted figure of merit for space radiation shielding
DeWitt JM, Benton ER. Appl Radiat Isot. 2020 Jul;161:109141. Epub 2020 Mar 30.
Summary:
The risk to space crew health and safety posed by exposure to space radiation is regarded as a significant obstacle to future human exploration missions to the Moon, Mars, and beyond. Engineers developing future spacecraft or planetary surface habitats can benefit from detailed knowledge of a broad range of possible materials that could provide improved protection to space crews from the deleterious effects of prolonged exposure to the space radiation environment. As one step towards providing this knowledge base, we have developed an empirical weighted figure of merit, referred to as shielding effectiveness, that quantifies the ability of a candidate material to shield space crews from the space radiation environment. The preliminary shielding effectiveness values for aluminum, copper, graphite, and water confirm the low Z principle for effective space radiation shielding, and, furthermore, these values tend to be lower when the effectiveness calculation is based on dose equivalent. Of the common materials studied here, at a bulkhead depth of 5 g/cm2, all materials provide a similar level of radiation protection to within standard error.
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Numerical investigation of radiation shielding properties of polyethylene-based nanocomposite materials in different space environments
Laurenzi S, de Zanet G, Santonicola MG. Acta Astronaut. 2020 Feb 18. [Article in Press]
Summary:
In this study, we numerically investigate the radiation properties of polyethylene-based nanocomposites for space protection using the HZETRN2015 code by NASA. In particular, we analyze the role of single-walled carbon nanotubes (SWCNT) and graphene oxide (GO) nanoplatelets, at different loadings, on the equivalent dose absorbed by the nanocomposites in various radiation fields in space. The choice of polyethylene as the optimal matrix for radiation shielding was confirmed by preliminary studies on different aerospace-grade polymers, aluminium and liquid hydrogen. Simulations were performed for the case of galactic cosmic rays, solar particles events, and for the LEO radiation environment. Composites made of polyethylene and boron carbide particles were also analyzed for comparison with the carbon-filled composites. Results from simulations show that the shielding properties are comparable to the neat polyethylene at low loadings (1-5 wt%) of filler, with the GO nanoplatelets being the best reinforcement for space radiation protection among the investigated fillers.
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Radiation engineering analysis of shielding materials to assess their ability to protect astronauts in deep space from energetic particle radiation
Acta Astronaut. 2020 Feb 15. Manning B, Singleterry R.
Summary:

This paper is a continuation of a paper written in 2013 (Same title, AA V.91 p.49-54). These papers together look at launch mass to LEO to get astronauts to Mars and back within a GCR proxy total mission exposure limit of 150 mSv effective dose. This paper (AA 2020-Feb-15 preprint) focuses on the difference between spherical vehicles (the original paper) and right circular cylinder vehicles. It also analyzes a whole body personal protection system and the tanking of shielding materials. A newer version of OLTARIS was used along with the latest GCR environment model. As in the previous paper, liquid hydrogen, liquid methane, water, polyethylene, and aluminum are used in the analyses. This paper shows that a single SLS launch of material will get the astronauts to their total proxy limit in about 180 days. No single launch configuration of materials will get an astronaut to 400 days (a typical Mars mission duration in transit). This prompted another study reported on in AIAA SPACE 2018-5360 "Maintaining Human Health for Human-Mars" by Robert Moses, Dennis Bushnell, et. al. that showed it is possible to get humans to and from Mars within the proxy limit; however, transit times of 60 days one-way are necessary. The last item touched on in this paper is an initial investigation of the ray tracing approximation used to convert CAD models of spacecraft to radiation analysis models that can be used in codes like OLTARIS. This is prompting new research in this area.

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Complex 33-beam simulated galactic cosmic radiation exposure impacts cognitive function and prefrontal cortex neurotransmitter networks in male mice.

Desai RI, Kangas BD, Luc OT, Solakidou E, Smith EC, Dawes MH, Ma X, Makriyannis A, Chatterjee S, Dayeh MA, Muñoz-Jaramillo A, Desai MI, Limoli CL. Complex 33-beam simulated galactic cosmic radiation exposure impacts cognitive function and prefrontal cortex neurotransmitter networks in male mice. Nat Commun. 2023 Nov 27;14(1):7779. doi: 10.1038/s41467-023-42173-x. PMID: 38012180; PMCID: PMC10682413.

Summary:

Astronauts will encounter extended exposure to galactic cosmic radiation (GCR) during deep space exploration, which could impair brain function. Here, we report that in male mice, acute or chronic GCR exposure did not modify reward sensitivity but did adversely affect attentional processes and increased reaction times. Potassium (K+)-stimulation in the prefrontal cortex (PFC) elevated dopamine (DA) but abolished temporal DA responsiveness after acute and chronic GCR exposure. Unlike acute GCR, chronic GCR increased levels of all other neurotransmitters, with differences evident between groups after higher K+-stimulation. Correlational and machine learning analysis showed that acute and chronic GCR exposure differentially reorganized the connection strength and causation of DA and other PFC neurotransmitter networks compared to controls which may explain space radiation-induced neurocognitive deficits.

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Effects of HZE-Particle Exposure Location and Energy on Brain Inflammation and Oxidative Stress in Rats.

Cahoon DS, Rabin BM, Fisher DR, Shukitt-Hale B. Effects of HZE-Particle Exposure Location and Energy on Brain Inflammation and Oxidative Stress in Rats. Radiat Res. 2023 Nov 1;200(5):431-443. doi: 10.1667/RADE-22-00041.1. PMID: 37758038.

Summary:

Astronauts on exploratory missions will be exposed to particle radiation of high energy and charge (HZE particles), which have been shown to produce neurochemical and performance deficits in animal models. Exposure to HZE particles can produce both targeted effects, resulting from direct ionization of atoms along the particle track, and non-targeted effects (NTEs) in cells that are distant from the track, extending the range of potential damage beyond the site of irradiation. While recent work suggests that NTEs are primarily responsible for changes in cognitive function after HZE exposures, the relative contributions of targeted and non-targeted effects to neurochemical changes after HZE exposures are unclear. The present experiment was designed to further explore the role of targeted and non-targeted effects on HZE-induced neurochemical changes (inflammation and oxidative stress) by evaluating the effects of exposure location and particle energy/linear energy transfer (LET). Forty-six male Sprague-Dawley rats received head-only or body-only exposures to 56Fe particles [600 MeV/n (75 cGy) or 1,000 MeV/n (100 cGy)] or 48Ti particles [500 MeV/n (50 cGy) or 1,100 MeV/n (75 cGy)] or no irradiation (0 cGy). Twenty-four h after irradiation, rats were euthanized, and the brain was dissected for analysis of HZE-particle-induced neurochemical changes in the hippocampus and frontal cortex. Results showed that exposure to 56Fe and 48Ti ions produced changes in measurements of brain inflammation [glial fibrillary astrocyte protein (GFAP)], oxidative stress [NADPH-oxidoreductase-2 (NOX2)] and antioxidant enzymes [superoxide dismutase (SOD), glutathione S-transferase (GST), nuclear factor erythroid 2-related factor 2 (Nrf2)]. However, radiation effects varied depending upon the specific measurement, brain region, and exposure location. Although overall exposures of the head produced more detrimental changes in neuroinflammation and oxidative stress than exposures of the body, body-only exposures also produced changes relative to no irradiation, and the effect of particle energy/LET on neurochemical changes was minimal. Results indicate that both targeted and non-targeted effects are important contributors to neurochemical changes after head-only exposure. However, because there were no consistent neurochemical changes as a function of changes in track structure after head-only exposures, the role of direct effects on neuronal function is uncertain. Therefore, these findings, although in an animal model, suggest that NTEs should be considered in the estimation of risk to the central nervous system (CNS) and development of countermeasures.

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Dosimetry of the PIM1 Pion Beam at the Paul Scherrer Institute for Radiobiological Studies of Mice

Desorgher L, Stabilini A, Rostomyan T, Reggiani D, Hajdas W, Marcinkowski RM, Vozenin MC, Limoli CL, Yukihara EG, Bailat C. Radiat Res. 2023; 200(4):357-365.

Summary:

Significant past work has identified unexpected risks of central nervous system (CNS) exposure to the space radiation environment, where long-lasting functional decrements have been associated with multiple ion species delivered at low doses and dose rates. As shielding is the only established intervention capable of limiting exposure to the dangerous radiation fields in space, the recent discovery that pions, emanating from regions of enhanced shielding, can contribute significantly to the total absorbed dose on a deep space mission poses additional concerns. As a prerequisite to biological studies evaluating pion dose equivalents for various CNS exposure scenarios of mice, a careful dosimetric validation study is required. Within our ultimate goal of evaluating the functional consequences of defined pion exposures to CNS functionality, we report in this article the detailed dosimetry of the PiMI pion beam line at the Paul Scherrer Institute, which was developed in support of radiobiological experiments. Beam profiles and contamination of the beam by protons, electrons, positrons and muons were characterized prior to the mice irradiations. The dose to the back and top of the mice was measured using thermoluminescent dosimeters (TLD) and optically simulated luminescence (OSL) to cross-validate the dosimetry results. Geant4 Monte Carlo simulations of radiation exposure of a mouse phantom in water by charged pions were also performed to quantify the difference between the absorbed dose from the OSL and TLD and the absorbed dose to water, using a simple model of the mouse brain. The absorbed dose measured by the OSL dosimeters and TLDs agreed within 5–10%. A 30% difference between the measured absorbed dose and the dose calculated by Geant4 in the dosimeters was obtained, probably due to the approximated Monte Carlo configuration compared to the experiment. A difference of 15–20% between the calculated absorbed dose to water at a 5 mm depth and in the passive dosimeters was obtained, suggesting the need for a correction factor of the measured dose to obtain the absorbed dose in the mouse brain. Finally, based on the comparison of the experimental data and the Monte Carlo calculations, we consider the dose measurement to be accurate to within 15–20%.

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Longitudinal Changes in Cerebral Perfusion, Perivascular Space Volume, and Ventricular Volume in a Healthy Cohort Undergoing a Spaceflight Analog

Tidwell JB, Taylor JA, Collins HR, Chamberlin JH, Barisano G, Sepehrband F, Turner MD, Gauthier G, Mulder ER, Gerlach DA, Roberts DR. Am J Neuroradiol. 2023; 44(9):1026-1031.

Summary:

BACKGROUND AND PURPOSE: A global decrease in brain perfusion has recently been reported during exposure to a ground-based spaceflight analog. Considering that CSF and glymphatic flow are hypothesized to be propelled by arterial pulsations, it is unknown whether a change in perfusion would impact these CSF compartments. The aim of the current study was to evaluate the relationship among changes in cerebral perfusion, ventricular volume, and perivascular space volume before, during, and after a spaceflight analog. MATERIALS AND METHODS: Eleven healthy participants underwent 30 days of bed rest at 6° head-down tilt with 0.5% atmospheric CO2 as a spaceflight analog. For each participant, 6 MR imaging brain scans, including perfusion and anatomic-weighted T1 sequences, were obtained before, during, and after the analog period. Global perfusion, ventricular volume, and perivascular space volume time courses were constructed and evaluated with repeated measures ANOVAs. RESULTS: Global perfusion followed a divergent time trajectory from ventricular and perivascular space volume, with perfusion decreasing during the analog, whereas ventricular and perivascular space volume increased (P < .001). These patterns subsequently reversed during the 2-week recovery period. CONCLUSIONS: The patterns of change in brain physiology observed in healthy participants suggest a relationship between cerebral perfusion and CSF homeostasis. Further study is warranted to determine whether a causal relationship exists and whether similar neurophysiologic responses occur during spaceflight.

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Effects of low-dose oxygen ions on cardiac function and structure in female C57BL/6J mice

Nemec-Bakk AS, Sridharan V, Landes RD, Singh P, Cao M, Dominic P, Seawright JW, Chancellor JC, Boerma M. Life Sci Space Res (Amst). 2022 Feb;32:105-12.

Summary:

Research on cardiovascular effects of simulated space radiation has thus far been performed in male animal models. In the current study, long-term effects of single low doses of oxygen ion radiation on the heart was studied in adult female C57BL/6J mice. Irradiation caused remodeling of existing collagens in the heart and an increase in left ventricular levels of the T-cell marker CD2, but these did not result in significant changes in cardiac function. Future studies need to make direct comparisons between male and female animals in radiation effects on the heart.

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Long-term sex- and genotype-specific effects of 56Fe irradiation on wild-type and APPswe/PS1dE9 transgenic mice.

Schroeder MK, Liu B, Hinshaw RG, Park MA, Wang S, Dubey S, Liu GG, Shi Q, Holton P, Reiser V, Jones PA, Trigg W, Di Carli MF, Caldarone BJ, Williams JP, O'Banion MK, Lemere CA.  [1/18/2022]

 Int J Mol Sci. 2021 Dec 10;22(24):13305.

Summary:

There is evidence that 56Fe irradiation, a significant component of space radiation, may be more harmful to males than to females and worsen Alzheimer's disease pathology in genetically vulnerable models. We irradiated 4-month-old male and female, wild-type and Alzheimer's-like APP/PS1 mice with 0, 0.10, or 0.50 Gy of 56Fe ions (1GeV/u). Mice underwent microPET scans before and 7.5 months after irradiation, a battery of behavioral tests at 11 months of age and were sacrificed for pathological and biochemical analyses at 12 months of age. 56Fe irradiation worsened amyloid-beta (Aβ) pathology, gliosis, neuroinflammation and spatial memory, but improved motor coordination, in male transgenic mice and worsened fear memory in wild-type males. These results provide evidence for sex-specific, long-term CNS effects of space radiation.

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Examining the Effects of 4He Exposure on the Gut-Brain Axis

Carli B. Jones; Lauren B. Peiffer; Catherine M. Davis; Karen S. Sfanos Radiat Res (2022) 197 (3): 242–252.

Summary:

There is limited research investigating the early effects of helium ion (4He) exposure on the gut-brain axis. We studied changes in GI microbiota and social odor recognition memory of rats acutely exposed to 4He (0, 5 or 25 cGy, 250 MeV/n). At 7 days following exposure, 25 cGy 4He resulted in deficits in social recognition memory, decreases in Akkermansia spp. and spore-forming bacteria, and changes in serotonin production within the intestine, without pathological changes to the GI tissues. These results suggest that the gut-brain axis can be disrupted following simulated space radiation exposure and have implications for astronaut health during exploratory class missions.

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Multi-domain touchscreen-based cognitive assessment of C57BL/6J female mice shows whole-body exposure to 56Fe particle space radiation in maturity improves discrimination learning yet impairs stimulus

Soler I, Yun S, Reynolds RP, Whoolery CW, Tran FH, Kumar PL, Rong Y, DeSalle MJ, Gibson AD, Stowe AM, Kiffer FC, Eisch AJ. Front Behav Neurosci. 2021 Oct 11;15:722780. Online ahead of print.

Summary:

Astronauts during interplanetary missions will be exposed to galactic cosmic radiation, including charged particles like 56Fe. Most preclinical studies with mature, "astronaut-aged" rodents suggest space radiation diminishes performance in classical hippocampal- and prefrontal cortex-dependent tasks. However, a rodent cognitive touchscreen battery unexpectedly revealed 56Fe radiation improves the performance of C57BL/6J male mice in a hippocampal-dependent task (discrimination learning) without changing performance in a striatal-dependent task (rule-based learning). As there are conflicting results on whether the female rodent brain is preferentially injured by or resistant to charged particle exposure, and as the proportion of female vs. male astronauts is increasing, further study on how charged particles influence the touchscreen cognitive performance of female mice is warranted. We hypothesized that, similar to mature male mice, mature female C57BL/6J mice exposed to fractionated whole-body 56Fe irradiation (3 × 6.7cGy 56Fe over 5 days, 600 MeV/n) would improve performance vs. Sham conditions in touchscreen tasks relevant to hippocampal and prefrontal cortical function [e.g., location discrimination reversal (LDR) and extinction, respectively]. In LDR, 56Fe female mice more accurately discriminated two discrete conditioned stimuli relative to Sham mice, suggesting improved hippocampal function. However, 56Fe and Sham female mice acquired a new simple stimulus-response behavior and extinguished this acquired behavior at similar rates, suggesting similar prefrontal cortical function. Based on prior work on multiple memory systems, we next tested whether improved hippocampal-dependent function (discrimination learning) came at the expense of striatal stimulus-response rule-based habit learning (visuomotor conditional learning). Interestingly, 56Fe female mice took more days to reach criteria in this striatal-dependent rule-based test relative to Sham mice. Together, our data support the idea of competition between memory systems, as an 56Fe-induced decrease in striatal-based learning is associated with enhanced hippocampal-based learning. These data emphasize the power of using a touchscreen-based battery to advance our understanding of the effects of space radiation on mission critical cognitive function in females, and underscore the importance of preclinical space radiation risk studies measuring multiple cognitive processes, thereby preventing NASA's risk assessments from being based on a single cognitive domain.

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Predicting space radiation single ion exposure in rodents: A machine learning approach

Prelich MT, Matar M, Gokoglu SA, Gallo CA, Schepelmann A, Iqbal AK, Lewandowski BE, Britten RA, Prabhu RK, Myers JG Jr.and published in Front Syst Neurosci. 2021 Oct 15;15:715433

Summary:

This study presents a data-driven machine learning approach to predict individual Galactic Cosmic Radiation (GCR) ion exposure for 4He, 16O, 28Si, 48Ti, or 56Fe up to 150 mGy, based on Attentional Set-shifting (ATSET) experimental tests. The analysis employs scores of selected input features and different normalization approaches which yield varying degrees of model performance. The current study shows that support vector machine, Gaussian naive Bayes, and random forest models are capable of predicting individual ion exposure using ATSET scores where corresponding Matthews correlation coefficients and F1 scores reflect model performance exceeding random chance. The study suggests a decremental effect on cognitive performance in rodents due to ≤150 mGy of single ion exposure, inasmuch as the models can discriminate between 0 mGy and any exposure level in the performance score feature space.

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The impact of deep space radiation on cognitive performance: From biological sex to biomarkers to countermeasures

Krukowski K, Grue K, Becker M, Elizarraras E, Frias ES, Halvorsen A, Koenig-Zanoff M, Frattini V, Nimmagadda H, Feng X, Jones T, Nelson G, Ferguson AR, Rosi S Sci Adv. 2021 Oct 15;7(42):eabg6702.

Summary:

These studies demonstrate sex-dimorphic responses in mice exposed to accelerated charged particles to simulate GCR (GCRsim); males displayed impaired spatial learning, whereas females did not. Mechanistically, these GCRsim-induced learning impairments corresponded with chronic microglia activation and synaptic alterations in the hippocampus. Temporary microglia depletion shortly after GCRsim exposure mitigated GCRsim-induced deficits measured months after the radiation exposure. Furthermore, blood monocyte levels measured early after GCRsim exposure were predictive of the late learning deficits and microglia activation measured in the male mice.

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Machine learning models to predict cognitive impairment of rodents subjected to space radiation

Matar M, Gokoglu SA, Prelich MT, Gallo CA, Iqbal AK, Britten RA, Prabhu RK, Myers JG Jr Front Syst Neurosci. 2021 Sep 13;15:713131.

Summary:

This research uses machine-learned computational analyses to predict the cognitive performance impairment of rats induced by irradiation. The experimental data in the analyses is from a rodent model exposed to = 15 cGy of individual Galactic Cosmic Radiation (GCR) ions: ⁴He, ¹⁶O, ²⁸Si, ⁴⁸Ti, or ⁵⁶Fe, expected for a Lunar or Mars mission. Here, the worst performing rats of the control group define the impairment thresholds based on population analyses via cumulative distribution functions, leading to the labeling of impairment for each subject. On a subject-based level, implementing Machine Learning (ML) classifiers such as the Gaussian Naïve Bayes, Support Vector Machine, and Artificial Neural Networks identifies rats that have a higher tendency for impairment after GCR exposure. One key finding of our study is that prescreen performance scores can be used as multidimensional input features to predict each rodent's susceptibility to cognitive impairment due to space radiation exposure. This result is significant to crewed space missions as it supports the potential of predicting an astronaut's impairment in a specific task before spaceflight through the implementation of appropriately trained ML tools.

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Effects of 5-ion beam irradiation and hindlimb unloading on metabolic pathways in plasma and brain of behaviorally tested WAG/Rij rats

Raber J, Holden S, Sudhakar R, Hall R, Glaeser B, Lenarczyk M, Rockwell K, Nawarawong N, Sterrett J, Perez R, Leonard SW, Morré J, Choi J, Kronenberg A, Borg A, Kwok A, Stevens JF, Olsen CM, Willey JS, Bobe G, Baker J. Front Physiol. 2021 Sep 27;12:746509

Summary:

A limitation of simulated space radiation studies is that radiation exposure is not the only environmental challenge astronauts face during missions. Therefore, we characterized behavioral and cognitive performance of male WAG/Rij rats 3 months after sham irradiation or total body irradiation with a simplified 5-ion mixed beam exposure in the absence or presence of simulated weightlessness using hindlimb unloading (HU) alone. Six months following behavioral and cognitive testing or 9 months following sham-irradiation or total body irradiation, plasma and brain tissues (hippocampus and cortex) were processed to determine whether the behavioral and cognitive effects were associated with long-term alterations in metabolic pathways in plasma and brain. Sham HU, but not irradiated HU, rats were impaired in spatial habituation learning. Rats irradiated with 1.5 Gy showed increased depressive-like behaviors. This was seen in the absence but not presence of HU. Thus, HU has differential effects in sham irradiated and irradiated animals and specific behavioral measures are associated with plasma levels of distinct metabolites 6 months later. The combined effects of HU and radiation on metabolic pathways in plasma and brain illustrate the complex interaction of environmental stressors and highlights the importance of assessing these interactions.

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Exposure to low (≤10 cGy) doses of 4He particles leads to increased social withdrawal and loss of executive function performance.

Burket JA, Matar M, Fesshaye A, Pickle JC, Britten RA.Radiat Res. 2021 Oct 1;196(4):345-54.Burket JA, Matar M, Fesshaye A, Pickle JC, Britten RA.Radiat Res. 2021 Oct 1;196(4):345-54.

Summary:

This study is the first to report that ≤10 cGy of 4He particles leads to a significant impairment of two advanced executive functions, constrained cognitive flexibility (ATSET assay) and insightful problem solving (UCFleX). The nature (loss of simple discrimination performance) and frequency of neurocognitive loss were very similar to that observed when higher Z(LET) particles were used, suggesting little LET dependency for executive function impairment.
Executive functions are also critical in regulating psychosocial activities. We thus established that exposure to 5 cGy of He, led to high levels of social withdrawal (within freely interacting dyads). The He-exposed rats have a significantly higher incidence and duration of self-grooming than did shams, which was even more surprising given that their dyad partners were able to physically interact with the irradiated rats (touching/climbing over them). Some individuals in confinement studies such as the Mars 500 study did socially withdraw (Basner et al, 2014), so there is a possibility that space radiation exposure could exacerbate such withdrawals.

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Space radiation-induced alterations in the hippocampal ubiquitin-proteome system

Tidmore A, Dutta SM, Fesshaye AS, Russell WK, Duncan VD, Britten RA. Int J Mol Sci. 2021 Jul 19;22(14):7713.

Summary:

Exposure of rodents to <20 cGy Space Radiation (SR) impairs performance in several hippocampus-dependent cognitive tasks, including spatial memory. However, there is considerable inter-individual susceptibility to develop SR-induced spatial memory impairment. In this study, a robust label-free mass spectrometry (MS)-based unbiased proteomic profiling approach was used to characterize the composition of the hippocampal proteome in adult male Wistar rats exposed to 15 cGy of 1 GeV/n ⁴⁸Ti and their sham counterparts. Unique protein signatures were identified in the hippocampal proteome of: (1) sham rats, (2) Ti-exposed rats, (3) Ti-exposed rats that had sham-like spatial memory performance, and (4) Ti-exposed rats that impaired spatial memory performance. Approximately 14% (159) of the proteins detected in hippocampal proteome of sham rats were not detected in the Ti-exposed rats. We explored the possibility that the loss of the Sham-only proteins may arise as a result of SR-induced changes in protein homeostasis. SR-exposure was associated with a switch towards increased pro-ubiquitination proteins from that seen in Sham. These data suggest that the role of the ubiquitin-proteome system as a determinant of SR-induced neurocognitive deficits needs to be more thoroughly investigated.

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Associations between lipids in selected brain regions, plasma miRNA, and behavioral and cognitive measures following 28Si ion irradiation
Minnier J, Emmett MR, Perez R, Ding LH, Barnette BL, Larios RE, Hong C, Hwang TH, Yu Y, Fallgren CM, Story MD, Weil MM, Raber J. Sci Rep. 2021 Jul 21;11(1):14899.
Summary:
To develop biomarkers of the space radiation response, BALB/c and C3H female and male mice and their F2 hybrid progeny were irradiated with 28Si ions (350 MeV/n, 0.2 Gy) and tested for behavioral and cognitive performance 1, 6, and 12 months following irradiation. There were associations between lipids in select brain regions, plasma miRNA, and cognitive measures and behavioral following 28Si ion irradiation. Different but overlapping sets of miRNAs in plasma were found to be associated with cognitive measures and behavioral in sham and irradiated mice at the three time points. The radiation condition revealed pathways involved in neurodegenerative conditions and cancers. Relationships were also revealed with CD68 in miRNAs in an anatomical distinct fashion, suggesting that distinct miRNAs modulate neuroinflammation in different brain regions. The associations between lipids in selected brain regions, plasma miRNA, and behavioral and cognitive measures following 28Si ion irradiation could be used for the development of biomarker of the space radiation response.
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An easy-to-use function to assess deep space radiation in human brains
Khaksarighiri S, Guo J, Wimmer-Schweingruber R, Narici L. Sci Rep. 2021 Jun 3;11(1):11687.
Summary:
Health risks from radiation exposure in space are an important factor for astronauts' safety as they venture on long-duration missions to the Moon or Mars. It is important to assess the radiation level inside the human brain to evaluate the possible hazardous effects on the central nervous system especially during solar energetic particle (SEP) events. We use a realistic model of the head/brain structure and calculate the radiation deposit therein by realistic SEP events, also under various shielding scenarios. We then determine the relation between the radiation dose deposited in different parts of the brain and the properties of the SEP events and obtain some simple and ready-to-use functions which can be used to quickly and reliably forecast the event dose in the brain. Such a novel tool can be used from fast nowcasting of the consequences of SEP events to optimization of shielding systems and other mitigation strategies of astronauts in space.
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Modeling space radiation induced cognitive dysfunction using targeted and non-targeted effects
Shuryak I, Brenner DJ, Blattnig SR, Shukitt-Hale B, Rabin BM. Sci Rep. 2021 Apr 23;11(1):8845
Summary:
Radiation-induced cognitive dysfunction is increasingly recognized as an important risk for human exploration of distant planets. Mechanistically-motivated mathematical modeling helps to interpret and quantify this phenomenon. Here we considered two general mechanisms of ionizing radiation-induced damage: targeted effects (TE), caused by traversal of cells by ionizing tracks, and non-targeted effects (NTE), caused by responses of other cells to signals released by traversed cells. The results of modeling analysis based on these mechanisms suggest that NTE-based radiation effects on brain function are potentially important for astronaut health and for space mission risk assessments.
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Life-long brain compensatory responses to galactic cosmic radiation exposure
Miry O, Zhang XL, Vose LR, Gopaul KR, Subah G, Moncaster JA, Wojnarowicz MW, Fisher AM, Tagge CA, Goldstein LE, Stanton PK. Sci Rep. 2021 Feb 22;11(1):4292.).
Summary:
To our knowledge, this study is the first to uncover lifespan-long effects of high-energy heavy particle radiation mimicking exposure to galactic cosmic radiation (GCR), on neurogenesis, synaptic plasticity, and learning and memory in mice. Changes observed 2 months after a single GCR exposure were characterized by reductions in hippocampal neurogenesis, smaller activity-dependent long-term potentiation of synaptic strength (LTP), and impaired spatial, hippocampus-dependent, learning acquisition. Six months after GCR exposure, impairments in learning disappeared, and LTP was actually enhanced. 12-20 months post-GCR exposure, we observed dramatic rebound increases in neurogenesis of newborn neurons in the dentate gyrus, larger LTP, and more rapid learning acquisition in a spatial learning task.
The GCR exposure studied was designed to mimic cumulative exposure levels expected on long-term manned missions to Mars. This lifespan study shows that such exposure can produce complex effects on the brain that are lifelong. The neurophysiological, cognitive and behavioral results of such long-term effects on astronauts is likely to be a complex combination of deficits and compensatory recovery mechanisms with their own unpredictable consequences. These consequences have the potential to affect the success of deep space manned missions, and the intrepid explorers throughout their lives. Deeper studies of the consequences of these long-lasting effects, and a search for ways to ameliorate them, will be a key goal in maximizing mission performance and success.
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Systemic HDAC3 inhibition ameliorates impairments in synaptic plasticity caused by simulated galactic cosmic radiation exposure in male mice
Keiser AA, Kramár EA, Dong T, Shanur S, Pirodan M, Ru N, Acharya MM, Baulch JE, Limoli CL, Wood MA., Neurobiol Learn Mem. 2020 Dec 23. Online ahead of print.
Summary:

Deep space travel presents a number of measurable risks including exposure to a spectrum of radiations of varying qualities, termed galactic cosmic radiation (GCR) that are capable of penetrating the spacecraft, traversing through the body and impacting brain function. Using rodents, studies have reported that exposure to simulated GCR leads to cognitive impairments associated with changes in hippocampus function that can persist as long as one-year post exposure with no sign of recovery. Here, we examined whether whole body exposure to simulated GCR using 6 ions and doses of 5 or 30 cGy interfered with the ability to update an existing memory or impact hippocampal synaptic plasticity, a cellular mechanism believed to underlie memory processes, by examining long term potentiation (LTP) in acute hippocampal slices from middle aged male mice 3.5-5 months after radiation exposure. Using a modified version of the hippocampus-dependent object location memory task developed by our lab termed "Objects in Updated Locations" (OUL) task we find that GCR exposure impaired hippocampus-dependent memory updating and hippocampal LTP 3.5-5 months after exposure. Further, we find that impairments in LTP are reversed through one-time systemic subcutaneous injection of the histone deacetylase 3 inhibitor RGFP 966 (10 mg/kg), suggesting that long lasting impairments in cognitive function may be mediated at least in part, through epigenetic mechanisms.

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Microglia depletion and cognitive functions after brain injury: From trauma to galactic cosmic ray
Paladini MS, Feng X, Krukowski K, Rosi S. Neurosci Lett. 2020 Nov 28. [Epub ahead of print] Review.
Summary:
Microglia are the resident immune cells of the central nervous system. Insults such as traumatic brain injury, therapeutic brain irradiation and galactic cosmic ray exposure are associated with maladaptive chronic microglia activation. Chronic microglia activation contributes to injury-related impairments in cognitive functions. Microglia depletion represents a useful tool for more extensive investigations of microglia roles, but also a potential therapeutic approach to ameliorate or prevent cognitive dysfunctions following brain injury.
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Multiple sensory illusions are evoked during the course of proton therapy
Narici L, Titova E, Obenaus A, Wroe A, Loredo L, Schulte R, Slater JD, Nelson GA. Life Sci Space Res. 2020 Aug;26:140-8.
Summary:
The effects of radiation on sensory physiological responses have been reported in astronauts and in patients undergoing radiotherapy. A retrospective study in a cohort of proton radiotherapy patients found conscious reporting of sensory illusions in visual, olfactory auditory and gustatory senses. Further, brain regions receiving the highest proton doses corresponded to the sensory anatomical structures. This study suggests that prospective studies interrogating illusions from all sensory modalities are warranted and could contribute to radiation risk assessments for space exploration and for radiotherapy patients.
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Can a comparison of clinical and deep space irradiation scenarios shed light on the radiation response of the brain?
C. Limoli, Br J Radiol. 2020 Nov 1;93(1115):20200245.
Summary:
The purpose of this article was to draw comparisons between two very different and distinct radiation exposure scenarios, and to discern whether any similarities between clinical brain tumor treatments and space radiation exposure could help in the assessment of clinical outcomes and/or risk mitigation following deep space travel.
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Sex-specific cognitive deficits following space radiation exposure
Parihar VK, Angulo MC, Allen BD, Syage A, Usmani MT, Passerat de la Chapelle E, Amin AN, Flores L, Lin X, Giedzinski E, Limoli CL Front Behav Neurosci. 2020 Sep 16;14:535885
Summary:
Data included in this manuscript indicate that fundamental differences in inflammatory cascades between male and female mice may drive divergent CNS radiation responses that differentially impact the structural plasticity of neurons and neurocognitive outcomes following cosmic radiation exposure.
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Response to comments by Bevelacqua and Mortazavi
Rabin BM, Cahoon DS, Shukitt-Hale B.Sci Space Res. 2020 Nov;27:111-2. Epub 2020 Sep 23
Summary:

The main thrust of the comments by Bevelacqua and Mortazavi (2020) about the paper by Cahoon et al. (2020) is that we ignored the potential adaptive responses resulting from low level exposure to radiation, a phenomenon known as "radiation hormesis". The adaptive response produced by preexposure to a low dose of radiation is considered a non-targeted effect of ionizing radiation. While we did show a non-targeted effect on brain function following exposure of the body only, we did not raise the issue of an adaptive response to radiation in our paper because our experimental design, using only a single exposure, did not allow an evaluation of the possible effects of preexposure on the production of neurochemical changes in the brain and the concomitant disruption of cognitive performance. Because the experiment was not designed to evaluate possible adaptive effects of preexposure to a low dose of radiation, we do not think that their comments are relevant.
Bevelacqua, J.J., Mortazavi, S.M.J., 2020. Comments on "Effects of partial- or whole-body exposures to 56Fe particles on brain function and cognitive performance in rats". Life Sci. Space Res.
Cahoon, D.S., Shukitt-Hale, B., Bielinski, D.F., Hawkins, E.M., Cacioppo, A.M., Rabin, B.M., 2020. Effects of partial- or whole-body exposures to 56Fe particles on brain function and cognitive performance in rats. Life Sci. Space Res. 27, 56-63.

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Mitigation of helium irradiation-induced brain injury by microglia depletion
Allen BD, Syage AR, Maroso M, Baddour AAD, Luong V, Minasyan H, Giedzinski E, West BL, Soltesz I, Limoli CL, Baulch JE, Acharya MM.and published in J Neuroinflammation. 2020 May 19;17(1):159.
Summary:
The efficacy of microglial depletion in restoring the cognitive health of mice exposed to cosmic radiation was demonstrated. Specifically, long term feeding of mice with the CSF1R inhibitor to deplete microglia after a single exposure with 30 Gy of (4)HE attenuated the alterations in a battery of neurological, and learning and memory tests in mice when compared to cohorts not given the inhibitor. Collectively data suggest that microglia play a critical role in cosmic radiation-induced cognitive deficits in mice and, that approaches targeting microglial function are poised to provide considerable benefit to the charged-particle exposed brain.
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Late effects of 1H + 16O on short-term and object memory, hippocampal dendritic morphology and mutagenesis
Kiffer F, Alexander T, Anderson J, Groves T, McElroy T, Wang J, Sridharan V, Bauer M, Boerma M, Allen A. and published in Front Behav Neurosci. 2020 Jun 26;14:96.
Summary:
We exposed 6-month-old male mice to whole-body 1H (0.5 Gy; 150 MeV/n; 18-19 cGy/minute) and an hour later to 16O (0.1Gy; 600 MeV/n; 18-33 Gy/min) at NASA's Space Radiation Laboratory as a galactic cosmic ray-relevant model. Mice were tested for cognitive behavior 9 months after exposure to elucidate late radiation effects. Radiation induced significant deficits in novel object recognition and short-term spatial memory (Y-maze). We detected no general effect of radiation on single-nucleotide polymorphisms in immediate early genes, and genes involved in inflammation but found a higher variant allele frequency in the antioxidants thioredoxin reductase 2 and 3 loci.
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Sleep Fragmentation Exacerbates Executive Function Impairments Induced by Low Doses of Si Ions
Richard A. Britten, Arriyam S. Fesshaye, Vania D. Duncan, Laurie L. Wellman, and Larry D. Sanford Radiation Research 194(2), 116-123, (30 June 2020).
Summary:
Astronauts on deep space missions will be required to work autonomously and thus their ability to perform executive functions could be critical to mission success. In addition to the health risks associated with SR exposure, astronauts have to contend with other stressors, of which inadequate sleep quantity and quality are considered to be major concerns. We have previously shown that a single session of fragmented sleep uncovered latent attentional set shifting (ATSET) performance deficits in rats exposed to protracted neutron irradiation that had no obvious defects in performance under rested wakefulness conditions. It was unclear if the exacerbating impact of sleep fragmentation (SF) only occurs in rats exposed to protracted low dose rate neutron exposures. In this study, we assessed whether SF also unmasks latent ATSET deficits in rats exposed to 5 cGy 600 MeV/n 28Si ions.
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Space radiation does not alter amyloid or tau pathology in the 3xTg mouse model of Alzheimer's
Owlett L, Belcher EK, Dionisio-Santos DA, Williams JP, Olschowka JA, O'Banion MK Life Sci Space Res. 2020 Nov;27:89-98. Epub2020 Aug 3.
Summary:
Space radiation can cause neuronal damage and degeneration, glial activation, and oxidative stress in the brain. Previous work demonstrated a worsening of Alzheimer’s disease-associated amyloid pathology in male APP/PS1 transgenic mice after HZE exposure. To determine whether tau pathology is altered by HZE particle or proton irradiation, we exposed 3xTg mice, which acquire both amyloid plaque and tau pathology with age, to iron, silicon, or solar particle event (SPE) irradiation at 9 months of age and evaluated behavior and brain pathology at 16 months of age. We found no differences in performance in fear conditioning and novel object recognition tasks between groups of mice exposed to sham, iron (10 and 100 cGy), silicon (10 and 100 cGy), or solar particle event radiation (200 cGy). 200 cGy SPE irradiated female mice had fewer plaques than sham-irradiated females but had no differences in tau pathology. Overall, females had worse amyloid and tau pathology at 16 months of age and demonstrated a reduced neuroinflammatory gene response to radiation. These findings uncover differences between mouse models following radiation injury and corroborate prior reports of sex differences within the 3xTg mouse model.
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Effects of partial- or whole-body exposures to 56Fe particles on brain function and cognitive performance in rats
Cahoon DS, Shukitt-Hale B, Bielinski DF, Hawkins EM, Cacioppo AM, Rabin BM. , Life Sci Space Res. 2020 Nov;27:56-63. Epub 2020 Jul 24.
Summary:
To determine the possible effects that irradiation of the body might have on neuronal function and cognitive performance, rats were given head-only, body-only or whole-body exposures to 56Fe particles. Cognitive performance (novel object recognition, operant responding) was tested in one set of animals; changes in neuronal function (oxidative stress, neuroinflammation) was tested in a second set of rats. The results indicated that there were no consistent differences in either behavioral or neurochemical endpoints as a function of the location of the irradiation.
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Effects of single-dose protons or oxygen ions on function and structure of the cardiovascular system in male Long Evans rats
Sridharan V, Seawright JW, Landes RD, Cao M, Singh P, Davis CM, Mao XW, Singh SP, Zhang X, Nelson GA, Boerma M. Life Sci Space Res. 2020 Aug;26:62-8. Epub 2020 May 22.
Summary:
This study used rat models to examine long-term effects of single low doses of protons and oxygen ions on function and structure of the heart. Data were obtained from a newly designed study as well as cardiac tissue specimens obtained through tissue sharing. Altogether, radiation induced only minor changes in cardiac function and pathology.
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Challenges to the Central Nervous System During Human Spaceflight Missions to Mars
Clément GR, Boyle RD, George KA, Nelson GA, Reschke MF, Williams TJ, Paloski WH. J Neurophysiol. 2020 Apr 15. [Epub ahead of print] Review.
Summary:
During the first 50+ years of human space flight, the primary interest of the neurophysiology community has been to use the sustained, but transient, elimination of gravitational stimulation to better understand the role of the vestibular and somatosensory systems in regulating spatial orientation, eye-head-hand coordination, locomotor control, and motion sickness. The implications of this research has ranged from understanding fundamental neurophysiological mechanisms, to issues in terrestrial medicine, to astronaut performance capabilities at various timeframes during and after missions. However, over the past two decades, as NASA has begun contemplating new missions of unprecedented durations and distances form Earth, a number of new questions have arisen regarding the implications of the neurophysiological and neuropsychological adaptation to the austere, isolated, confined environment that small groups of astronauts would have to endure for many months at a time, as well as the effects of continuous exposure to the low dose rate of highly charged and energetic particles of the omnipresent galactic cosmic radiation on the structure and function of the central nervous system throughout and after these missions. This article reviews the open questions and key results to date of the entire spectrum of neurophysiological studies carried out in recent years.
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Altered Cognitive Flexibility and Synaptic Plasticity in the Rat Prefrontal Cortex after Exposure to Low (≤15 cGy) Doses of ²⁸Si Radiation
Richard A. Britten, Vania D. Duncan, Arriyam Fesshaye, Emil Rudobeck, Gregory A. Nelson, and Roman Vlkolinsky. Radiation Research 193(3), 223-235, (2 February 2020).
Summary:
This study measured cognitive flexibility performance, glutamatergic synaptic transmission and plasticity in the prelimbic area (PrL) of the medial prefrontal cortex (mPFC) of ~10-month-old (at the time of irradiation) male Wistar rats exposed to 1-15 cGy 600 MeV/n ²⁸Si beams. Significantly impaired performance was seen in the simple (SD) and compound discrimination (CD) stages of the attentional set shifting (ATSET) task. However, there was a pronounced non-linear dose response for cognitive impairment The irradiated rats were also screened for performance in a task for unconstrained cognitive flexibility (UCFlex), often referred to as creative problem solving. Exposure to 1, 5 and 10 cGy resulted in a significant reduction in UCFlex performance, in an apparent all-or-none responsive manner. Importantly, performance in the ATSET test was not indicative of UCFlex performance. From a risk assessment perspective, these findings suggest that a value based on a single behavioral end point may not fully represent the cognitive deficits induced by space radiation, even within the cognitive flexibility domain. After completion of the cognitive flexibility testing, in vitro electrophysiological assessments of glutamatergic synaptic transmission and plasticity were performed in slices of the PrL cortex of 10 cGy irradiated rats. There was no obvious correlation between magnitudes of these electrophysiological decrements and the cognitive performance status of the irradiated rats. These data suggest that while radiation-induced changes in synaptic plasticity in the PrL cortex may be associated with cognitive impairment, they are most likely not the sole determinant of the incidence and severity of such impairments.
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Particle radiation-induced dysregulation of protein homeostasis in primary human and mouse neuronal cells
Shaler T, Lin H, Bakke J, Chen S, Grover A, Chang P Life Sci Space Res (Amst). 2020;25:9-17.
Summary:
Space particle radiations may cause significant damage to proteins and oxidative stress in the cells within the central nervous system and pose a potential health hazard to humans in long-term manned space explorations., We employed a quantitative proteomics method to evaluate the impact of particle-radiation induced alterations in three major pUb-linked chains at lysine residues Lys-48 (K-48), Lys-63 (K-63), and Lys-11 (K-11), and probed for global proteomic changes in mouse and human neural cells that were irradiated with low doses of 250 MeV proton, 260 MeV/u silicon or 1 GeV/u iron ions. The results suggest that the quality of the particle radiation plays a key role in the level, linkage and cell type specificity of protein homeostasis in key populations of neuronal cells.
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Mitigation of helium irradiation-induced brain injury by microglia depletion
Allen BD, Syage AR, Maroso M, Baddour AAD, Luong V, Minasyan H, Giedzinski E, West BL, Soltesz I, Limoli CL, Baulch JE, Acharya MM J Neuroinflammation. 2020 May 19;17(1):159.
Summary:
Cosmic radiation exposures have been found to elicit cognitive impairments involving a wide-range of underlying neuropathology including elevated oxidative stress, neural stem cell loss, and compromised neuronal architecture. Cognitive impairments have also been associated with sustained microglia activation following low dose exposure to helium ions. Space-relevant charged particles elicit neuroinflammation that persists long-term post-irradiation. Here, we investigated the potential neurocognitive benefits of microglia depletion following low dose whole body exposure to helium ions.
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Multi-domain cognitive assessment of male mice shows space radiation is not harmful to high-level cognition and actually improves pattern separation
Whoolery CW, Yun S, Reynolds RP, Lucero MJ, Soler I, Tran FH, Ito N, Redfield RL, Richardson DR, Shih HY, Rivera PD, Chen BPC, Birnbaum SG, Stowe AM, Eisch AJ. Sci Rep. 2020 Feb 17;10(1):2737
Summary:

It is understandable that HZE particle exposure is presumed to have a negative influence on some lower and high-level cognitive functions, as many studies support this conclusion. However, our study shows this is not universally true. Mature male mice that receive whole-body exposure to two different HZE particles perform similarly to control mice on many high-level cognitive tasks, reflecting the functional integrity of key neural circuits. Strikingly, mice irradiated with either 56Fe or 28Si actually perform "better" than control mice in both appetitive and aversive pattern separation tasks. Our work urges revisitation of the generally-accepted conclusion that space radiation is detrimental to cognition.

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The Potential Effects of Radiation on the Gut-Brain Axis
Carli B. Jones, Catherine M. Davis, and Karen S. Sfanos.Radiation Research: March 2020, Vol. 193, No. 3, pp. 209-222
Summary:

Over the course of a lifetime, humans may be exposed to different types of radiation, typically in the form of low-linear energy transfer (LET) radiation, which is used, for example, in cancer treatment. In addition, astronauts may be exposed to high-LET radiation in outer space. Here, we propose that alterations to the gastrointestinal (GI) microbiota may occur when exposure to either low- or high-LET radiation, and that these alterations may perturb important relationships that exist between the GI microbiota and human health. For example, the GI microbiota can communicate with the brain via various pathways and molecules, such as the enteric nervous system, the vagus nerve, microbial metabolites and the immune system. This relationship has been termed the "gut-brain axis". Alterations to the composition of the GI microbiome can lead to alterations in its functional metabolic output and means of communication, therefore potentially causing downstream cognitive effects. Consequently, studying how radiation can affect this important network of communication could lead to new and critical interventions, as well as prevention strategies. Herein, we review the evidence supporting a relationship between radiation exposure and disruption of the gut-brain axis as well as summarize strategies that may be used to counter the effects of radiation exposure on the GI microbiome.

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Effects of chronic exposure to a mixed field of neutrons and photons on behavioral and cognitive performance in mice.
Perez R, Younger S, Bertheau E, Fallgren C, Weil M, Raber J. Behav Brain Res. 2019 Nov 22. [Epub ahead of print]
Summary:
In this study, the effects of high LET radiation delivered at low dose rate which may have relevance to space radiation exposures received by astronauts beyond low Earth orbit were assessed. More specifically, we assessed the effects chronic neutron exposure starting at 60 days of age on behavioral and cognitive performance of BALB/c female and C3H male mice at 600 and 700 days of age. Dose- and time point-dependent effects on various distinct measures of behavioral and cognitive performance of BALB/c female and C3H male mice were revealed. Different outcome measures show distinct dose-response relationships, with some anticipated to worsen performance during space missions, like increased measures of anxiety, while other anticipated to enhance performance, such as increased nest building and object recognition.
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Cranial irradiation mediated spine loss is sex-specific and complement receptor-3 dependent in male mice.
Hinkle JJ, Olschowka JA, Love TM, Williams JP, O'Banion MK. Sci Rep. 2019 Dec 11;9(1):18899.
Summary:
Previous rodent studies demonstrated that irradiation induces significant loss in dendritic spine number and alters spine morphology; these changes are associated with behavioral task deficits. In the current study sexual dimorphisms in irradiation-mediated alterations of microglia activation markers and dendritic spine density are described. Moreover, the significant dendritic spine loss observed in male mice following irradiation was complement receptor 3 (CR3)-dependent, revealing a specific and targetable mechanism for radiation effects on synaptic structure.
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Microgravity and cosmic radiations during space exploration as a window into neurodegeneration on Earth.
Sprugnoli G, Cagle YD, Santarnecchi E. JAMA Neurol. 2019 Nov 25. [Epub ahead of print]
Summary:
Astronauts involved in long-duration spaceflight missions are exposed to microgravity and cosmic radiations, considered responsible of profound changes in brain structure and function. In particular, microgravity is related to cephalad fluid shift that potentially affects protein clearance mechanisms, while cosmic radiations seem to promote the accumulation of amyloid-β in mouse models, and consequently alter hippocampus-related cognition. A pattern of "spaceflight-induced accelerated brain aging" emerges, raising on one hand important issues about astronauts' health, while, on the other, offering the opportunity to deepen the understanding of neurodegenerative diseases on Earth and develop potential countermeasures.
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Meta-analysis of Cognitive Performance by Novel Object Recognition after Proton and Heavy Ion Exposures.
Eliedonna Cacao and Francis A. Cucinotta Radiation Research: November 2019, Vol. 192, No. 5, pp. 463-472.(2019)
Summary:
Experimental studies of cognitive detriments in mice and rats after proton and heavy ion exposures have been performed by several laboratories to investigate possible risks to astronauts exposed to cosmic rays in space travel and patients treated for brain cancers with proton and carbon beams in Hadron therapy. However, distinct radiation types and doses, cognitive tests and rodent models have been used by different laboratories, while few studies have considered detailed dose-response characterizations, including estimates of relative biological effectiveness (RBE). Here we report on the first quantitative meta-analysis of the dose response for proton and heavy ion rodent studies of the widely used novel object recognition (NOR) test, which estimates detriments in recognition or object memory. Our study reveals that linear or linear-quadratic dose-response models of relative risk (RR) do not provide accurate descriptions. However, good descriptions for doses up to 1 Gy are provided by exponentially increasing fluence or dose-response models observed with an LET dependence similar to a classical radiation quality response, which peaks near 100-120 keV/µm and declines at higher LET values. Exponential models provide accurate predictions of experimental results for NOR in mice after mixed-beam exposures of protons and 56Fe, and protons, 16O and 28Si. RBE estimates are limited by available X-ray or gamma-ray experiments to serve as a reference radiation. RBE estimates based on use of data from combined gamma-ray and high-energy protons of low-LET experiments suggest modest RBEs, with values <8 for most heavy ions, while higher values <20 are based on limited gamma-ray data. In addition, we consider a log-normal model for the variation of subject responses at defined dose levels. The log-normal model predicts a heavy ion dose threshold of approximately 0.01 Gy for NOR-related cognitive detriments.
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Predictions of cognitive detriments from galactic cosmic ray exposures to astronauts on exploration missions
Cucinotta FA, Cacao E. Life Sci Space Res. 2019 Oct 16. [Article in Press]
Summary:
For the first-time we report on predictions on cognitive detriments from galactic cosmic ray (GCR) exposures on long-duration space missions outside the protection of the Earth's magnetosphere and solid body shielding. Estimates are based on a relative risk (RR) model of the fluence response for proton and heavy ion in rodent studies using the widely used novel object recognition (NOR) test, which estimates detriments in recognition or object memory. Our recent meta-analysis showed that linear and linear-quadratic dose response models were not accurate, while exponential increasing fluence response models based on particle track structure provided good descriptions of rodent data for doses up to 1 Gy. Using detailed models of the GCR environment and particle transport in shielding and tissue, we predict the excess relative risk (ERR) for NOR detriments for several long-term space mission scenarios. Predictions suggest ERR < 0.15 for most space mission scenarios with ERR<0.1 for 1-year lunar surface missions, and about ERR~0.1 for a 1000 day Mars mission for average solar cycle conditions. We discuss possible implications of these ERR levels of cognitive performance detriments relative to other neurological challenges such as rodent models of Alzheimer's disease (AD), Parkinson's disease (PD) and traumatic brain injury (TBI). Comparisons suggest a small but potentially clinically significant risk for possible space mission scenarios.
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Space-like
Liu B, Hinshaw RG, Le KX, Park MA, Wang S, Belanger AP, Dubey S, Frost JL, Shi Q, Holton P, Trojanczyk L, Reiser V, Jones PA, Trigg W, Di Carli MF, Lorello P, Caldarone BJ, Williams JP, O'Banion MK, Lemere CA. Sci Rep. 2019 Aug 20;9(1):12118.
Summary:
This study investigated the effects of exposure to space radiation on behavioral and neuropathological changes in mice. Four-month old Alzheimer's disease (AD)-like transgenic (Tg) mice and wildtype (WT) littermates were irradiated with a single, whole-body dose of 10 or 50 cGy ⁵⁶Fe ions (1 GeV/u) at Brookhaven National Laboratory. Sex-, genotype-, and dose-dependent changes in locomotor activity, contextual fear conditioning, grip strength, and motor learning were observed 1.5 months later mostly in Tg mice but not WT mice. Few changes were seen in general health, depression, or anxiety. MicroPET imaging of the translocator protein ligand 2 months post-irradiation showed no radiation-specific change in neuroinflammation, while brain examination indicated that radiation reduced cerebral amyloid-β levels and microglia activation in female Tg mice, modestly increased microhemorrhages in 50 cGy irradiated male WT mice and did not affect synaptic marker levels compared to sham controls. In summary, specific short-term changes in neuropathology and behaviour induced by ⁵⁶Fe irradiation were observed, possibly having implications for long-term space travel.
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New concerns for neurocognitive function during deep space exposures to chronic, low dose rate, neutron radiation
Acharya MM, Baulch JE, Klein PM, Baddour AAD, Apodaca LA, Kramar EA, Alikhani L, Garcia C Jr, Angulo MC, Batra RS, Fallgren CM, Borak TB, Stark CEL, Wood MA, Britten RA, Soltesz I, Limoli CL. eNeuro 5 August 2019, 6 (4). 10.1523/ENEURO.0094-19.2019.
Summary:
Using a new, low dose-rate neutron irradiation facility, we have uncovered that realistic, low dose-rate exposures produce serious neurocognitive complications associated with impaired neurotransmission. Chronic (6 month) low-dose (18 cGy) and dose rate (1 mGy/d) exposures of mice to a mixed field of neutrons and photons result in diminished hippocampal neuronal excitability and disrupted hippocampal and cortical long-term potentiation. Furthermore, mice displayed severe impairments in learning and memory, and the emergence of distress behaviors.
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Comments on "New concerns for neurocognitive function during deep space exposures to chronic, low dose rate, neutron radiation."
Bevelacqua JJ, Welsh J, Mortazavi S. eNeuro. 2019 Dec 17. [Epub ahead of print]
Summary:
Evaluations of the biological effects of space radiation must carefully consider the biological system response and the specific nature of the source term. Acharya et al. review neurocognitive function during deep space exposures to chronic, low dose rate, neutron radiation, but do not utilize a source term that reflects the actual space environment in terms of radiation types and their respective energies. In addition, important biological effects including adaptive response to the space radiation environment are not addressed.
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Effects of exposure to
Rabin BM, Miller MG, Larsen A, Spadafora C, Zolnerowich NN, Dell'Acqua LA, Shukitt-Hale B. Life Sci Space Res. 2019 Jul 10.
Summary:
Exploratory class missions to other planets will include both male and female astronauts. Previous research has indicated that female subjects do not show a disruption of cognitive performance following exposure to HZE particles. Because estrogen can function as a neuroprotectant, the cognitive performance of intact and ovariectomized female rats with estradiol or vehicle implants was tested following exposure to ¹²C (290 MeV/n) or ⁴He particles (300 MeV/n). The results indicated that exposure to ¹²C or ⁴He particles did not disrupt operant performance in the intact rats. Estradiol implants exacerbated the disruptive effects of radiation on performance. Although estrogen does not appear to function as a neuroprotectant following exposure to space radiation, the data suggest that intact females may be less responsive to the deleterious effects of exposure to space radiation on cognitive performance, possibly due to the effects of estrogen on cognitive performance.
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Risks of cognitive detriments after low dose heavy ion and proton exposures
Cucinotta FA, Cacao E. Int J Radiat Biol. 2019 May 23. [Epub ahead of print]
Summary:
Purpose: Heavy ion and proton brain irradiations occur during space travel and in Hadron therapy for cancer. Heavy ions produce distinct patterns of energy deposition in neuron cells and brain tissues compared to X-rays leading to large uncertainties in risk estimates. We make a critical review of findings from research studies over the last 25 years for understanding risks at low dose.
Conclusions: A large number of mouse and rat cognitive testing measures have been reported for a variety of particle species and energies for acute doses. However tissue reactions occur above dose thresholds and very few studies were performed at the heavy ion doses to be encountered on space missions (<0.04 Gy/y) or considered dose-rate effects, such that threshold doses are not known in rodent models. Investigations of possible mechanisms for cognitive changes have been limited by experimental design with largely group specific and not subject specific findings reported. Persistent oxidative stress and activated microglia cells are common mechanisms studied, while impairment of neurogenesis, detriments in neuron morphology, and changes to gene and protein expression were each found to be important in specific studies. Future research should focus on estimating threshold doses carried out with experimental designs aimed at understating causative mechanisms, which will be essential for extrapolating rodent findings to humans and chronic radiation scenarios, while establishing if mitigation are needed.
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Radiation-induced DNA damage cooperates with heterozygosity of TP53 and PTEN to generate high grade gliomas
Todorova PK, Fletcher-Sananikone E, Mukherjee B, Kollipara R, Vemireddy V, Xie XJ, Guida PM, Story MD, Hatanpaa K, Habib AA, Kittler R, Bachoo R, Hromas R, Floyd JR, Burma S. Cancer Res. 2019 May 14. pii: canres.0680.2019 [Epub ahead of print]
Summary:
Using transgenic mouse models, this study uncovers mechanisms by which ionizing radiation, especially particle radiation, promotes the development of lethal brain cancers called glioblastoma. Of special relevance to long-distance space missions, the study clearly shows that high-LET heavy ions carry a much greater carcinogenic risk compared to low-LET protons or X-rays. Importantly, the paper describes a versatile mouse model that can be used in the future for the testing of countermeasures to prevent brain cancer development from radiation exposure.
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Behavioral effects of space radiation: A comprehensive review of animal studies
Kiffer F, Boerma M, Allen A. Life Sci Space Res. 2019 Feb 19. [Article in Press]
Summary:
This article provides a comprehensive review of prior published work on the effects of protons, helium and heavy ions on cognitive function in mouse and rat models. As this field of research is currently in a transition towards studying mixed ion fields, this review is intended as a reference of prior results of behavioral assays after single ion exposures.
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Neurochemical insights into the radiation protection of astronauts: Distinction between low- and moderate-LET radiation components
Belov OV, Belokopytova KV, Kudrin VS, Molokanov AG, Shtemberg AS, Bazyan AS. Phys Med. 2019 Jan;57:7-16.
Summary:
Radiation protection of astronauts remains an ongoing challenge in preparation of deep space exploratory missions. Exposure to space radiation consisting of multiple radiation components is associated with a significant risk of experiencing central nervous system (CNS) detriments, potentially influencing the crew operational decisions. Developing of countermeasures protecting CNS from the deleterious exposure requires understanding the mechanistic nature of cognitive impairments induced by different components of space radiation. The current study was designed to identify differences in neurochemical modifications caused by exposure to low- and moderate-LET radiations and to elucidate a distinction between the observed outcomes. We exposed rats to accelerated protons (170 MeV; 0.5 keV/μm) or to carbon ions (12C; 500 MeV/u; 10.5 keV/μm) delivered at the same dose of 1 Gy. Neurochemical alterations were evaluated 1, 30, and 90 days after exposure via indices of the monoamine metabolism measured in five brain structures, including prefrontal cortex, hypothalamus, nucleus accumbens, hippocampus and striatum. We obtained the detailed patterns of neurochemical modifications after exposure to the mentioned radiation modalities. Our data show that the enhancement in the radiation LET from relatively low to moderate values leads to different neurochemical outcomes and that a particular effect depends on the irradiated brain structure. We also hypothesized that exposure to the moderate-LET radiations can induce a hyperactivation of feedback neurochemical mechanisms, which blur metabolic deviations and lead to the delayed impairments in brain functions. Based on our findings we discuss possible contribution of the observed changes to behavioural impairments.
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Exposure to ?15 cGy of 600 MeV/n 56Fe Particles Impairs Rule Acquisition but not Long-Term Memory in the Attentional Set-Shifting Assay
Jewell JS, Duncan VD, Fesshaye A, Tondin A, Macadat E, and Britten RA. Radiation Research. 190(6):565-575, 2018.
Summary:
This paper describes our study of the impact of 56Fe ions (a major component of Galactic Cosmic rays) on the ability of rats to perform attentional set shifting (ATSET), one form of executive function. In this study we used rats that were maintained on a rigorous exercise regimen and that were prescreened for competency in the ATSET test. We discovered that the rats maintained a good working memory of the rules of the ATSET test for at least 6 months, even after irradiation, but that the irradiated rats had an impaired ability to learn a new set of rules when presented with a modified version of the ATSET test. Should similar effects occur in astronauts, exposure to space radiation may only impact the astronauts' ability to solve problems that they have not previously encountered.
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The final frontier: Transient microglia reduction after cosmic radiation exposure mitigates cognitive impairments and modulates phagocytic activity
Rosi S. Brain Circ. 2018 Jul-Sep;4(3):109-13. Review.
Summary:
Here, we discuss the potential of transient microglia depletion after the brain irradiation to reset the altered immune system activation and eliminate any potential long-term cognitive effects. Temporary microglia depletion showed promise in preventing any deleterious cognitive impairments following exposure to elements of cosmic radiation, such as helium and high-charge nuclei. The understanding of long-term radiation-induced cognitive impairments is vital for the protection of future astronauts and equally as important for current cancer patients.
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Psycho-emotional status but not cognition is changed under the combined effect of ionizing radiations at doses related to deep space missions
Kokhan VS, Shakhbazian EV, Markova NA. Behav Brain Res. 2019 Jan 15;362:311-8.
Summary:
Initially, the paradigm about the strictly negative impact of ionizing radiation (IR) on the central nervous system dominated. However, data on the stimulating effect of moderate doses of ionizing radiation on cognitive abilities, as well as on the anxiolytic and antidepressant effects of IR, gradually accumulated. In the present work, a study was conducted of the serotonergic system in the brain structures that are closely involved in the implementation of the response to stress. The results revealed an anxiogenic and, at the same time, antidepressant effect of IR. At the same time, the positive effect of IR on the spatial learning performance of rats was obtained. Obviously, we are seeing a number of neurocompensatory and neuroadaptive CNS reactions to the effect of IR. Within the limits of sensitivity of the tests used and within the limits of doses of the combination of ionizing radiations used (comparable to that in the implementation of the 860-day Mars mission), we conclude that IR is relatively safe for CNS functions.
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Effects of head-only or whole-body exposure to very low doses of
Rabin BM, Poulose SM, Bielinski DF, Shukitt-Hale B. Life Sci Space Res. 2019 Feb 5. [Article in Press]
Summary:
A significant portion of the total dose experienced by astronauts may be expected to come from exposure to low LET 4He particles. Changes in neuronal function and cognitive performance could be observed following both head-only and whole-body exposures to 4He particles at doses as low as 0.01-0.025 cGy. These results, therefore, suggest the possibility that astronauts on exploratory class missions may be at a greater risk for HZE-induced deficits than previously anticipated.
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Modeling Reveals the Dependence of Hippocampal Neurogenesis Radiosensitivity on Age and Strain of Rats.
Cacao E, Kapukotuwa S and Cucinotta FA. Front. Neurosci. 12:980.
Summary:
Cognitive dysfunction following radiation treatment for brain cancers in both children and adults have been correlated to impairment of neurogenesis in the hippocampal dentate gyrus. In this paper, we have extended our previous mathematical model of radiation-induced hippocampal neurogenesis impairment of C57BL/6 mice to delineate the time, age, and dose dependent alterations in neurogenesis of a diverse strain of rats. We considered four compartments to model hippocampal neurogenesis and its impairment following radiation exposures: (1) neural stem cells (NSCs), (2) neuronal progenitor cells or neuroblasts (NB), (3) immature neurons (ImN), and (4) glioblasts (GB). Additional consideration of dose and time after irradiation dependence of microglial activation and a possible shift of NSC proliferation from neurogenesis to gliogenesis at higher doses is established. A major result of this work is predictions of the rat strain and age dependent differences in radiation sensitivity and sub-lethal damage repair that can be used for predictions for arbitrary dose and dose-fractionation schedules.
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Female mice are protected from space radiation-induced maladaptive responses
Krukowski K, Grue K, Frias ES, Pietrykowski J, Jones T, Nelson G, Rosi S. Brain Behav Immun. 2018 Aug 11.
Summary:
A single exposure to simulated GCR induces long-term cognitive and behavioral deficits only in the male cohorts but not in female. Mechanistically, the maladaptive behavioral responses observed only in the male cohorts correspond with microglia activation and synaptic loss in the hippocampus, a brain region involved in the cognitive domains reported here. Our findings suggest that GCR exposure can regulate microglia activity and alter synaptic architecture, which in turn leads to a range of cognitive alterations in a sex dependent manner.
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Temporary microglia-depletion after cosmic radiation modifies phagocytic activity and prevents cognitive deficits.
Krukowski K, Feng X, Paladini MS, Chou A, Sacramento K, Grue K, ..., Rosi S. Scientific Reports, 8, 7857 (2018).
Summary:
Temporary microglia depletion, one week after cosmic radiation, prevents the development of long-term memory deficits. The repopulated microglia present a modified functional phenotype with reduced phagocytic activity shown to be involved in microglia-synapses interaction. Our data provide mechanistic evidence for the role of microglia in the development of cognitive deficits after cosmic radiation exposure. To our knowledge this is the first report to identify a therapeutic approach for treating GCR-induced deficits.
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Detrimental effects of helium ion irradiation on cognitive performance and cortical levels of MAP-2 in B6D2F1 mice.
Raber J, Torres ERS, Akinyeke T, Lee J, Weber Boutros SJ, Turker MS, Kronenberg A. Int J Mol Sci. 2018 Apr 20;19(4):E1247.
Summary:
The space radiation environment includes helium (4He) ions that may impact brain function. As little is known about the effects of exposures to 4He ions on the brain, we assessed the behavioral and cognitive performance of C57BL/6J x DBA2/J F1 (B6D2F1) mice three months following irradiation with 4He ions (250 MeV/n; linear energy transfer (LET) = 1.6 keV/μm; 0, 21, 42 or 168 cGy). 4He ion irradiation impaired cognitive function and reduced the levels of the dendritic marker microtubule-associated protein 2 (MAP-2) in the cortex.
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Impaired attentional set-shifting performance after exposure to 5 cGy of 600 MeV/n (28)Si particles.
Britten RA, Jewell JS, Duncan VD, Hadley MM, Macadat E, Musto AE, La Tessa C. Radiat Res. Epub 2018 Jan 8. 2018 Mar;189(3):273-282.
Summary:

The long lag time for communication on a deep space mission will require that astronauts work more autonomously than on previous missions, and thus their ability to perform executive functions could be critical to mission success. Executive functions are a set of higher order cognitive abilities that animals utilize to assess changing situation and to achieve a desired goal in the most efficient and acceptable way (Assess, Adapt, Achieve!). In this paper we have determined that low doses (5 cGy) of 600 MeV/n 28Si ions impairs one executive function (cognitive flexibility, specifically the simple discrimination task in the attentional set shifting test). If astronauts were to experience GCR-induced simple discrimination impairments, they would be unable to identify key factors to successfully resolve a situation. Si ions impaired attentional set shifting performance at lower doses than the heavier ions we have previously studied, but when iso-fluences of the Si, Ti and Fe ions were compared, there were no significant differences in the severity of the impaired performance, but there were ion-specific decrements in the ability of rats to perform within the various stages of the test. This study further supports the notion that "mission-relevant" doses of HZE particles (<20 cGy) can impair certain aspects of attentional set shifting performance, but there may be some ion-specific changes in the specific cognitive domains impaired.

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Late effects of 1H irradiation on hippocampal physiology.
Kiffer F, Howe AK, Carr H, Wang J, Alexander T, Anderson JE, Groves T, Seawright JW, Sridharan V, Carter G, Boerma M, Allen AR. Life Sci Space Res. 2018 Mar 15. [Article in Press]
Summary:
This study examined the effects of protons, an abundant charged particle in both galactic cosmic rays and solar particle events, on cognitive function and hippocampus morphology in adult male C57BL/6 mice. Nine months after exposure to protons (150 MeV), mice showed a reduced ability to distinguish novel objects in a Novel Object Recognition test, indicative of reduced non-spatial memory. These results coincided with decreases in spine density and dendrite morphology in the hippocampus. The results suggest that proton irradiation caused late changes in neuronal morphology necessary for normal hippocampal processing.
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Early effects of 16O radiation on neuronal morphology and cognition in a murine model.
Carr H, Alexander TC, Groves T, Kiffer F, Wang J, Price E, Boerma M, Allen AR. Life Sci Space Res. 2018 Mar 14. [Article in Press]
Summary:
There is concern about potential adverse effects of high atomic number and energy (HZE) radiation on brain morphology. In this study, adult male C57BL/6 mice were exposed to oxygen ions (600 MeV/n, 0.1 - 1 Gy) and the hippocampus was examined two weeks after irradiation. Significant changes in spine density of neurons and in the expression of receptors that modulate synaptic function were observed, suggesting that oxygen ions have early deleterious effects on mature neurons that are associated with hippocampal learning and memory.
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Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice.
Parihar VK, Maroso M, Syage A, Allen BD, Angulo MC, Soltesz I, Limoli CL. Exp Neurol. 2018 Mar 11. [Epub ahead of print]
Summary:
Of the many perils associated with deep space travel to Mars, neurocognitive complications associated with cosmic radiation exposure are of particular concern. Despite these realizations, whether and how realistic doses of cosmic radiation cause cognitive deficits and neuronal circuitry alterations several months after exposure remains unclear. In addition, even less is known about the temporal progression of cosmic radiation-induced changes transpiring over the duration of a time period commensurate with a flight to Mars. Here we show that rodents exposed to the second most prevalent radiation type in space (i.e. helium ions) at low, realistic doses, exhibit significant hippocampal and cortical based cognitive decrements lasting 1 year after exposure. Cosmic-radiation-induced impairments in spatial, episodic and recognition memory were temporally coincident with deficits in cognitive flexibility and reduced rates of fear extinction, elevated anxiety and depression like behavior. At the circuit level, irradiation caused significant changes in the intrinsic properties (resting membrane potential, input resistance) of principal cells in the perirhinal cortex, a region of the brain implicated by our cognitive studies. Irradiation also resulted in persistent decreases in the frequency and amplitude of the spontaneous excitatory postsynaptic currents in principal cells of the perirhinal cortex, as well as a reduction in the functional connectivity between the CA1 of the hippocampus and the perirhinal cortex. Finally, increased numbers of activated microglia revealed significant elevations in neuroinflammation in the perirhinal cortex, in agreement with the persistent nature of the perturbations in key neuronal networks after cosmic radiation exposure. These data provide new insights into cosmic radiation exposure, and reveal that even sparsely ionizing particles can disrupt the neural circuitry of the brain to compromise cognitive function over surprisingly protracted post-irradiation intervals.
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Whole-Body Oxygen (16O) Ion-Exposure-Induced Impairments in Social Odor Recognition Memory in Rats are Dose and Time Dependent.
Ami Mange, Yuqing Cao, SiYuan Zhang, Robert D. Hienz, and Catherine M. Davis (2018) Whole-Body Oxygen (16O) Radiation Research: March 2018, Vol. 189, No. 3, pp. 292-299.
Summary:
Our paper reports dose- and time-dependent effects of acute exposure to 16O ions (5 and 25 cGy, 1000 MeV/n) on a social odor recognition memory test in male rats. At 30-days after radiation exposure, all exposed rats displayed a memory deficit, however, at 6-months following radiation exposure, this deficit was only evident in the 25 cGy exposed group. No differences in Ki67 staining, a marker of cell proliferation, were found in the subventricular zone between the sham controls, 5 cGy or 25 cGy exposed rats when assessed at 6-months following radiation exposure. This work demonstrates that low-dose HZE exposure can significantly impair memory for social odors in rats, which suggests that HZE exposure might negatively affect social processing.
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Biophysics Model of Heavy-Ion Degradation of Neuron Morphology in Mouse Hippocampal Granular Cell Layer Neurons.
Alp M and Cucinotta FA. (2018) Radiation Research: March 2018, Vol. 189, No. 3, pp. 312-325.
Summary:
Exposure to heavy-ion radiation during cancer treatment or space travel may cause cognitive detriments that have been associated with changes in neuron morphology and plasticity. Observations in mice of reduced neuronal dendritic complexity have revealed a dependence on radiation quality and absorbed dose, suggesting that microscopic energy deposition plays an important role. In this work we used morphological data for mouse dentate granular cell layer (GCL) neurons and a stochastic model of particle track structure and microscopic energy deposition (ED) to develop a predictive model of high-charge and energy (HZE) particle-induced morphological changes to the complex structures of dendritic arbors.
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Stem cell therapies for the resolution of radiation injury to the brain.
Smith SM, Limoli CL. Curr Stem Cell Rep. 2017 Dec;3(4):342-7. Review.
Summary:
Transplantation of human stem cells in the irradiated brain was first shown to resolve radiation-induced cognitive dysfunction in a landmark paper by Acharya et al., appearing in PNAS in 2009. Since that time, work from the same laboratory as well as other groups have reported on the beneficial (as well as detrimental) effects of stem cell grafting after cranial radiation exposure. Improved learning and memory found many months after engraftment has since been associated with a preservation of host neuronal morphology, a suppression of neuroinflammation, improved myelination and increased cerebral blood flow.
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Whole-Body Exposure to 28Si-Radiation Dose-Dependently Disrupts Dentate Gyrus Neurogenesis and Proliferation in the Short Term and New Neuron Survival and Contextual Fear Conditioning in the Long Term.
Whoolery CW, Walker AK, Richardson DR, Lucero MJ, Reynolds RP, Beddow DH, Clark KL, Shih HY, LeBlanc JA, Cole MG, Amaral WZ, Mukherjee S, Zhang S, Ahn F, Bulin SE, DeCarolis NA, Rivera PD, Chen BPC, Yun S, Eisch SJ. Radiation Research: Nov 2017;188(5):532-551.
Summary:
To compare the influence of 28Si exposure on indices of neurogenesis and hippocampal function with previous studies on 56Fe exposure, 9-week-old C57BL/6J and Nestin-GFP mice received whole-body 28Si-particle-radiation exposure. In contrast to the clearly observed radiation-induced, dose-dependent reductions in the short-term group across all markers, only a few neurogenesis indices were changed in the long-term irradiated groups. Compared to previously reported studies, present data suggest that 28Si-radiation exposure damages neurogenesis, but to a lesser extent than 56Fe radiation and that low-dose 28Si exposure induces abnormalities in hippocampal function, disrupting fear memory but also inducing anxiety-like behavior. Furthermore, exposure to 28Si radiation decreased new neuron survival in long-term male groups but not females suggests that sex may be an important factor when performing brain health risk assessment for astronauts traveling in space.
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Low-dose proton radiation effects in a transgenic mouse model of Alzheimer's disease - Implications for space travel.
Rudobeck E, Bellone JA, Szücs A, Bonnick K, Mehrotra-Carter S, Badaut J, Nelson GA, Hartman RE, Vlkolinsky R. PLoS One. 2017 Nov 29;12(11):e0186168.
Summary:
Space radiation represents a significant health risk for astronauts and it may accelerate the onset of Alzheimer's disease (AD). Although protons represent the main constituent in the space radiation spectrum, their effects on AD-related pathology have not been tested. We irradiated 3-month-old APP/PSEN1 transgenic (TG) and wild type (WT) mice with protons (150 MeV; 0.1-1.0 Gy; whole body) and evaluated functional and biochemical hallmarks of AD. We performed behavioral tests in the water maze (WM) before irradiation and in the WM and Barnes maze at 3 and 6 months post-irradiation to evaluate spatial learning and memory. We also performed electrophysiological recordings in vitro in hippocampal slices prepared 6 and 9 months post-irradiation to evaluate excitatory synaptic transmission and plasticity. Next, we evaluated amyloid β (Aβ) deposition in the contralateral hippocampus and adjacent cortex using immunohistochemistry. In cortical homogenates, we analyzed the levels of the presynaptic marker synaptophysin by Western blotting and measured pro-inflammatory cytokine levels (TNFα, IL-1β, IL-6, CXCL10 and CCL2) by bead-based multiplex assay. TG mice performed significantly worse than WT mice in the WM. Irradiation of TG mice did not affect their behavioral performance, but reduced the amplitudes of population spikes and inhibited paired-pulse facilitation in CA1 neurons. These electrophysiological alterations in the TG mice were qualitatively different from those observed in WT mice, in which irradiation increased excitability and synaptic efficacy. Irradiation increased Aβ deposition in the cortex of TG mice without affecting cytokine levels and increased synaptophysin expression in WT mice (but not in the TG mice). Although irradiation with protons increased Aβ deposition, the complex functional and biochemical results indicate that irradiation effects are not synergistic to AD pathology.
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Long-Term Deficits in Behavior Performances Caused by Low- and High-Linear Energy Transfer Radiation.
Patel R, Arakawa H, Radivoyevitch T, Gerson SL and Welford SM. Radiation Research. 2017; 188(6):672-680.
Summary:
Across a range of LET sources, we found that different ion species have different detrimental impacts at extended time points post exposure that can lead sustained declines in behavioral performances. A significant dose effect was observed on recognition memory and activity levels measured 9 months postirradiation, regardless of radiation source. In contrast, we observed that each ion species had a distinct effect on anxiety, motor coordination and spatial memory at extended time points.
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Irradiation of Neurons with High-Energy Charged Particles: An In Silico Modeling Approach
Alp M, Parihar VK, Limoli CL, Cucinotta FA (2015) PLoS Comput Biol 11(8): e1004428.
Summary:
This paper describes the spatial dependence of a particle's microscopic dose deposition events on a detailed neuron structure. Heavy ions including iron, carbon and hydrogen particles, and energetic electrons that are common in space radiation exposures are considered. The computational model covers the stochastics of the generation of energy deposition events, delivery of particle beams and possible encounter schemes of microscopic dose and neuronal morphology. Results from this in silico study can be used to consider experimental studies in order to understand structural and functional neuronal damage following irradiation.
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Bi-directional and shared epigenomic signatures following proton and
Impey, S., Jopson, T, Pelz, C., Tafessu, A, Fareh, F., Zuloaga, D., Marzulla, T., Riparip, L., Stewart, B., Rosi, S, Turker, M.S., Raber, J. Scientific Reports, 7, 10227 (2017)
Summary:
As the brain's response to radiation exposure is an important concern for patients undergoing cancer therapy and astronauts on long missions in deep space. We assessed whether this response is specific and prolonged and is linked to epigenetic mechanisms, focusing on the response of the hippocampus at early (2-weeks) and late (20-week) time points following whole body proton irradiation. Significant overlap was observed between DNA methylation changes at the 2 and 20-week time points, demonstrating specificity and retention of changes in response to radiation and a novel class of DNA methylation change was observed following space irradiation characterized by both increased and decreased cytosine hydroxymethylation (5hmC) levels along the entire gene body. These changes mapped to genes encoding neuronal functions including postsynaptic gene ontology categories, indicating that the brain's response to proton irradiation is both specific and prolonged and involves novel remodeling of non-random regions of the epigenome.
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Changes in the Hippocampal Proteome Associated with Spatial Memory Impairment after Exposure to Low (20 cGy) Doses of 1 GeV/n 56Fe Radiation.
Richard A. Britten, Jessica S. Jewell, Leslie K. Davis, Vania D. Miller, Melissa M. Hadley, O. John Semmes, György Lonart, and Sucharita M. Dutta (2017) . Radiation Research: March 2017, Vol. 187, No. 3, pp. 287-297.
Summary:
This paper is the first to apply an unbiased proteomic profiling approach to identify the mechanisms underlying neurocognitive impairment by GCR. This approach provides a snapshot of the composition of the brain (in this case the hippocampus) , the data can then be mined to determine what pathways are active in the irradiated versus unirradiated individuals. Importantly, not all irradiated individuals develop neurocognitive impairment, suggesting that some individuals are able to ameliorate the deleterious effects of the GCR while others are unable to do so. This situation provides a unique opportunity to increase our understanding of how GCR impacts upon neurophysiology, what adaptive responses can be invoked to prevent the emergence of GEFI, as well as the pathways that are altered when neurocognitive impairment occurs. It may be possible to use such knowledge to develop two alternative countermeasure strategies, one that preserves critical pathways prophylactically and one that invokes restorative pathways after GCR exposure.
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Epigenetic determinants of space radiation-induced cognitive dysfunction.
Acharya MM, Baddour AA, Kawashita T, Allen BD, Syage AR, Nguyen TH, Yoon N, Giedzinski E, Yu L, Parihar VK, Baulch JE. Sci Rep. 2017 Feb 21;7:42885.
Summary:
While it has been clearly shown that space radiation exposures induce dramatic alterations in CNS function, the mechanisms that contribute to radiation-induced cognitive dysfunction are poorly understood. This study tested the hypothesis that neuroepigenetic mechanisms underlie, at least in part, these radiation-induced cognitive impairments. We demonstrated that mice exposed to 20 cGy of 28Si particles had elevated levels of DNA methylation that correlated with impaired ability to perform behavioral tasks that measure episodic, spatial and temporal memory. Inhibition of DNA methylation by disruption of S-adenylmethionine metabolism protected against and mitigated the changes in global DNA methylation in the irradiated brain and improved cognition, supporting the hypothesis that neuroepigenetic aberrations contribute to cognitive deficits following space relevant radiation exposures.
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Neurogenic effects of low-dose whole-body HZE (Fe) ion and gamma irradiation.
Sweet TB, Hurley SD, Wu MD, Olschowka JA, Williams JP, O'Banion MK. Radiat Res. 2016 Dec 01. [Epub ahead of print]
Summary:
Although it is well known that radiation adversely impacts adult hippocampal neurogenesis and this has been suggested as one factor contributing to cognitive deficits following brain radiation exposure, the dose threshold for radiation effects on neurogenesis has not been thoroughly investigated. Using doses ranging from 1 to 300 cGy of iron HZE particles (1 GeV/n) or gamma irradiation from a cesium source with young C57BL/6 mice, acute decreases in hippocampal neurogenesis were detected at doses of 30 and 100 cGy for iron ions and gamma radiation, respectively. Significant reduction in doublecortin-positive, newly differentiated neurons was observed at 100 cGy for both radiation types. These data complement an earlier study of proton exposure (1 GeV) that showed effects on both acute cell division and long-term neurogenesis at 50 cGy (Sweet et al., Radiat. Res. 182:18, 2014) and will aide in our understanding of radiation effects on central nervous system function.
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Neurophysiology of space travel: Energetic solar particles cause cell type-specific plasticity of neurotransmission.
Lee SH, Dudok B, Parihar VK, Jung KM, Zöldi M, Kang YJ, Maroso M, Alexander AL, Nelson GA, Piomelli D, Katona I, Limoli CL, Soltesz I. Brain Struct Funct. 2016 Nov 30. [Epub ahead of print]
Summary:
Evidence that energetic solar particles cause cell type-specific and persistent alterations in neurotransmission. Specifically, irradiation caused a significant increase in GABA release from cannabinoid receptor 1 (CB1) expressing basket cells onto pyramidal cell neurons in the CA1, an effect that could be abolished by CB1 blockade. The nature of these synaptic changes are consistent with the observed disruptions in cognitive dysfunction and point to the possibility of developing targeted therapeutic interventions to mitigate radiation-induced space brain during interplanetary travel.
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Modeling Heavy-Ion Impairment of Hippocampal Neurogenesis after Acute and Fractionated Irradiation.
Cacao, E. and Cucinotta, F. A. Radiat. Res. 186, Published on-line ahead of print (2016).
Summary:
Radiation-induced impairment of neurogenesis in the hippocampal dentate gyrus is a concern due to its reported association with cognitive detriments after radiotherapy for brain cancers and the possible risks to astronauts chronically exposed to space radiation. We used a system of nonlinear ordinary differential equations (ODEs) to represent age, time after exposure and dose-dependent changes to several cell populations participating in neurogenesis, as reported in mouse experiments. We compared our model to experimental data for X rays, and protons, carbon and iron particles, including data for fractionated iron-particle irradiation.
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Cosmic radiation exposure and persistent cognitive dysfunction.
Parihar VK, Allen BD, Caressi C, Kwok S, Chu E, Tran KK, Chmielewski NN, Giedzinski E, Acharya MM, Britten RA, Baulch JE, Limoli CL, published in Scientific Reports 6, Article number: 34774 (2016).
Summary:
A study from the laboratory of Professor Charles Limoli has found that exposures to low doses of charged particles found in galactic cosmic rays causes long-term impairments in learning and memory. These cognitive deficits are associated with significant reductions in the structural complexity of neurons and elevated neuroinflammation. These findings highlight the importance of understanding space radiation effects on the brain, and point to the unique hazards associated with such exposures.
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Individual variations in dose response for spatial memory learning among outbred Wistar rats exposed from 5 to 20 cGy of Fe particles.
Wyrobek AJ, Britten RA. Environ Mol Mutagen. 2016 May 30. [Epub ahead of print]
Summary:
A report on measurements of spatial memory learning among genetically outbred male Wistar rats exposed to graded doses of (56) Fe particles (sham, 5, 10, 15, and 20 cGy; 1 GeV/n), assessed on a Barnes maze. The findings suggest that genetically diverse individuals can vary substantially in their spatial memory learning, and that exposures at low doses appear to preferentially impact poor learners.
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Contrasting the effects of proton irradiation on dendritic complexity of subiculum neurons in wild type and MCAT mice.
Chmielewski NN, Caressi C, Giedzinski E, Parihar VK, Limoli CL. Environ Mol Mutagen. 2016 Mar 20. [Epub ahead of print]
Summary:
Our most recent findings extend our prior work previously published in Antioxidants & Redox Signaling (ref below) and now shows that similar protective effects can be demonstrated in the subiculum after proton irradiation by increasing mitochondrial antioxidant capacity. Our findings support the overall idea that altered redox homeostasis in the irradiated brain contributes to impaired neurotransmission that adversely affects cognitive function.
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Proton irradiation induces persistent and tissue-specific DNA methylation changes in the left ventricle and hippocampus.
Soren Impey, Carl Pelz, Amanuel Tafessu, Tessa Marzulla, Mitchell S. Turker and Jacob Raber. BMC Genomics 2016 17:273
Summary:
Persistent epigenetic changes that result from environmental exposures include gains or losses of DNA methylation of cytosine, which can impact gene expression. In this unbiased genome-wide DNA methylation study, we compared the long-term epigenetic effects of whole body proton irradiation in the mouse hippocampus and left ventricle. The DNA methylation data showed tissue-dependent effects of proton irradiation. Many regions affected in the ventricle mapped to genes involved in cardiovascular function pathways, whereas many regions affected in the hippocampus mapped to genes involved in neuronal functions. Importantly, the DNA methylation data revealed significant major pathway changes in response to a single proton irradiation that are related to known pathophysiologic processes.
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Impaired spatial memory performance in adult Wistar rats exposed to low (5-20 cGy) doses of 1 GeV/n Fe particles.
Britten RA, Jewell JS, Miller VD, Davis LK, Hadley MM, Wyrobek AJ. Radiat Res. 2016 Mar 185(3):332-7.
Summary:
Our paper reports on the impact that mission relevant doses of 1 GeV/n 56Fe particles has on spatial memory performance ( a cognitive function that is highly dependent upon the hippocampus). When the overall population is considered there is a significant impairment of cognitive function, but there are individual rats that retain the ability to conduct spatial memory. A novel aspect of this paper is that we analyzed the effects of radiation-induced impairments on spatial memory performance using traditional metrics based on cohort means, but also used a metric that reflects the performance of each individual rat, and then determined the proportion of individuals in each experimental cohort whose performances are impaired (Z score of >2). We believe that presenting the data in this format will be more useful to NASA when they conduct a Probabilistic Risk Analysis for this issue.
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Sex- and dose-dependent effects of calcium ion irradiation on behavioral performance of B6D2F1 mice during contextual fear conditioning training.
Raber J, Weber S, Kronenberg A, Turker MS. Life Sci Space Res. 2016 Mar 22. [Article in Press]
Summary:
In this study, the effects of 40Ca ion irradiation on behavioral and cognitive performance were assessed for the first time. 40Ca ion irradiation reduced the activity of the mice in a novel environment in a dose-dependent fashion and reduced the response to shock in female, but not male, mice. In contrast, 40Ca ion irradiation did not affect fear learning, fear memory, or extinction of fear memory. These data suggest that brain areas involved in emotional reactions to novelty and aversive environmental stimuli might be particularly susceptible to effects of 40Ca ion irradiation.
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⁵⁶Fe irradiation alters spine density and dendritic complexity in the mouse hippocampus.
Allen AR, Raber J, Chakraborti A, Sharma S, Fike JR. Radiat Res. 2015 Nov 18. [Epub ahead of print]
Summary:
Health risks associated with high-LET space radiation exposure include cognitive injury, which may involve modifications to dendritic structure and/or alterations in dendritic spine density and morphology in the hippocampus, a brain area important for cognitive performance. Mice were either whole-body irradiated with 0.5 Gy 56Fe (600 MeV/n) or sham irradiated and three months later they were tested for locomotor activity and habituation and their brains analyzed for hippocampal spine morphology. Compared to sham-irradiated mice, irradiated mice moved less when first introduced to the environment and showed a compromised dendritic architecture and reduced spine density in the hippocampus. Future studies are warranted to determine the molecular mechanism underlying the deleterious effects of high-LET radiation on mature neurons associated with hippocampal learning and memory.
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Irradiation of neurons with high-energy charged particles: An in silico modeling approach.
Alp M, Parihar VK, Limoli CL, Cucinotta FA. PLoS Comput Biol. 2015 Aug; 11(8): e1004428.
Summary:
This paper describes the spatial dependence of a particle’s microscopic dose deposition events on a detailed neuron structure. Heavy ions including iron, carbon and hydrogen particles, and energetic electrons are considered. Results show that the heterogeneity of heavy particle tracks at low doses, compared to the more uniform dose distribution of electrons, juxtaposed with neuron morphology make it necessary to model the spatial dose painting for specific neuronal components.
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Fractionated radiation exposure of rat spinal cords leads to latent neuro-inflammation in brain, cognitive deficits, and alterations in apurinic endonuclease.
Suresh Kumar MA, Peluso M, Chaudhary P, Dhawan J, Beheshti A, Manickam K, Thapar U, Pena L, Natarajan M, Hlatky L, Demple B, Naidu M. 1. PLoS One. 2015 Jul 24;10(7):e0133016.
Summary:
Spinal cords of rat were used as an in vivo model for measuring possible latent effects of protons and particle radiation on the differentiation oligodendrocyte precursor cells (OPC), using low LET (X-rays and protons (1 Gy)) and high LET (28Si/ 56Fe) radiation. This study focused on the role of the base excision repair protein Apurinic Endonuclease-1 (APE1) in the rat spinal cords OPC differentiation. Our studies show for the first time, that fractionation of protons cause latent damage to spinal cord architecture while fractionation of HZE (28Si) induced increases in APE1 with single dose, which then decreased with fractionation.
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A single low dose of proton radiation induces long-term behavioral and electrophysiological changes in mice.
Bellone JA, Rudobeck E, Hartman RE, Szücs A, Vlkolinský R. Radiat Res. 2015 Jul 24. [Epub ahead of print]
Summary:
Exposure to high-LET charged particles, at doses similar to those anticipated during deep space missions, was previously shown in transgenic (TG) mice to promote Alzheimer’s disease (AD)-like neurodegeneration. The authors found that proton radiation impaired reversal learning in the water maze and increased synaptic excitability in CA1 neurons, but suppressed their propensity for epileptiform activity. These baseline radiation responses to protons in healthy subjects suggest that astronauts traveling outside Earth’s magnetosphere may be at increased risk of developing long-term decrements associated with hippocampal dysfunction.
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Acute effects of exposure to Fe and O particles on learning and memory.
Rabin BM, Poulose SM, Carrihill-Knoll KL, Ramirez F, Bielinski DF, Heroux N, Shukitt-Hale B. Radiat Res. 2015 Jul 24. [Epub ahead of print]
Summary:
The experiments reported in this paper were designed to determine (1) the acute effects (24-48 hr) of exposure to 16O and 56Fe on cognitive performance; (2) whether exposure to HZE particles affected learning or memory; and (3) the relationship between HZE particle-induced oxidative stress and neuroinflammation in specific brain regions and cognitive performance. The results indicated that the acute effects of irradiation on cognitive performance are on memory, not learning. The effects of exposure to HZE particles on oxidative stress and neuroinflammation and their relationship to cognitive performance indicated that, although the effects of exposure are widespread, only changes in specific regions of the brain may be related to changes in cognitive function.
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(28)Silicon irradiation impairs contextual fear memory in B6D2F1 mice.
Raber J, Marzulla T, Stewart B, Kronenberg A, Turker MS. Radiat Res. 2015 Jun; 183(6):708-12. Epub 2015 May 26.
Summary:
In mouse studies, C57Bl6/J homozygous wild-type mice and genetic mutant mice on a C57Bl6/J background have typically been used for assessing effects of space radiation on cognition and little is known about the radiation response of mice on a heterozygous background. In the study published in the June issue of Radiation Research, 28Si irradiation was shown to impair hippocampus-dependent contextual fear memory in C57Bl6/J x DBA2/J F1 (B6D2F1) mice three months following irradiation. In contrast, in an earlier study contextual fear memory was enhanced three months following irradiation of C57Bl6/J mice with 28Si. Thus, B6D2F1 mice seem more susceptible than C57Bl6/J mice to detrimental effects of 28Si irradiation and underline the importance of considering strains with distinct genetic backgrounds for evaluating the effects of space irradiation on the brain.
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Lack of reliability in the disruption of cognitive performance following exposure to protons.
Rabin, B. M., Heroux, N. A., Shukitt-Hale, B., Carrihill-Knoll, K. L., Beck, Z., & Baxter, C. (2015 Radiation and Environmental Biophysics, 54: 285-295.
Summary:
A series of three replications were run to determine the reliability with which exposure to protons produces a disruption of cognitive performance, using a novel object recognition task and operant responding on an ascending fixed-ratio task. For the first two replications, rats were exposed to head-only exposures to 1000 MeV/n protons at the NASA Space Radiation Laboratory. For the third replication, subjects were given head-only or whole-body exposures to both 1000 and 150 MeV/n protons. The results were characterized by a lack of consistency in the effects of exposure to protons on the performance of these cognitive tasks, both within and between replications.
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What happens to your brain on the way to Mars?
Vipan K. Parihar, Barrett Allen, Katherine K. Tran, Trisha G. Macaraeg,Esther M.Chu, Stephanie F.Kwok, Nicole N. Chmielewski, Brianna M. Craver, Janet E. Baulch, Munjal M. Acharya, Francis A.Cucinotta, Charles L. Limoli. published Sci. Adv. 2015;1:e1400256 1 May 2015.
Summary:
Our study provides evidence that suggests exposure to space radiation poses a risk for developing cognitive decrements. Mice subjected to low doses of charged particles showed impaired learning and memory when subjected to behavioral testing 6 weeks later. Cognitive deficits coincided with a range of structural and synaptic alterations to neurons located in the medial prefrontal cortex. Reductions in dendritic complexity and spine density can directly disrupt neurotransmission and cognition. Our findings suggest that similar types of cognitive complications may arise in astronauts subjected to the space radiation environment during a long term deep space mission to Mars.
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Persistent oxidative stress in human neural stem cells exposed to low fluences of charged particles.
Baulch JE, Craver BM, Tran KK, Yu L, Chmielewski N, Allen BD, Limoli CL. Redox Biol. 2015 Aug 11;5:24-32. Epub 2015 Mar 11.
Summary:
In this study we investigated whether space relevant fluences of charged particles caused oxidative stress in cultures of human neural stem cells that was proportional to the microdosimetric properties of the incident particle. Dose and temporal responses for radiation-induced oxidative stress were probed through the use of intracellular fluorogenic dyes that exhibit relative specificity for certain reactive species. Increased fluorescent signals derived from the oxidation of selected redox sensitive dyes provided a quantitative measure of oxidative stress after exposure. Data showed that the total dose, rather than particle energy and/or LET was the predominate factor dictating the extent and duration of oxidative stress in irradiated populations of human neural stem cells.
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Space radiation risks to the central nervous system. (Review)
Cucinotta, F.A., Alp, M., Sulzman, F.M., Wang, M. Life Sci. Space Res, 2014;2:54-69
Summary:
In this report we summarize recent space radiobiology studies of CNS effects from particle accelerators simulating space radiation using experimental models, and make a critical assessment of their relevance with respect to doses and the dose rates to be incurred on a Mars Mission. Prospects for understanding dose, dose-rate and radiation quality dependencies of CNS effects and extrapolation to human risk assessments are described.
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Novel images and novel locations of familiar images as sensitive translational cognitive tests in humans.
J. Raber. published in Behav Brain Res. 2015 Feb 2. [Epub ahead of print].
Summary:
Cognitive tests involving preferential exploration of familiar objects in novel locations and of novel objects are particularly sensitive to detect effects of space irradiation in rodents. Based on the rodent test of object recognition, a human test of object recognition was developed, the Novel Image Novel Location (NINL) test, containing panels with three images each. As this test does not involve language and is sensitive to detect of apolipoprotein E4, a risk factor for age-related cognitive decline and Alzheimer's disease, in the healthy oldest-old (mean age 81 years), it would also be good to consider the NINL test for assessing cognitive performance in astronauts during and/or following space missions.
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Impact of breathing 100% oxygen on radiation-induced cognitive impairment.
Wheeler K, Payne V, D' Agostino R, Walb M, Munley M, Metheny-Barlow L, Robbins M. Radiation Research: November 2014, Vol. 182, No. 5, pp. 580-585
Summary:
Astronauts are exposed to space radiations while breathing 100% oxygen during an EVA. Given that brain irradiation can cause cognitive impairment and oxygen is a potent radiosensitizer, astronauts may have a greater risk of developing radiation-induced cognitive impairment during an EVA. In this study, unanesthetized and unrestrained rats were whole-body irradiated with 18 MV X-rays at a low dose rate of ~425 mGy/min while breathing either air or 100% oxygen for 30 min before, during and 2 h postirradiation. Within the study's limitations, breathing 100% oxygen under simulated EVA conditions, increased rather than decreased, cognitive function at all doses when compared to irradiated air-breathing rats. Thus, astronauts are not likely to be at a greater risk of developing cognitive impairment when exposed to space radiations while breathing 100% oxygen during an EVA.
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Lifetime evaluation of left ventricular structure and function in male ApoE null mice after gamma and space-type radiation exposure.

Brojakowska A, Jackson CJ, Bisserier M, Khlgatian MK, Jagana V, Eskandari A, Grano C, Blattnig SR, Zhang S, Fish KM, Chepurko V, Chepurko E, Gillespie V, Dai Y, Kumar Rai A, Garikipati VNS, Hadri L, Kishore R, Goukassian DA. Lifetime evaluation of left ventricular structure and function in male ApoE null mice after gamma and space-type radiation exposure. Front Physiol. 2023 Nov 20;14:1292033. doi: 10.3389/fphys.2023.1292033. PMID: 38054039; PMCID: PMC10694360.

Summary:

The space radiation (IR) environment contains high charge and energy (HZE) nuclei emitted from galactic cosmic rays with the ability to overcome current shielding strategies, posing increased IR-induced cardiovascular disease risks for astronauts on prolonged space missions. Little is known about the effect of 5-ion simplified galactic cosmic ray simulation (simGCRsim) exposure on left ventricular (LV) function. Three-month-old, age-matched male Apolipoprotein E (ApoE) null mice were irradiated with ¹³⁷Cs gamma (γ; 100, 200, and 400 cGy) and simGCRsim (50, 100, 150 cGy all at 500 MeV/nucleon (n)). LV function was assessed using transthoracic echocardiography at early/acute (14 and 28 days) and late/degenerative (365, 440, and 660 days) times post-irradiation. As early as 14 and 28-days post IR, LV systolic function was reduced in both IR groups across all doses. At 14 days post-IR, 150 cGy simGCRsim-IR mice had decreased diastolic wall strain (DWS), suggesting increased myocardial stiffness. This was also observed later in 100 cGy γ-IR mice at 28 days. At later stages, a significant decrease in LV systolic function was observed in the 400 cGy γ-IR mice. Otherwise, there was no difference in the LV systolic function or structure at the remaining time points across the IR groups. We evaluated the expression of genes involved in hemodynamic stress, cardiac remodeling, inflammation, and calcium handling in LVs harvested 28 days post-IR. At 28 days post-IR, there is increased expression of Bnp and Ncx in both IR groups at the lowest doses, suggesting impaired function contributes to hemodynamic stress and altered calcium handling. The expression of Gals3 and β-Mhc were increased in simGCRsim and γ-IR mice respectively, suggesting there may be IR-specific cardiac remodeling. IR groups were modeled to calculate the Relative Biological Effectiveness (RBE) and Radiation Effects Ratio (RER). No lower threshold was determined using the observed dose-response curves. These findings do not exclude the possibility of the existence of a lower IR threshold or the presence of IR-induced cardiovascular disease (CVD) when combined with additional space travel stressors, e.g., microgravity.

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Impacts of radiation exposure, hindlimb unloading, and recovery on murine skeletal muscle cell telomere length

Tichy ED, Lee J, Li G, Estep KN, Brad Johnson F, Mourkioti F. NPJ Microgravity. 2023; 9(1):76.

Summary:

Astronauts are exposed to harsh conditions, including cosmic radiation and microgravity. Spaceflight elongates human telomeres in peripheral blood, which shorten upon return to Earth and approach baseline levels during postflight recovery. Astronauts also encounter muscle atrophy, losing up to 20% loss of muscle mass on spaceflights. Telomere length changes in muscle cells of astronauts remain unexplored. This study investigates telomere alterations in grounded mice experiencing radiation exposure and muscle atrophy, via a hindlimb unloading spaceflight mimicking model. We find telomere lengthening is present in muscle stem cells and in myofiber nuclei, but not in muscle-resident endothelial cells. We further assessed telomere length in the model following hindlimb unloading recovery. We find that telomere length failed to return to baseline values. Our results suggest a role for telomeres in muscle acclimatization, which is relevant for the well-being of astronauts in space, and upon their return to Earth.

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Female astronauts: Impact of space radiation on menopause

Bruce I. Rose, Eur J Obstet Gynecol Reprod Biol. 2022 Apr 1;271:210-3.

Summary:

Space travel has different effects on the reproductive capacity of women compared to men. The radiation exposure intrinsic to deep space travel causes destruction of some of a woman's primordial follicles. Data suggests that a typical Mars mission may reduce a women's ovarian reserve by about 50%. This has consequences to a woman's reproductive capacity and, more significantly, decreases the time interval to her menopause. A reduced time interval to menopause is associated with earlier mortality. Estrogen replacement therapy and cryopreservation of a female astronaut's oocytes may be used to address these issues. However, cortical tissue freezing provides advantages to more directly compensate for these workplace complications. Cortical tissue freezing especially provides advantages if there are plans to reproduce in an extraterrestrial location.

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Mitigation of late cardiovascular effects of oxygen ion radiation by γ-tocotrienol in a mouse model

Nemec-Bakk AS, Sridharan V, Landes RD, Singh P, Cao M, Seawright JW, Liu X, Zheng G, Dominic P, Pathak R, Boerma M. Life Sci Space Res (Amst). 2021 Nov;31:43-50

Summary:

γ-tocotrienol is an anti-oxidant, modifies cholesterol metabolism, and has anti-inflammatory and endothelial cell protective properties. This study shows that γ-tocotrienol mitigated effects of oxygen ion irradiation on cardiac function and structure in a mouse model, suggesting that γ-tocotrienol has potential as a countermeasure against degenerative tissue effects of high-LET radiation on the heart.

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Long-term effects of very low dose particle radiation on gene expression in the heart: Degenerative disease risk
Garikipati VNS, Arakelyan A, Blakely EA, Chang PY, Truongcao MM, Cimini M, Malaredy V, Bajpai A, Addya S, Bisserier M, Brojakowska A, Eskandari A, Khlgatian MK, Hadri L, Fish KM, Kishore R, Goukassian DA Cells. 2021 Feb 13;10(2):387
Summary:
In this study, we provide the transcriptome analysis of mouse hearts exposed to low and very low doses of gamma-IR ¹³⁷Cs (40-160 cGy), ¹⁴Si-IR (4-32 cGy, 260 MeV/n) or ²²Ti-IR (3-26 cGy, 1 GeV/n) ion irradiation. Our results show that 16 months after a single low- or very low doses of IR exposure, the gene expression in the heart tissue is significantly differentially regulated compared to the sham-treated, non-irradiated controls, suggesting there are long-term effects on dysregulation of different molecular pathways that are associated with various disease and biological processes. Additionally, our bioinformatics analyses revealed the following: (i) there were no clear lower IR thresholds for HZE- or γ-IR; (ii) there were 12 common differentially expressed genes across all 3 IR types; (iii) these 12 overlapping genes predicted various degrees of cardiovascular, pulmonary, and metabolic diseases, cancer, and aging; and (iv) these 12 genes revealed an exclusive non-linear DEG pattern in ¹⁴Si- and ²²Ti-IR-exposed hearts, whereas two-thirds of γ-IR-exposed hearts revealed a linear pattern of DEGs.
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Changes in one-carbon metabolism and DNA methylation in the hearts of mice exposed to space environment-relevant doses of oxygen ions (
Miousse IR, Skinner CM, Sridharan V, Seawright JW, Singh P, Landes RD, Cheema AK, Hauer-Jensen M, Boerma M, Koturbash I. Life Sci Space Res. 2019 August; 22, 8-15.
Summary:
Cardiovascular disease constitutes an important threat to humans after space missions beyond the Earth's magnetosphere. We investigated the effects of ¹⁶O on the cardiac methylome and one-carbon metabolism in male C57BL/6 J mice. Left ventricles were examined 14 and 90 days after exposure to space-relevant doses of 0.1, 0.25, or 1 Gy of ¹⁶O (600 MeV/n). DNA methylation in repetitive elements was elevated, particularly after 90 days, while expression showed first a decrease followed by an increase in transcript abundance. Metabolomics analysis revealed that metabolites involved in homocysteine remethylation, central to DNA methylation, were unaffected by radiation, but the transsulfuration pathway was impacted after 90 days, with a large increase in cystathione levels at the lowest dose.
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Radiation-induced cardiovascular disease: Mechanisms and importance of linear energy transfer.
Sylvester CB, Abe JI, Patel ZS, Grande-Allen KJ. Front Cardiovasc Med. 2018 Jan 31;5:5. Review.
Summary:
The link between radiation and CVD is well established in human cohorts at doses greater than 0.5 Gy. Most knowledge about radiation-induced cardiovascular disease (RICVD) comes from populations exposed to low-linear energy transfer (LET) photons. More recently, high-LET radiation is being tested as a therapy for cancer. High-LET therapy more closely replicates the high energy and atomic weight component of space radiation to which astronauts will be subjected, but how high-LET radiation affects the cardiovascular system is not yet completely understood. This review examines the clinical, molecular, and animal studies that investigate the effects of high-LET radiation on the cardiovascular system and compares those results to current knowledge of low-LET radiation. It further elaborates on how advances within NASA's research program as well as within the terrestrial work with cancer therapy can inform both the risk of RICVD and mitigation strategies.
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Low doses of oxygen ion irradiation cause long-term damage to bone marrow hematopoietic progenitor and stem cells in mice.
Wang Y, Chang J, Li X, Pathak R, Sridharan V, Jones T, Mao XW, Nelson G, Boerma M, Hauer-Jensen M, Zhou D, Shao L. PLoS One: 2017 Dec 12;12(12):e0189466.
Summary:
While high energy charged particle irradiation as found in space is known to have short-term adverse effects on the hematopoietic system, long-term effects are not well studied. This experiment used a mouse model of oxygen ion exposure to assess stem and progenitor cells isolated from the bone marrow at three months after exposure. The cells of irradiated animals showed increased levels of reactive oxygen species and reduced performance in cell function assays. These results suggest that high energy charged particle irradiation can have long-term adverse effects on the hematopoietic system.
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Dose- and ion-dependent effects in the oxidative stress response to space-like radiation exposure in the skeletal system.
Alwood JS, Tran LH, Schreurs AS, Shirazi-Fard Y, Kumar A, Hilton D, Tahimic CGT, Globus RK. Int J Mol Sci. 2017 Oct 10;18(10):E2117.
Summary:
This article reports on impairment of osteoblastogenesis in 16-weeks old, male, C57BL6/J mice by protons (150 MeV/n) 56Fe ions (600 MeV/n) using either low (5 or 10 cGy) or high (50 or 200 cGy) doses at NASA's Space Radiation Lab. The authors' conclusion is that high-LET irradiation at 200 cGy impaired osteoblastogenesis and regulated steady-state gene expression of select redox-related genes during osteoblastogenesis, which may contribute to persistent bone loss.
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Different sequences of fractionated low-dose proton and single iron-radiation-induced divergent biological responses in the heart.
Sasi SP, Yan X, Zuriaga-Herrero M, Gee H, Lee J, Song J, Onufrak J, Morgan J, Enderling H, Walsh K, Kishore R, Goukassian DA. Radiat Res. August 2017, Vol. 188, No. 2, pp. 191-203.(2017).
Summary:
We previously reported the effects of a single, whole-body, low-dose 1H (0.5 Gy, 1 GeV) and 56Fe (0.15 Gy, 1 GeV/nucleon) ion irradiation on the CV system during normal aging and under ischemic conditions. These studies signified the long-term (up to 10 months) negative effects of irradiation on systolic and diastolic functions of the heart accompanied by increased hypertrophic signaling contributing to heart failure. In the model of acute myocardial infarct, the cardiac tissue recovery and regeneration after exposure to 0.15 Gy 56Fe radiation demonstrated long-lasting detrimental effects including loss of cardiac function and worsened cardiac remodeling over the period of 10 months. On the other hand, 0.5 Gy 1H irradiation induced positive effects during recovery after a MI event, which may be attributed to a possible ischemic preconditioning-like effect of low-proton irradiation of the heart in case of possible adverse cardiac event, such as acute myocardial infarct (AMI). Because there is essentially no data available on the effects of different sequential, fractionated low-dose charged particle (SPE-like proton and HZE) irradiations to the CV system, we used same murine models to examine the effects of acute, whole-body fractionated low-dose 1H exposure by itself and in combination with a single low dose of 56Fe radiation before or after fractionated 1H to emulate a possible space-like environment. Our1H vs. a single 56Fe-IR. These findings also provide initial mechanistic insight into the development of CV morbidity and mortality induced by mixed charged particle radiation in the heart tissue. Additionally, they emphasize the necessity to determine underlying molecular mechanisms responsible for this significant mix ion fractionation and sequence-dependent divergent responses in the heart during aging and in case of a possible ischemic cardiovascular event.
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Heart Disease Mortality in the Life Span Study, 1950-2008.
Ikuno Takahashi, Yukiko Shimizu, Eric J. Grant, John Cologne, Kotaro Ozasa, and Kazunori Kodama (2017). Radiation Research: March 2017, Vol. 187, No. 3, pp. 319-332.
Summary:
Cardiovascular disease (CVD), i.e., stroke and heart disease consists of various subtypes that have potentially different radiation dose responses, as well as subtype-specific risks that have not been fully evaluated. The goal of this study was to clarify the radiation risk of subtype-specific heart disease over different time periods. Radiation dose response was examined for mortality from several heart disease subtypes in 86,600 members of the Life Span Study (LSS) cohort during 1950-2008. These subtypes included ischemic heart disease (IHD), valvular heart disease (VHD), hypertensive organ damage (HOD) and heart failure (HF).
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Short-term effects of low-LET radiation on the endothelial barrier: Uncoupling of PECAM-1 and the production of endothelial microparticles.
Templin T, Sharma P, Guida P, Grabham P. Radiat Res. 2016 Dec 1. [Epub ahead of print]
Summary:

A study from the laboratory of Dr Peter Grabham is one of the first published reports of the production and release of "cell dust" also known as endothelial micro-particles (EMPs) by the microvasculature in response to radiation. The response was first recognized as an acute dip in trans-endothelial electrical resistance 3 hours after exposure to doses as low as 2 Gy Gamma radiation. The report shows that photons (Gamma and X rays), but not low-LET charged particles (Protons and Helium ions), caused the acute uncoupling of the cell adhesion molecule PECAM-1 and the production and release of EMPs containing PECAM-1 from human endothelial monolayers and 3-D microvessel models. This response occurs at two physiological extremes and is thus likely to occur in vivo under any conditions. Considering the recent interest in PECAM-1 positive EMPs and their possible role in pathological related processes such as platelet aggregation and leukocyte extravasation, the photon-induced uncoupling of PECAM-1 and the production and release of EMPs into the blood stream has the potential to be of highly significant clinical importance.

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Apollo lunar astronauts show higher cardiovascular disease mortality: Possible deep space radiation effects on the vascular endothelium.
Delp MD, Charvat JM, Limoli CL, Globus RK, Ghosh P. Sci Rep. 2016 Jul 28;6:29901.
Summary:
The primary purpose of this study was to determine whether mortality rates due to cardiovascular disease (CVD), cancer, accidents and all other causes of death differ in (1) astronauts who never flew orbital missions in space, (2) astronauts who flew only in low Earth orbit (LEO), and (3) Apollo lunar astronauts, the only humans to have traveled beyond Earth's magnetosphere. Results show there were no differences in CVD mortality rate between non-flight (9%) and LEO (11%) astronauts. However, the CVD mortality rate among Apollo lunar astronauts (43%) was 4-5 times higher than in non-flight and LEO astronauts. Measurements of simulated weightlessness and space-relevant total-body irradiation on vascular responsiveness in mice are interpreted to show that irradiation may lead to occlusive artery disease, and may be an important risk factor for CVD among astronauts exposed to deep space radiation.
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No evidence for an increase in circulatory disease mortality in astronauts following space radiation exposures.
F.A. Cucinotta et al., Life Sciences in Space Research (2016).
Summary:
Important deficiencies in the methods and assumptions on radiation exposures used by Delp et al. are discussed and judged to cast serious doubt on their conclusions.
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Mechanisms of phosphene generation in ocular proton therapy as related to space radiation exposure.
Chuard D, Anthonipillai V, Dendale R, Nauraye C, Khan E, Mabit C, De Marzi L, Narici L, Life Sci Space Res. 2016, Jul 7. [Article in Press]
Summary:
Cosmic rays are well known to produce anomalous visual percepts in astronauts. Nevertheless, we do not yet have a detailed idea of the mechanisms by which this happens. The development of ground-based medical facilities using proton beams represents a great opportunity to study this phenomenon much more easily than in space. This article is about a study carried out at ICPO, a proton therapy centre in France. About 60% of the patients treated there report anomalous light flashes. Our analysis suggests a possible twofold mechanism of phosphene generation based on (i) light due to nuclear interactions and radioactive decay and (ii) direct excitation of the nerve fibres in the back of the eye and/or chemiluminescence near the retina.
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Effects of High-LET Radiation Exposure and Hindlimb Unloading on Skeletal Muscle Resistance Artery Vasomotor Properties and Cancel- lous Bone Microarchitecture in Mice.
Ghosh, P., Behnke, B. J., Stabley, J. N., Kilar, C. R., Park, Y., Narayanan, A., Alwood, J. S., Shirazi-Fard, Y., Schreurs, A-S., Globus, R. K. and Delp, M. D. . Radiat. Res. 185, 257- 266 (2016).
Summary:
Both hindlimb unloading, a rodent model to simulate a weightless environment, and high-LET total-body irradiation, an exposure paradigm to simulate deep space radiation, have been previously shown to induce endothelial cell dysfunction in arterial vessels. The purpose of this study was to determine whether the combination of these two environmental factors has a greater impact on vascular function than each produce individually. Both hindlimb unloading and total-body irradiation depressed endothelium-dependent vasodilation, and the combination of the two induced an even greater endothelial dysfunction. If these findings translate to humans, the results suggest that the interaction of weightlessness and deep space radiation to impair vascular endothelial cell function may create greater risk for occlusive arterial disease in astronauts than previously estimated.
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Space radiation and cardiovascular disease risk.
Boerma M, Nelson GA, Sridharan V, Mao XW, Koturbash I, Hauer-Jensen M. World J Cardiol. 2015 Dec 26;7(12):882-8. Review.
Summary:
This review article provides an overview of our current knowledge of the effects of space radiation on the cardiovascular system. To introduce this topic, general characteristics of ionizing radiation are described, and cardiovascular effects of ionizing radiation on Earth are summarized. While knowledge of the health effects of exposure to ionizing radiation on Earth can be obtained from clinical and epidemiological studies, estimates of the health risks of space radiation are largely obtained from animal and cell culture models. Because these types of experiments have begun fairly recently, the identification of potential pharmacological countermeasures to prevent or mitigate these effects is still in its infancy.
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A priming dose of protons alters the early cardiac cellular and molecular response to 56Fe irradiation.
Ramadan SS, Sridharan V, Koturbash I, Miousse IR, Hauer-Jensen M, Nelson GA, Boerma M., published in Life Sci Space Res. 2016 Dec 14. [Article in Press]
Summary:
This study used a mouse model to examine some of the potential effects of space radiation on the heart. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we examined the effects of a low dose of protons (0.1 Gy, 150 MeV) to a subsequent higher dose of iron ions (0.5 Gy, 600 MeV/n). The two radiation exposures were 24 hours apart. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine the expression of protein markers. Exposure to iron ions caused an increase in markers of cardiac remodeling, inflammatory infiltration, and cell death. Exposure to protons 24 hours before iron ions prevented all of the responses to iron ions. These results indicate that a low dose of protons may prime the heart to respond differently to a subsequent exposure to heavy ions.
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Effects of dietary aspirin on high-LET radiation-induced prostaglandin E2 levels and gastrointestinal tumorigenesis in Apc1638N/+ mice

Suman S, Kumar S, Moon BH, Angdisen J, Kallakury BVS, Datta K, Fornace AJ Jr. and published in Life Sci Space Res (Amst). 2021 Nov;31:85-91.

Summary:

Exposure to high-LET heavy-ions during deep space missions will probably increase gastrointestinal (GI)-cancer mortality risk for astronauts, and by one estimate may exceed the current NASA’s limit of < 3% REID (Radiation exposure-induced death) from cancer. Development of a safe and effective countermeasure agent against heavy-ion radiation induced GI-tumorigenesis would be of obvious benefit – particularly if chronic use is well tolerated. For example, multiple studies have reported reduced colorectal cancer incidence with chronic aspirin intake. Previously, we reported that upregulation of cyclooxygenase-2/prostaglandin E2 (COX2/PGE2) signaling coincides with persistent inflammation and GI-tumorigenesis after heavy-ion radiation exposure. Therefore, aspirin, a well-known inhibitor of the COX/PGE2 pathway, was evaluated as a potential countermeasure against heavy ion-induced GI- tumorigenesis using a surrogate mouse model of human GI cancer i.e. Apc1638N/+ mice. Animals were fed either standard or aspirin supplemented diet starting at 4 weeks of age until the end of the study. After one month on the aspirin diet, mice were exposed to heavy-ion (28Si-ion) radiation, and intestinal tumor number, cluster, size, and serum PGE2 levels were analyzed. Aspirin led to a significant reduction in serum PGE2, however, aspirin did not reduce heavy-ion induced GI-tumorigenesis. In summary, this study suggests that aspirin is not effective in the prevention of heavy-ion induced GI-tumorigenesis. While COX2/PGE2 signaling was reduced by aspirin, our study indicates that other cancer-associated pathways can drive HZE ion tumorigenesis.

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Transcriptomic analysis links hepatocellular carcinoma (HCC) in HZE ion irradiated mice to a human HCC subtype with favorable outcomes
Ding LH, Yu Y, Edmondson EF, Weil MM, Pop LM, McCarthy M, Ullrich RL, Story MD. Sci Rep. 2021 Jul 7; 11(1): 14052
Summary:
High-charge, high-energy ion particle (HZE) radiations are extraterrestrial in origin and characterized by high linear energy transfer (high-LET), which causes more severe cell damage than low-LET radiations like γ-rays or photons. High-LET radiation poses potential cancer risks for astronauts on deep space missions, but the studies of its carcinogenic effects have relied heavily on animal models. It remains uncertain whether such data are applicable to human disease. Here, we used genomics approaches to directly compare high-LET radiation-induced, low-LET radiation-induced and spontaneous hepatocellular carcinoma (HCC) in mice with a human HCC cohort from The Cancer Genome Atlas (TCGA). We identified common molecular pathways between mouse and human HCC and discovered a subset of orthologous genes (mR-HCC) that associated high-LET radiation-induced mouse HCC with a subgroup (mrHCC2) of the TCGA cohort. The mrHCC2 TCGA cohort was more enriched with tumor-suppressing immune cells and showed a better prognostic outcome than other patient subgroups.
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Effects of low dose space radiation exposures on the splenic metabolome
Laiakis EC, Shuryak I, Deziel A, Wang YW, Barnette BL, Yu Y, Ullrich RL, Fornace AJ Jr, Emmett MR., Int J Mol Sci. 2021 Mar 17;22(6):3070.
Summary:
In this study, we investigated the effects in the overall metabolism of three different low dose radiation exposures (γ-rays, ¹⁶O, and ⁵⁶Fe) in spleens from male C57BL/6 mice at 1, 2, and 4 months after exposure. Forty metabolites were identified with significant enrichment in purine metabolism, tricarboxylic acid cycle, fatty acids, acylcarnitines, and amino acids. Early perturbations were more prominent in the γ irradiated samples, while later responses shifted towards more prominent responses in groups with high energy particle irradiations. Regression analysis showed a positive correlation of the abundance of identified fatty acids with time and a negative association with γ-rays, while the degradation pathway of purines was positively associated with time. Taken together, there is a strong suggestion of mitochondrial implication and the possibility of long-term effects on DNA repair and nucleotide pools following radiation exposure.
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Dose fractionation during puberty is more detrimental to mammary gland development than an equivalent acute dose of radiation exposure
Wiedmeyer B, To J, Sridharan DM, Chien LC, Snijders AM, Mori H, Pluth JM. Int J Radiat Oncol Biol Phys. 2021 Apr 1;109(5):1521-32.
Summary:
In this work we have investigated using a mouse model system how two types of radiation dose regimens may differentially impact mammary organ formation during an especially sensitive window in development, puberty. Our data revealed that fractionated radiation exposures produced greater immune and mammary defects as compared to controls and that these effects were more pronounced in the more radiation sensitive, BALB/c mice. Together, these findings suggest that fractionated low dose exposures are potentially more damaging to organ development as compared to an equivalent single acute exposure and that genetic background is an important parameter that can modify the severity of these effects.
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Tumor aggressiveness is independent of radiation quality in murine hepatocellular carcinoma and mammary tumor models
Udho EB, Huebner SM, Albrecht DM, Matkowskyj KA, Clipson L, Hedican CA, Koth R, Snow SM, Eberhardt EL, Miller D, Van Doorn R, Gjyzeli G, Spengler EK, Storts DR, Thamm DH, Edmondson EF, Weil MM, Halberg RB, Bacher JW. in Int J Radiat Biol. 2021 Mar 15;1-35. Online ahead of print.
Summary:
The goal of this research is to test whether high-LET HZE radiation induced tumors are more aggressive. Murine models of mammary and liver cancer were used to compare the impact of exposure to 0.2Gy of 300MeV/n silicon ions, 3 Gy of γ-rays or no radiation. For the mammary cancer models, there was no significant change in the tumor latency or metastasis in silicon-irradiated mice compared to controls. For the liver cancer models, we observed an increase in tumor incidence but not tumor aggressiveness in irradiated mice. Thus, enhanced aggressiveness does notappear to be a uniform characteristic of all tumors in HZE-irradiated animals.
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Inflammation mediates the development of aggressive breast cancer following radiotherapy
Ma L, Gonzalez-Junca A, Zheng Y, Ouyang H, Illa-Bochaca I, Horst KC, Krings G, Wang Y, Fernandez-Garcia I, Chou W, Barcellos-Hoff MH. in Clin Cancer Res. 2021 Jan 5. Online ahead of print.
Summary:
The mechanisms by which radiation increases cancer risk include targeted effects in the irradiated cell, like mutation, and non-targeted effects that signal among cells in response to damage. The research reported by Ma et al. evaluates the contribution of targeted versus non-targeted radiation effects to the development of breast cancer. In women treated with radiation for early cancer, breast cancer risk is significantly elevated, but more importantly, radiation-preceded breast cancer is a more aggressive disease. Ma et al. analyzed the composition of breast cancers arising in women who treated for Hodgkin's lymphoma and used a series of genetic-chimera mouse experiments to examine how a single, low dose radiation exposure altered mammary carcinogenesis. They show that the tumor microenvironment of radiation-preceded breast cancer was markedly immunosuppressive compared to that of age-matched sporadic breast cancer as evidenced by high levels of cyclooxygenase-2 and transforming growth factor-beta and low lymphocytic infiltrate. Mouse tumors arising after irradiation were also characterized by an immunosuppressive microenvironment. A series of experiments showed that this feature of radiation-preceded breast cancers occurred even when the epithelium was not irradiated and in the absence of adaptive immunity. However, the immunosuppressive features were eliminated by administration of a short course of aspirin after irradiation to reduce low-level inflammation. These studies support anti-inflammatory treatments as a means to reduce aggressive cancers that occur after radiation exposure.
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Characterization of exosome release and extracellular vesicle-associated miRNAs for human bronchial epithelial cells irradiated with high charge and energy ions
Li Z, Jella KK, Jaafar L, Moreno CS, Dynan WS. Life Sci Space Res. 2020 Nov 5. [Article in Press]
Summary:
Exposure of human bronchial epithelial cells to energetic heavy ions, representative of species found in galactic cosmic rays, stimulates exosome release. Preparations enriched for these nanometer-scale extracellular vesicles contain pro-inflammatory damage-associated molecular patterns, together with a variety of microRNAs (miRNAs). The miRNA profile is skewed toward a small number of species involved in cancer initiation and progression, consistent with a role in mediating non-targeted radiation effects.
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Comparative RNA-Seq transcriptome analyses reveal dynamic time-dependent effects of 56Fe, 16O, and 28Si irradiation on the induction of murine hepatocellular carcinoma
Nia AM, Khanipov K, Barnette BL, Ullrich RL, Golovko G, Emmett MR. BMC Genomics. 2020 Jul 1;21(1):453
Summary:
We performed comparative RNA-Seq transcriptomic analyses to assess the carcinogenic effects of 600 MeV/n ⁵⁶Fe (0.2 Gy), 1 GeV/n ¹⁶O (0.2 Gy), and 350 MeV/n ²⁸Si (0.2 Gy) ions in a mouse model for irradiation-induced hepatocellular carcinoma (HCC). C3H/HeNCrl mice were subjected to total body irradiation to simulate space environment HZE-irradiation, and liver tissues were extracted at five different time points post-irradiation to investigate the time-dependent carcinogenic response at the transcriptomic level. A large number of transcripts were found differentially expressed post-HZE irradiation. Additionally, a handful of novel differentially expressed unannotated transcripts were discovered for each HZE ion. Taken together, these findings may provide a better understanding of biological mechanisms underlying risks for HCC after HZE irradiation and may also have important implications for the discovery of potential countermeasures against and identification of biomarkers for HZE-induced HCC.
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Protons Show Greater Relative Biological Effectiveness for Mammary Tumorigenesis with Higher ERα- and HER2-Positive Tumors Relative to γ-rays in APC^Min/+ Mice
Suman, S., Shuryak, I., Kallakury, B., Brenner, D. J., Fornace, A. J., Jr, Johnson, M. D., & Datta, K. Int J Radiat Oncol Biol Phys. 2020;107(1):202-211.
Summary:
This study provides insight into proton radiation-induced mammary carcinogenesis that has implications for long-duration deep space missions and breast cancer risk in astronauts. In this paper, we demonstrated that the APC^Min/+ mouse model has a good signal-to-noise ratio for proton-induced mammary tumorigenesis, which also correlates with dysregulated APC observed in a substantial portion of human breast cancer patients. Our study also establishes that estrogen signaling through ER? and HER2 are actively involved in promoting breast cancer after radiation exposures, so this can provide leads for developing strategies to block aspects of the estrogenic response, which could benefit astronauts as well as radiotherapy patients. Although this study establishes the female APC^Min/+ mouse as a relevant model for space radiation-induced mammary tumorigenesis studies, further experiments using GCR and SPE beams are required to address the uncertainties in breast cancer risk modeling for long duration space missions.
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Genomic mapping in outbred mice reveals overlap in genetic susceptibility for HZE ion- and γ-ray-induced tumors
Edmondson EF, Gatti DM, Ray FA, Garcia EL, Fallgren CM, Kamstock DA, Weil MM. Sci Adv. 2020 Apr;6(16):eaax5940.
Summary:
Using a mouse model of genetic diversity, we find that the histotype spectrum of HZE ion-induced tumors is similar to the spectra of spontaneous and γ-ray-induced tumors and that the genomic loci controlling susceptibilities overlap between groups for some tumor types. Where it occurs, this overlap indicates shared tumorigenesis mechanisms regardless of the type of radiation exposure and supports the use of human epidemiological data from γ-ray exposures to predict cancer risks from galactic cosmic rays.
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Bcl2-induced DNA replication stress promotes lung carcinogenesis in response to space radiation
Xie M, Park D, Sica GL, Deng X. and published in Carcinogenesis. 2020 Mar 11. [Epub ahead of print]
Summary:
Bcl2 not only functions as a potent antiapoptotic molecule but also as an oncogenic protein that induces DNA replication stress. To test the role and mechanism of Bcl2 in high-LET space radiation-induced lung carcinogenesis, we created lung-targeting Bcl2 transgenic C57BL/6 mice using the CC10 promoter to drive Bcl2 expression selectively in lung tissues. Intriguingly, lung-targeting transgenic Bcl2 inhibits ribonucleotide reductase activity, reduces dNTP pool size and retards DNA replication fork progression in mouse bronchial epithelial cells. After exposure of mice to space radiation derived from ⁵⁶iron, ²⁸silicon or protons, the incidence of lung cancer was significantly higher in lung-targeting Bcl2 transgenic mice than in wild type mice, indicating that Bcl2-induced DNA replication stress promotes lung carcinogenesis in response to space radiation. The findings provide some evidence for the relative effectiveness of space radiation and Bcl-2 at inducing lung cancer in mice.
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Aggressive mammary cancers lacking lymphocytic infiltration arise in irradiated mice and can be prevented by dietary intervention.
Omene C, Ma L, Moore J, Ouyang H, Illa-Bochaca I, Chou W, Patel MS, Sebastiano C, Demaria S, Mao JH, Karagoz K, Gatza ML, Barcellos-Hoff MH. Cancer Immunol Res. 2019 Dec 12. [Epub ahead of print]
Summary:
Using a radiation-genetic mammary chimera model we developed to evaluate how carcinogenesis is affected by radiation-induced, non-mutational processes, we examined the relationship between tumor microenvironment (TME) components and breast cancer phenotypes arising from Trp53-null mammary chimeras as a function of two factors, radiation type and host age. Densely ionizing radiation (DIR), which is present in the space radiation environment and used in radiation oncology, has potentially greater carcinogenic effect compared to sparsely ionizing radiation (SIR) that is prevalent on earth. Because occupational exposure (e.g. astronauts) and most radiotherapy occur in adults, here, we considered age at exposure as a factor. Here we show that compared to our prior studies in 10 week-old mice, the effect of radiation quality was greater in aged mice (10 months old), demonstrating that DIR was more effective than SIR at inducing aggressive tumors. However, tumors arising in both DIR- and SIR-irradiated hosts were characterized by rapid growth rate and an immunosuppressive TME, both of which we have previously reported in young mice. Only tumors arising in irradiated mice were devoid of lymphocytic infiltrates, suggesting that non-mutational, radiation effects promoted immune evasion. This prompted us to use caffeic acid phenethyl ester (CAPE), the major active component in propolis, a honeybee product that possesses immunomodulatory (anti-inflammatory) and anti-cancer properties. CAPE administered post-radiation in the diet of 10-week old mice prevented establishment of aggressive tumors with an immunosuppressive TME. These studies suggest that systemic inflammation and erosion of antitumor immunity elicited by radiation can be targeted after exposure to prevent aggressive tumors.
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Lung cancer progression using fast switching multiple ion beam radiation and countermeasure prevention
Luitel K, Kim SB, Barron S, Richardson JA, Shay JW. Life Sci Space Res. 2019 Aug 1. [Article in Press]
Summary:
We exposed the whole body of a lung cancer susceptible mouse model (K-ras^LA-1) to three sequential ion beams: Protons (H) (120 MeV/n) 20 cGy, Helium (He) (250 MeV/n) 5.0 cGy, and Silicon (Si) (300 MeV/n) 5.0 cGy with a dose rate of 0.5 cGy/min and a total dose of 30 cGy in two different orders: 3B-1 (H→He→Si) and 3B-2 (Si→He→H) and used 30 cGy H single-ion beam as a reference. In this study we show that whole-body irradiation with H→He→Si increases the incidence of premalignant lesions and systemic oxidative stress in mice 100 days post-irradiation more than (Si→He→H) and H only irradiation. Additionally, we observed an increase in adenomas with atypia and adenocarcinomas in H→He→Si irradiated mice but not in (Si→He→H) or H (30 cGy) only irradiated mice. When we used the H→He→Si irradiation sequence but skipped a day before exposing the mice to Si, we did not observe the increased incidence of cancer initiation and progression. We also found that a non-toxic anti-inflammatory, anti-oxidative radioprotector (CDDO-EA) reduced H→He→Si induced oxidative stress and cancer initiation almost back to baseline. Thus, exposure to H→He→Si elicits significant changes in lung cancer initiation that can be mitigated using CDDO-EA.
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Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine
Kumar S, Suman S, Fornace AJ Jr, Datta K., published in Proc Natl Acad Sci U S A. 2018 Oct 1. [Epub ahead of print]
Summary:
Kumar report that HZE ion radiation leads to important long-term perturbations in intestinal function. The Georgetown group showed ten years ago that HZE ions induce a persistent oxidative-stress state and pro-inflammatory phenotype in gastrointestinal (GI) and other tissues. The Shay laboratory (a member of their GI NSCOR program) further expanded on this in a 2015 report in Oncogene showing changes in gene expression in GI tissues reminiscent of the senescence-associated inflammatory response (SIR) after space radiation. In the current publication, the authors now show that HZE ions trigger perturbations in key proteins and often their transcript levels that are known to control normal GI epithelial cell maturation and function. Interestingly, cell migration along the crypt-villus axis in small intestine was persistently decreased after a low dose of 56Fe radiation relative to control and γ-rays. Wnt/β-catenin and its downstream EphrinB/EphB signaling are key to GI epithelial proliferation and positioning during migration, and both were upregulated. In addition, factors involved in cell polarity, cell adhesion, and cell-extracellular matrix interactions were persistently downregulated. These changes were accompanied by changes in barrier function and nutrient absorption factors, as well as increased intestinal tumorigenesis. Along with these changes, increasing levels of oxidative stress and DNA damage were seen up to a year after irradiation. These effects correlated with higher levels of senescent cells in GI crypts and features of the senescence-associated secretory phenotype (SASP) and the SIR. A working model was proposed whereby HZE ions cause sufficient damage to induce senescent GI cells, and that senescent-cell associated signaling molecules trigger long-term oxidative stress and a feedback loop leading to a gradual increase in senescent cells in GI crypts with increasing levels of DNA damage.
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Exposure to galactic cosmic radiation compromises DNA repair and increases the potential for oncogenic chromosomal rearrangement in bronchial epithelial cells.
Li Z, Jella KK, Jaafar L, Li S, Park S, Story MD, Wang H, Wang Y, Dynan WS. Sci Rep. 2018 Jul 23;8(1):11038.
Summary:
The authors of this study investigated persistent effects of galactic cosmic ray exposure on DNA repair capacity in human lung-derived epithelial cells, Replicate cell cultures were irradiated with 48-Ti ions or reference γ-rays, then challenged by expression of a Cas9/sgRNA pair that creates double-strand breaks simultaneously in the EML4 and ALK loci. Misjoining, which creates an EML4-ALK fusion oncogene, was significantly elevated in 48-Ti-irradiated populations relative to controls or γ-ray-irradiated samples and was frequently accompanied by deletions, consistent with a shift toward error-prone alternative nonhomologous end joining repair.
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Charged-Iron-Particles Found in Galactic Cosmic Rays are Potent Inducers of Epithelial Ovarian Tumors.
Mishra B, Lawson GW, Ripperdan R, Ortiz L, Ludere U. Radiation Research 190(2):142-150. 2018.
Summary:
Astronauts traveling in deep space are exposed to radioactive particles, such as iron ions, from galactic cosmic rays. We previously showed that irradiation of adult female mice with iron ions destroys ovarian follicles, causing premature ovarian failure, and we hypothesized that these mice would subsequently develop ovarian tumors. To test this, we aged female mice for 15 months after irradiation with 50 cGy iron ions, which is about the total dose of radiation astronauts would receive during a 3 year Mars mission. Irradiated mice had a 4-fold increased incidence of ovarian tumors compared to non-irradiated controls. The tumors were positive for cytokeratin, indicating that they were epithelial tumors. Most human ovarian cancers are also epithelial. These results raise concerns about ovarian tumors as possible late consequences of deep space travel in female astronauts.
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High-LET Radiation Increases Tumor Progression in a K-Ras-Driven Model of Lung Adenocarcinoma.
Asselin-Labat ML, Rampersad R, Xu X, Ritchie ME, Michalski J, Huang L, Onaitis MW. Radiation Research. Nov 2017; 188(5):562-570.
Summary:
A mouse model of lung adenocarcinoma driven by oncogenic K-Ras was used to ascertain the effect of low- and high-LET radiation on tumor formation. We observed increased tumor progression and tumor cell proliferation after single dose or fractionated high-LET doses, which was not observed in mice exposed to low-LET radiation. Location of the tumor nodules was not affected by radiation, indicating that the cell of origin of K-Ras-driven tumors was the same in irradiated or nonirradiated mice. Gene expression analysis revealed an upregulation of genes involved in cell proliferation and DNA damage repair. This study provides evidence that exposure to a single dose or fractionated doses of high-LET radiation induces molecular and cellular changes that accelerate lung tumor growth.
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Lesion complexity drives age related cancer susceptibility in human mammary epithelial cells.
Sridharan DM, Enerio S, Pluth JM. Aging (Albany NY). 2017 Feb 28. [Epub ahead of print]
Summary:

Age is a key parameter that impacts cancer susceptibility to carcinogenic exposures. However the effects of complexity of the damage induced on mechanisms that maintain genomic integrity and its relationship to age are unclear. In recent work published in the Aging Journal, titled "Lesion complexity drives age related cancer susceptibility in human mammary epithelial cells", Dr Janice Pluth's lab at LBL have attempted to address this gap by employing radiation as a tool to generate lesions of different complexity in a wide cohort of normal primary human mammary epithelial cell strains derived from women of various ages. They note unique dose and age related changes in the frequency of centrosome aberrations and stem cell populations following exposures that cause complex damages. These studies suggest that complex damages can threaten the genome stability of the stem cell population in older people. These effects will likely be exacerbated by age-associated deterioration in function and accentuate age-related cancer predisposition.

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High energy particle radiation-associated oncogenic transformation in normal mice: Insight into the connection between activation of oncotargets and oncogene addiction.
Aravindan N, Aravindan S, Manickam K, Natarajan M. Sci Rep. 2016 Nov 23;6:37623.
Summary:
This article describes a possible course of oncogenic transformation of normal tissue in wild type C57BL/6 mice after high energy particle radiation exposure. The study identified a tissue-specific molecular blue print pertaining to oncogene adduction that could mediate radiogenic cell transformation after high LET radiation. This response was found to be relatively distinct from the low LET radiation response at similar dose equivalence. In addition, this study underscores some of the potential biomarkers that can be pursued to determine the differential response of major organs to different qualities of radiation. The study provides valuable insight in determining human health risk in space and protracted post-treatment normal tissue toxicity.
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Harderian Gland Tumorigenesis: Low-Dose and LET Response.
Polly Y. Chang, Francis A. Cucinotta, Kathleen A. Bjornstad, James Bakke, Chris J. Rosen, Nicholas Du, David G. Fairchild, Eliedonna Cacao, and Eleanor A. Blakely (2016) Radiation Research: May 2016, Vol. 185, No. 5, pp. 449-460.
Summary:
This study fills gaps in the historical Harderian gland tumorigenesis data at 260 MeV/u silicon (LET ~70 keV/μm) and 1,000 MeV/u titanium (LET ~100 keV/μm, single doses and fractionated exposures to simulate chronic exposure). Modeling of the data show that a nontargeted effect model provides a better fit than the targeted effect model, providing important information at space-relevant doses of heavy ions.
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Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses.
Kim SB, Bozeman RG, Kaisani A, Kim W, Zhang L, Richardson JA, Wright WE, Shay JW. Oncogene. 2015 Oct 19. [Epub ahead of print]
Summary:
We used a mouse model of colon cancer susceptibility (CPC;Apc) to determine the biological effects of equivalent doses of proton (2Gy, 50 MeV/n, 20 cGy/min), protons provided at a lower dose rate as a solar particle event (SPE) simulation (2 Gy, 50-150 MeV/n, 1.7 cGy/min), and as x-rays (2 Gy 250 kVp, 20 cGy/min). While the unirradiated control mice had a 6.3% invasive cancer incidence, the x-ray treated cohort had a slight increase to 8.0% invasive cancers. The single acute dose proton irradiated mice had an 11.1% incidence of invasive cancers suggesting that protons may cause a modest increase in advanced cancers compared to terrestrial radiation in a mouse model of colon cancer susceptibility. Significantly, the SPE simulation (2 Gy protons provided over 2 hrs in 62 mice) resulted in a highly significant increase in the incidence of invasive colon cancers (25.8%). In the tumor-adjacent normal colonic tissues in the mice exposed to the SPE simulation (100 days post-irradiation) there was an increase in a panel of senescence-associated inflammatory response genes (SIRs). To test if inflammatory responses were involved in the increase in invasive cancers in the SPE irradiated mice we provided in lab chow an anti-inflammatory, anti-oxidant countermeasure (CDDO-EA, a synthetic triterpenoid) 3 days prior to SPE irradiation without additional CDDO-EA following irradiation. We observed a decreases in the inflammatory responses and the frequency of invasive cancers in the SPE treated mice, which was reduced to 15.2% with no side effects to any mice. CDDO analogs are currently in several human clinical trials with a good safety profile and may be important in reducing proton and HZE-ion exposure-associated tumor initiation and progression. Experiments are in progress using lower SPE simulation doses and other HZE-ions in a mouse model of colon cancer or lung cancer susceptibility. In addition, experiments to test if CDDO-EA is also a mitigator of radiation exposure are in progress.
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Combined exposure to protons and 56Fe leads to overexpression of Il13 and reactivation of repetitive elements in the mouse lung.
Nzabarushimana E, Prior S, Miousse IR, Pathak R, Allen AR, Latendresse J, Olsen RHJ, Raber J, Hauer-Jensen M, Nelson GA, Koturbash I..Life Sci Space Res. 2015 Aug 18.
Summary:
While previous studies have been devoted primarily to the effects of a single source of space radiation, there is an imperative need to utilize exposures to two or more sources to better simulate the occupational exposure that will be encountered by astronauts. In this study, the authors aimed to investigate the pro-fibrotic and epigenetic effects of exposure to protons and/or 56Fe ions in the dose range relevant to a space mission in the mouse lung 1 month after irradiation. Combined exposure to protons and 56Fe did not lead to detectable histopathological changes and increased expression of Tgfβ1 in the mouse lung. At the same time, combined exposure to protons and 56Fe resulted in substantially increased levels of Il13, a gene whose overexpression alone is sufficient to induce non-allergic asthma or induction of fibrosis, independently of Tgfβ1. Furthermore, decreased expression of the major maintenance DNA methyltransferase Dnmt1 and reactivation of repetitive elements - retrotransposons LINE-1 and SINE B1, and major and minor satellites were detected in the lungs of mice exposed to protons and 56Fe. The results of this study indicate that combined exposure to protons and 56Fe ions in the dose range relevant to a space mission may exert more severe pulmonary effects than exposure to either of these sources alone.
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Elucidation of changes in exposed human bronchial epithelial cells to radiations of increasing LET.
Ding LH, Park S, Xie Y, Girard L, Minna JD, Story MD. Mutagenesis. 2015 May 22. [Epub ahead of print]
Summary:
In this study, we investigated the role of ionizing radiation with increasing LETs in transforming human bronchial epithelial cells that varied in their oncogenic potential because of their genetic background. HBEC3KT cell lines were immortalized by overexpressing CDK4 and hTERT while the syngeneic HBEC3KT-R53RAS contain an additional p53 knockdown vector and overexpress mutant kRAS. Baseline transformation frequency for HBEC3KT is 10 times lower than its progressed counterpart HBEC3KT-P53RAS. As early as 6 day post-IR, cellular transformation was 1-2 logs higher increased in the oncogenically progressed HBEC3KT-p53RAS cells while gene expression profiles identified pathways that contribute to transformation including HIF-1α, mTOR, IGF-1, RhoA and the ERK/MAPK pathways upregulated in the progressed cell line. Our data suggested greater risk of lung cancer for heavy particles exposure in individuals harboring cancer-prone genetic changes.
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Ionizing radiation stimulates expression of pro-osteoclastogenic genes in marrow and skeletal tissue.
Alwood JS, Shahnazari M, Chicana B, Schreurs AS, Kumar A, Bartolini A, Shirazi-Fard Y, Globus RK. J Interferon Cytokine Res. 2015 Mar 3. [Epub ahead of print]
Summary:
Irradiation causes a very rapid loss of mineralized bone tissue via increased resorption by osteoclasts. In this study, adult mice were exposed to HZE (56Fe) or 137Cs radiation to evaluate expression levels of genes known to mediate osteoclastogenesis. This work shows a time-dependent, radiation-induced increase in skeletal expression of Rankl, the obligate cytokine for osteoclast differentiation, as well as other pro-resorption cytokines (Mcp1, Tnf, Csf1, Il6), markers of osteoclast activation (Acp5, Ctk, NfatC1), and oxidative stress responses (nfe2l2). These molecular responses to radiation preceded (< 3 days) the manifestation of bone loss (3-7 days). The findings have relevance to skeletal fragility caused by radiation exposure either on Earth or in space.
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Relative Effectiveness at 1 Gy after Acute and Fractionated Exposures of Heavy Ions with Different Linear Energy Transfer for Lung Tumorigenesis.
Ya Wang, Xiang Wang, Alton B. Farris III, Ping Wang, Xiangming Zhang, Hongyan Wang, and (2015), Radiation Research: February 2015, Vol. 183, No. 2, pp. 233-239.
Summary:
Lung cancer is the most commonly diagnosed cancer as well as the leading cause of cancer death in humans; therefore, studying radiation-induced lung tumorigenesis is critical for estimating the risk of space radiation to astronauts. In this study, we show that all these tested HZE particles (iron, silicon, oxygen) induced a higher incidence of lung tumorigenesis than x-rays, the relative effectiveness at 1 Gy was > 6 and silicon exposure induced more aggressive lung tumors.
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Low- and High-LET Radiation Drives Clonal Expansion of Lung Progenitor Cells In Vivo.
Farin, A. M., Manzo, N. D., Terry, K. L., Kirsch, D. G. and Stripp, B. R. Radiat. Res. 183,124-132 (2015).
Summary:
Astronauts are exposed to varying doses and qualities of ionizing radiation during space travel. However, little is known about the effects of ionizing radiation on epithelial progenitor cells that maintain the respiratory system. We hypothesized that ionizing radiation exposure would compromise progenitor cell function leading to changes in their capacity for epithelial maintenance. We assessed progenitor cell function and capacity for clonal expansion following exposure to either X-rays or 56Fe using genetic lineage tracing in combination with in vitro and in vivo assays. We found that progenitor cells were lost in a radiation dose and quality-dependent manner, but surviving progenitor cells undergo significant clonal expansion for epithelial maintenance. Based on our data, we propose a model in which radiation induces a dose-dependent decrease in the pool of available progenitor cells, leaving fewer progenitors able to maintain the airway long-term.
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Densely Ionizing Radiation Acts via the Microenvironment to Promote Aggressive Trp53 Null Mammary Carcinomas.
Illa-Bochaca I, Ouyang H, Tang J, Sebastiano C, Mao JH, Costes SV, Demaria S, Barcellos-Hoff MH. Cancer Res. 2014 Oct 10. pii: canres.1212.2014.
Summary:
Ionizing radiation is a complete carcinogen, able to both initiate malignant transformation by causing mutations in cells and to promote cancer progression by acting systemically via the tissue microenvironment. Here, the authors use a radiation mammary chimera, in which the host is irradiated but the mammary epithelium is not, to demonstrate that densely ionizing radiation (350 MeV/amu Si) acts via the microenvironment to promotes development of aggressive mammary tumors. Compared to sham-irradiated mice, a class of hormone receptor negative tumors grew faster and were more metastic in Si-particle irradiated mice. This study suggests that the response of tissues to densely ionizing radiation is an important component of its carcinogenic action; unlike mutations per se, the response of the microenvironment is amenable to countermeasures.
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Dermatopathology effects of simulated SPE radiation exposure in the porcine model.
Sanzari JK, Diffenderfer ES, Hagan S, Billings PC, Gridley DS, Seykora JT, Kennedy AR, Cengel KA. Dermatopathology the porcine model. Life Sci Space Res. 2015 Jun 18.
Summary:
Solar particle event radiation increases an astronaut's risk of the acute radiation syndrome, prodromal effects, and/or skin damage. In this article, solar particle event-like radiation was simulated with either electron or proton radiation. Minipig skin was microscopically evaluated after nonhomogenous, total body radiation exposure at skin doses as high as 10 Gy. Maximum melanin deposition occurred at 14 days post-radiation with increased proliferation and skin thickening as well as DNA damage as late as 7 days post-radiation, indicative of post-inflammatory hyperpigmentation. These acute changes may be part of or trigger a larger inflammatory response, which may pose a hazard during deep space travel, especially if exacerbated by additional space environment factors.
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Effects of High- and Low-LET Radiation on Human Hematopoietic System Reconstituted in Immunodeficient Mice.
Hoehn D, Pujol-Candell M, Young EF, Serban G, Shuryak I, Maerki J, Xu Z, Chowdhury M, Luna AM, Vlad G and Smilenov LB. Radiat Res. 191, 162-175 (2019).
Summary:
Over the last 50 years, a number of important physiological changes in humans who have traveled on spaceflights have been catalogued. Of major concern are the short- and long-term radiation-induced injuries to the hematopoietic system that may be induced by high-energy galactic cosmic rays encountered on interplanetary space missions. To collect data on the effects of space radiation on the human hematopoietic system in vivo, we used a humanized mouse model. In this study, we irradiated humanized mice with 0.4 Gy of 350 MeV/n 28Si ions, a dose that has been shown to induce tumors in tumor-prone mice and a reference dose that has a relative biological effectiveness of 1 (1 Gy of 250-kVp X rays). Cell counts, cell subset frequency and cytogenetic data were collected from bone marrow spleen and blood of irradiated and control mice at short-term (7, 30 and 60 days) and long-term (6-7 months) time points postirradiation. The data show a significant short-term effect on the human hematopoietic stem cell counts imparted by both high- and low-LET radiation exposure. The radiation effects on bone marrow, spleen and blood human cell counts and human cell subset frequency were complex but did not alter the functions of the hematopoietic system. The long-term data acquired from high-LET irradiated mice showed complete recovery of the human hematopoietic system in all hematopoietic compartments. The combined results demonstrate that, in spite of early perturbation, the longer term effects of high-LET radiation are not detrimental to human hematopoiesis in our system of study.
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A Report on Animal Experimentation at the Frontiers of Molecular, Cellular, and Tissue Radiobiology

Summary:
A select panel, chaired by Mina Bissell, Lawrence Berkeley National Laboratory, evaluated the extent to which experiments with animal models are essential for the development of new and more accurate predictions of risks associated with exposure to HZE particles. The report was published October 7, 1996.
Posted to Background, May 17, 2011.
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From Mice and Men to Earth and Space: Joint NASA–NCI Workshop on Lung Cancer Risk Resulting from Space and Terrestrial Radiation
Jerry Shay, Francis Cucinotta, Frank Sulzman, Norman Coleman, and John Minna
Summary:

A report of a joint NASA-NCI Workshop on lung cancer risk has been published as a Meeting Report in Cancer Research, requiring a subscription, or payment, to view the article: From Mice and Men to Earth and Space: Joint NASA-NCI Workshop on Lung Cancer Risk Resulting from Space and terrestrial Radiation was written by Jerry Shay, Francis Cucinotta, Frank Sulzman, Norman Coleman, and John Minna.
Posted November 15, 2011

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Physical basis of radiation protection in space trave
Marco Durante and Francis Cucinotta.
Summary:
The article provides a detailed review of the space radiation environment, space radiation transport, and shielding.
Posted November 15, 2011
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A Qualitative Investigation of Space Exploration Medical Evacuation Risks.

Almand A, Ko SY, Anderson A, Keller RJ, Zero M, Anderson AP, Laws JM, Lehnhardt K, Easter BD. A Qualitative Investigation of Space Exploration Medical Evacuation Risks. Aerosp Med Hum Perform. 2023 Dec 1;94(12):875-886. doi: 10.3357/AMHP.6262.2023. PMID: 38176032.

Summary:

INTRODUCTION: Exploration beyond low Earth orbit requires innovative solutions to support the crew medically, especially as the opportunity for timely evacuation to Earth diminishes. This includes assessing the risks and benefits that a complicated medical evacuation (MEDEVAC) poses to the injured crewmember, the crew, and the mission. This qualitative study identifies common MEDEVAC risk assessment principles used in spaceflight and other extreme environments to better inform future risk assessment tools and exploration mission concepts. METHODS: Semistructured interviews were conducted with subject matter experts in spaceflight and analog domains, including polar operations, undersea operations, combat medicine, and mountaineering. Transcripts were analyzed using the qualitative method of Thematic Analysis with the technique of consensus, co-occurrence, and comparison. RESULTS: Subject matter experts described 18 themes divided into two main categories: Primary Risk Considerations (e.g., crew, mission, resources, time) and Contributing Factors (e.g., psychological considerations, medical preparation, politics). DISCUSSION: Primary Risk Considerations can assess MEDEVAC risk across mission phases, with Contributing Factors acting as premission tools to adjust those risks. Inter- and intracategory connections identified medical support considerations, MEDEVAC support considerations, and philosophy as the most impactful Contributing Factors. Medical support considerations, psychological considerations, and political considerations were found to have unique aspects given the distances and societal impact of exploration vs. low Earth orbit spaceflight. The Contributing Factor theme of decision making was determined to be unique due to its impacts across both categories. These findings expand current considerations and are important inputs for exploration mission MEDEVAC Concepts of Operations.

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Human Health on the Moon and Beyond and the Results of the Spaceflight for Everybody Symposium

Schneider V, Siegel B, Allen JR. Aerosp Med Hum Perform. 2023; 94(8):634-643.

Summary:

In 2022, the National Aeronautics and Space Administration (NASA) began launching missions to establish a sustainable human presence on the Moon. One key to success will be maintaining human health. In preparation for longer missions with more diverse crews, the Spaceflight for Everybody Symposium was held to review currently known human spaceflight biomedical knowledge, the future of exploration space medicine, and the ability of NASA to manage the spaceflight human health risks and enable exploration. The symposium highlighted the future of precision health/personalized medicine, the possible spaceflight health acute and lifetime illnesses, and the challenge of identifying appropriate prevention, treatment, rehabilitation, and autonomous medical systems for long-duration spaceflight. The symposium was organized to look back at NASA exploration, science, and leadership successes, celebrate NASA women’s leadership, and focus on future Artemis activities, including research and development that will benefit both spaceflight and terrestrial life. NASA current preparations for returning to the Moon have led to increased acknowledgment of the importance of workforce diversity, i.e., to use the best candidate in every work position, including the plan for the first woman and person of color to land on the Moon. NASA is developing plans to use commercial spaceflight research opportunities when the International Space Station is no longer available. Astronaut health decisions will consist of individualized health risk determinations and mitigation strategies and increased medical self-care. Research findings include improved exploration cardiovascular, musculoskeletal, and radiation risk reduction and improved interpersonal support for both astronaut crews and mission control personnel.

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Genomic changes driven by radiation-induced DNA damage and microgravity in human cells

Beheshti A, McDonald JT, Hada M, Takahashi A, Mason CE, Mognato M. and published in Int J Mol Sci. 2021 Oct;22(19):10507. Review

Summary:

The space environment consists of a complex mixture of different types of ionizing radiation and altered gravity that represents a threat to humans during space missions. In particular, individual radiation sensitivity is strictly related to the risk of space radiation carcinogenesis. Therefore, in view of future missions to the Moon and Mars, there is an urgent need to estimate as accurately as possible the individual risk from space exposure to improve the safety of space exploration. In this review, we survey the combined effects from the two main physical components of the space environment, ionizing radiation and microgravity, to alter the genetics and epigenetics of human cells, considering both real and simulated space conditions. Data collected from studies on human cells are discussed for their potential use to estimate individual radiation carcinogenesis risk from space exposure.

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Contemporary biomedical engineering perspective on volitional evolution for human radiotolerance enhancement beyond low-Earth orbit

Borg AM, Baker JE. Synth Biol (Oxf). 2021 Sep 2;6(1):ysab023.

Summary:

Despite developments in the prediction of and protection against radiation events beyond Earth's protective magnetosphere, sustained astronaut exposure to cosmic radiation events remains unavoidable. This danger is a primary focus of NASA when expanding humankind's presence to Mars and beyond. The authors identify various genes which are known to confer radioprotection, and discuss current technological and ethical limitations in incorporating them into astronauts. Even if allowed and perfected, genetic engineering for radiation protection would still necessitate additional solutions for comprehensive safety; some possibilities discussed include synthetic torpor and advanced propulsion systems.

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Space radiation protection countermeasures in microgravity and planetary exploration

Montesinos CA, Khalid R, Cristea O, Greenberger JS, Epperly MW, Lemon JA, Boreham DR, Popov D, Gorthi G, Ramkumar N, Jones JA. Life (Basel). 2021 Aug 14;11(8):829. Review.

Summary:

We summarize the current state of knowledge regarding potential means to reduce the biological effects of space radiation. New countermeasure strategies for exploration-class missions are proposed, based on recent advances in nutrition, pharmacologic, and immune science.

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A proposed change to astronaut exposures limits is a giant leap backwards for radiation protection

Francis A. Cucinotta, Walter Schimmerling, Eleanor A. Blakely, Tom K. Hei, Life Sciences in Space Research, 31, 2021, 59-70,ISSN 2214-5524

Summary:

A recent NAS report, in an effort to minimize differences in age and sex on flight opportunities, suggests a 600 mSv career effective dose limit based on a median estimate to reach 3% cancer fatality for 35-year old females. The NAS report does not call out examples where females would be excluded from space missions planned in the current decade using the current radiation limits at NASA. In addition, there are minimal considerations of the level of risk to be encountered at this exposure level with respect to the uncertainties of heavy ion radiobiology, and risks of cancer, as well as cognitive detriments and circulatory diseases. Furthermore, their recommendation to limit Sieverts and not risk in conjunction with a waiver process is essentially a recommendation to remove radiation limits for astronauts. We discuss issues with several of the NAS recommendations with the conclusion that the recommendations could have negative impacts on crew health and safety, and violate the three principles of radiation protection (to prevent clinically significant deterministic effects, limit stochastic effects, and practice ALARA), which would be a giant leap backwards for radiation protection.

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Cancer incidence and mortality in the USA Astronaut Corps, 1959-2017
Reynolds R, Little MP, Day S, Charvat J, Blattnig S, Huff J, Patel ZS. Occup Environ Med. 2021 May 26. Online ahead of print.
Summary:
Cancer incidence and mortality are important outcomes in the surveillance of long-term astronaut health. In this work, we compare cancer incidence rates, cancer-specific mortality rates, and cancer case-fatality ratios in US astronauts with those in the US general population. Overall cancer incidence and mortality were slightly lower than expected from national rates with SIR = 82 (95% CI=63-104) and SMR 72 (95% CI 44-111) with a modest 14% reduction in case-fatality ratio. We note a significant increase in incidence of melanoma that is consistent with that observed in aircraft pilots, suggesting this may be associated with ultraviolet radiation or lifestyle factors rather than any astronaut-specific exposure. Reductions in lung cancer incidence and mortality, and trends toward such reductions in colon cancer, may be explained in part by healthy lifestyle, as well as differential screening among astronauts.
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The individual and combined effects of spaceflight radiation and microgravity on biologic systems and functional outcomes
Willey JS, Britten RA, Blaber E, Tahimic CGT, Chancellor J, Mortreux M, Sanford LD, Kubik AJ, Delp MD, Mao XW.and published in J Environ Sci Health C Toxicol Carcinog. 2021;39(2):129-179.
Summary:
Microgravity and radiation present outside of low earth orbit represent risks to astronaut health and performance during and/or after planned long-duration missions. Most ground-based analogues (e.g., mouse or rat studies) that investigate these risks focus on each individual hazard in isolation. However, astronauts will face these (and other) hazards simultaneously during future missions, and thus understanding the biologic and functional responses of combined hazards are necessary for developing appropriate countermeasures. This review describes the biologic and functional outcomes observed in the skeletal, ocular, cardiovascular, and central nervous systems, and also stem cell responses, after exposure to ground-based microgravity (e.g., tail suspension to impart hind limb unloading and partial weight bearing models) and radiation simulations. In vitro studies and spaceflight data are discussed as appropriate.
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Red risks for a journey to the red planet: The highest priority human health risks for a mission to Mars
Z. Patel, T. Brunstetter, W. Tarver, A. Whitmire, S. Zwart, S. Smith, J. Huff. Nature Partner Journals Microgravity , vol. 6, article 33, 2020
Summary:

NASA's plans for space exploration include a return to the Moon to stay on the lunar surface with an orbital outpost. This station will be a launch point for voyages to destinations further away in our solar system, including journeys to the red planet Mars. To ensure success of these missions, health and performance risks associated with the unique hazards of spaceflight must be adequately controlled. These hazards are linked with over 30 human health risks as documented by NASA's Human Research Program. The risks ranked as "red" have the highest priority based on both the likelihood of occurrence and the severity of their impact on human health, performance in mission, and long-term quality of life. These include: (1) space radiation health effects of cancer, cardiovascular disease, and cognitive decrements (2) Spaceflight-Associated Neuro-ocular Syndrome (3) behavioral health and performance decrements, and (4) inadequate food and nutrition. In this review, we provide a primer on these "red" risks for the research community. The aim is to inform the development of studies and projects with high potential for generating both new knowledge and technologies to assist with mitigating multisystem risks to crew health during exploratory missions.

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Spaceflight medical countermeasures: A strategic approach for mitigating effects from solar particle events
Lisa Cantrell, Int J Radiat Biol. 2020 Sep 18.
Summary:
NASA was recently charged with returning humans to the lunar surface within the next five years. This will require preparation for spaceflight missions of longer distance and duration than ever performed in the past. Protecting the crew and mission from the hazards associated with spaceflight will be a priority, particularly space radiation. Physical shielding, space weather monitoring, and more recently storm shelters are all possible means of protecting crew during a SPE. This paper discusses the mitigation strategies in the event of a SPE that can be implemented for Artemis missions and identifies numerous areas of research for future improvements.
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Practicalities of dose management for Japanese astronauts staying at the International Space Station
T Komiyama, Ann ICRP. 2020 Sep 24.
Summary:
Japanese astronauts started staying at the International Space Station (ISS) in 2009, with each stay lasting for approximately 6 months. In total, seven Japanese astronauts have stayed at the ISS eight times. As there is no law for protection against space radiation exposure of astronauts in Japan, the Japan Aerospace Exploration Agency (JAXA) created its own rules and has applied them successfully to radiation exposure management for Japanese ISS astronauts, collaborating with ISS international partners. Regarding dose management, JAXA has implemented several dose limits to protect against both the stochastic effects of radiation and dose-dependent tissue reactions. The scope of the rules includes limiting exposure during spaceflight, exposure during several types of training, and exposure from astronaut-specific medical examinations. We, therefore, are tasked with calculating the dose from all exposure types applied to the dose limits annually for each astronaut. Whenever a Japanese astronaut is at the ISS, we monitor readings of an instrument in real-time to confirm that the exposed dose is below the set limits, as the space radiation environment can fluctuate in relation to solar activity.
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Benchmarking risk predictions and uncertainties in the NSCR model of GCR cancer risks with revised low LET risk coefficients
Cucinotta FA, Cacao E, Kim M-HY, Saganti PB. Life Sci Space Res. 2020 Jul 26.
Summary:
We report on the contributions of model factors that appear in projection models to the overall uncertainty in cancer risks predictions for exposures to galactic cosmic ray (GCR) in deep space, including comparisons with revised low LET risks coefficients. Annual GCR exposures to astronauts at solar minimum are considered. Uncertainties in low LET risk coefficients, dose and dose-rate modifiers, quality factors (QFs), space radiation organ doses, non-targeted effects (NTE) and increased tumor lethality at high LET compared to low LET radiation are considered. For the low LET reference radiation parameters we use a revised assessment of excess relative risk (ERR) and excess additive risk (EAR) for radiation induced cancers in the Life-Span Study (LSS) of the Atomic bomb survivors that was recently reported, and also consider ERR estimates for males from the International Study of Nuclear Workers (INWORKS). For 45-y old females at mission age the risk of exposure induced death (REID) per year and 95% confidence intervals is predicted as 1.6% [0.71, 1.63] without QF uncertainties and 1.64% [0.69, 4.06] with QF uncertainties. However, fatal risk predictions increase to 5.83% [2.56, 9.7] based on a sensitivity study of the inclusion of non-targeted effects on risk predictions. For males a comparison using LSS or INWORKS lead to predictions of 1.24% [0.58, 3.14] and 2.45% [1.23, 5.9], respectively without NTEs. The major conclusion of our report is that high LET risk prediction uncertainties due to QFs parameters, NTEs, and possible increase lethality at high LET are dominant contributions to GCR uncertainties and should be the focus of space radiation research.
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Cancer incidence risks above and below 1 Gy for radiation protection in space
Hafner L, Walsh L, Schneider U. Life Sci Space Res. 2020 Sep 14.
Summary:
The risk assessment quantities called lifetime attributable risk (LAR) and risk of exposure-induced cancer (REIC) are used to calculate the cumulative cancer incidence risks for astronauts, attributable to radiation exposure accumulated during long term lunar and Mars missions. In order to analyse the impact of a different neutron RBE on the risk quantities, a model for the neutron relative biological effectiveness (RBE) relative to gammas in the Life Span Study (LSS) is developed. The suitability of these risk assessment measures for the use of cancer risk calculation for astronauts as well as the impact of including an excess absolute risk (EAR) baseline scaling and different weightings of the excess risk models is discussed.
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Do we really need the "detriment" for radiation protection?
Breckow, J. Radiat Environ Biophys 59, 343-348 (2020).
Summary:
The purpose of the ICRP detriment concept is to enable a quantitative comparison of stochastic radiation damage for the various organs. For this purpose, the organ-specific nominal risk coefficients are weighted with a function that is intended to express the amount of damage or, respectively, the severity of a disease. This function incorporates a variety of variables that do not depend on radiation parameters, but on characteristics of the disease itself. The question is raised as to whether the rather subtle way of defining the amount of damage is necessary for radiation protection purposes and whether a much simpler relationship can serve for this purpose as well or even better.
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The effect of low temperatures on environmental radiation damage in living systems: Does hypothermia show promise for space travel?

Fukunaga H. Int J Mol Sci. 2020 Sep 1;21(17):E6349. Review.

Summary:

This literature review provides an overview of the progress to date in the interdisciplinary research field of radiation biology and hypothermia and addresses possible issues related to hypothermic treatments as countermeasures against GCR.

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A methodology for investigating the impact of medical countermeasures on the risk of exposure induced death
Werneth CM, Slaba TC, Blattnig SR, Huff JL, Norman RB. Life Sci Space Res (Amst). 2020;25:72-102.
Summary:
Recent meta-analyses have demonstrated the efficacy of medical countermeasures (MCM) in the reduction of background cancer mortality and incidence rates in humans. This manuscript presents a general methodology for incorporating MCM into the NASA Space Radiation Cancer Risk model and includes modifications to the background mortality rates and radiation risk coefficients to numerically quantify the reduction of the Risk of Exposure Induced Death (REID). As an example of the method, data from aspirin and warfarin human cohort studies are employed as MCM in a sensitivity analysis to project the potential reduction in REID for crew members embarking on a one-year deep space mission.
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Space Radiation Biology for "Living in Space"
Furukawa S, Nagamatsu A, Nenoi M, Fujimori A, Kakinuma S, Katsube T, Wang B, Tsuruoka C, Shirai T, Nakamura AJ, Sakaue-Sawano A, Miyawaki A, Harada H, Kobayashi M, Kobayashi J, Kunieda T, Funayama T, Suzuki M, Miyamoto T, Hidema J, Yoshida Y, Takahashi A. Biomed Res Int. 2020 Apr 8;2020:4703286. Review.
Summary:
In the first part of this review, we provide an overview of the space radiation environment and briefly present current and future endeavors that monitor different space radiation environments. We then present research evaluating adverse biological effects caused by exposure to various space radiation environments and how these can be reduced. We especially consider the deleterious effects on cellular DNA and how cells activate DNA repair mechanisms. The latest technologies being developed, e.g., a fluorescent ubiquitination-based cell cycle indicator, to measure real-time cell cycle progression and DNA damage caused by exposure to ultraviolet radiation are presented. Progress in examining the combined effects of microgravity and radiation to animals and plants are summarized, and our current understanding of the relationship between psychological stress and radiation is presented. Finally, we provide details about protective agents and the study of organisms that are highly resistant to radiation and how their biological mechanisms may aid developing novel technologies that alleviate biological damage caused by radiation. Future research that furthers our understanding of the effects of space radiation on human health will facilitate risk-mitigating strategies to enable long-term space and planetary exploration.
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Individual response of humans to ionising radiation: governing factors and importance for radiological protection
K. E. Applegate, W. Rühm, A. Wojcik, M. Bourguignon, A. Brenner, K. Hamasaki, T. Imai, M. Imaizumi, T. Imaoka, S. Kakinuma, T. Kamada, N. Nishimura, N. Okonogi, K. Ozasa, C. E. Rübe, A. Sadakane, R. Sakata, Y. Shimada, K. Yoshida & S. Bouffler. Radiation and Environmental Biophysics (2020) 59:185-209
Summary:
This article summarizes initial ICRP workshops, held in Japan, to engage with scientists on current knowledge of individual response to ionizing radiation. The ICRP task group asked a series of questions as part of its mandate to focus its literature review. To summarize, the article discusses what are the ways to quantify the potential impact of individual response to radiation on the incidence of cancers, non-cancer diseases and normal tissue reactions?
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Acute radiation risk assessment and mitigation strategies in near future exploration spaceflights.
Hu S, Barzilla JE, Semones E. Life Sci Space Res. 2019 Oct 31. [Article in Press]
Summary:
A brief summary of the features of radiation exposure if astronauts encounter severe SPEs beyond Low Earth Orbit (LEO), the evidence of ARS radiobiological studies at exposure levels close to recommended limits, and the shortcomings of previous dose projection approaches for ARS risk assessment. Some ARS biomathematical models, particularly those pertinent to the dose ranges that severe SPEs beyond LEO could generate, are reviewed and evaluated, focusing on their capability to predict the incidence of performance incapacitation and time-phased health effects with subsequent medical care recommendations. Using onboard active dosimeter input for estimating organ doses and likely clinical outcomes for SPEs in real time, a new strategy for ARS assessment and mitigation is described to cope with the potential threats of severe SPEs for planned deep space missions.
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On prognostic estimates of radiation risk in medicine and radiation protection
Ulanowski A, Kaiser JC, Schneider U, Walsh L. Radiation and Environmental Biophysics. August 2019, Volume 58, Issue 3, pp 305-319.
Summary:
Exposure to ionising radiation is known to increase risks of harmful health effects, of which malignant neoplasms receive special attention due to deadly hazards they bring. In many situations of unavoidable radiation exposure, either occupational or medical, risks of additional future health effects are estimated and compared with spontaneous incidence observed in the contemporary population. Correspondingly, the conventional techniques of radiation risk assessment are bound to use of the contemporary demographic and health data and are representative for an average member of the current general population. However, medical patients treated with radiation are unlikely to be similar to the average, mostly healthy, member of the general population; people exposed occupationally, like astronauts, are often selected based on their health status, they undergo periodical medical checks and screenings and due to these they can be hardly represented by the average population member. Use of current, cross-sectional, population statistics for projection of lifetime radiation risks also brings significant uncertainties to the risk estimates due to unknown future changes of health and vital statistics This paper reviews the conventional metrics used to express future radiation risks, demonstrates their limitations and difficulties with their use, and suggest an alternative quantity to express the risk, which is insensitive to competing risks and robust against unknown future changes in the population's health and demographic data. The authors examine which risk metrics better represent atypical groups, like medical patients or astronauts; are robust to variability of individual properties, pre-selection and screening; and allow risk projections with unknown secular trends.
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What does radiation biology tell us about potential health effects at low dose and low dose rates.
Azzam EI. J Radiol Prot. 2019 Jun 19. [Epub ahead of print]
Summary:
The health risks to humans exposed to low dose and low dose rate ionizing radiation remain ambiguous and are the subject of debate. The need to establish risk assessment standards based on the mechanisms underlying low dose/low fluence radiation exposures has been recognized by scholarly and regulatory bodies as critical for reducing the uncertainty in predicting adverse health risks of human exposure to low doses of radiation. Here, a brief review of laboratory-based evidence of molecular and biochemical changes induced by low doses and low dose rates of radiation is presented. In particular, two phenomena, namely bystander effects and adaptive responses that may impact low level radiation health risks are discussed together with the need for further studies. The expansion of this knowledge by considering the important variables that affect the radiation response (e.g., genetic susceptibility, time after exposure), and using the latest advances in experimental models and bioinformatics tools, may guide epidemiological studies towards reducing the uncertainty in predicting the potential health hazards of exposure to low dose radiation.
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Funding for radiation research: past, present and future
Cho K, Imaoka T, Klokov D, Paunesku T, Salomaa S, Birschwilks M, Bouffler S, Brooks AL, Hei TK, Iwasaki T, Ono T, Sakai K, Wojcik A, Woloschak GE, Yamada Y, Hamada N. International Journal of Radiation Biology. 2019;95,1-25.
Summary:
For more than a century, ionizing radiation has been indispensable mainly in medicine and industry. Radiation research is a multidisciplinary field that investigates radiation effects. Radiation research was very active in the mid- to late 20th century, but has then faced challenges, during which time funding has fluctuated widely. Here we review historical changes in funding situations in the field of radiation research, particularly in Canada, European Union countries, Japan, South Korea, and the US. We also provide a brief overview of the current situations in education and training in this field. A better understanding of the biological consequences of radiation exposure is becoming more important with increasing public concerns on radiation risks and other radiation literacy. Continued funding for radiation research is needed, and education and training in this field are also important.
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Fluence-to-effective dose conversion coefficients for male astronauts.
Timoshenko GN, Belvedersky MI. J Radiol Prot. 2019 Jun;39(2),511-21.
Summary:
The problem of the reliable estimation of astronauts' radiation exposure doses in deep space is very important and relevant in connection with the accepted space research programmes. The effective dose value based on ICRP Publication 103 presents too conservative an estimate of an astronaut's radiation risk. A more realistic dose can be calculated on the basis of relationships between the radiation quality factor and linear energy transfer or linear energy or Z*2/β 2, according to the NASA concept. In addition, it is reasonable to use a set of tissue weighting coefficients (normalised relative detriments) that have been averaged over a cohort of working age males similar to the male astronaut cohort. The closest to the male astronauts is the NASA cohort of males aged 30-60 years who have never smoked. The fluence-to-effective dose equivalent conversion coefficients calculated specially for male astronauts are compared. Different approaches to radiation risk estimation for astronauts are discussed.
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The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight
Garrett-Bakelman FE et al. Science. 2019;364,eaau8650.
Summary:

The research is featured on the cover of the journal issue with the caption: "A study of identical twins identifies molecular, physiological, and cognitive changes specific to one twin who spent a year living aboard the International Space Station. The cover depicts the twins and their respective Earth-bound and space residencies, with a rocket and the International Space Station in the background."

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The Million Person Study, whence it came and why.
Boice JD Jr, Cohen SS, Mumma MT, Ellis ED. Int J Radiat Biol. 2019 Mar 4. [Epub ahead of print]
Summary:
The study of low dose and low-dose rate exposure is of immeasurable value in understanding the possible range of health effects from prolonged exposures to radiation. The Million Person Study of Low-Dose Health Effects (MPS) was designed to evaluate radiation risks among healthy American workers and veterans who are more representative of today's populations than are the Japanese atomic bomb survivors exposed briefly to high-dose radiation in 1945. A million persons were needed for statistical reasons to evaluate low-dose and dose-rate effects, rare cancers, intakes of radioactive elements, and differences in risks between women and men.
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The Million Person Study relevance to space exploration and Mars
Boice JD Jr. Int J Radiat Biol. 2019 Mar 4. [Epub ahead of print]
Summary:
Understanding the health consequences of exposure to radiation received gradually over time is critically needed. The National Aeronautics and Space Administration (NASA) bases its safety standards on the acute exposures received by Japanese atomic bomb survivors. Such a brief exposure differs appreciably from the chronic radiation received during a two to three year mission to Mars. NASA also applies an individual risk-based system for radiation protection that accounts for age, sex, smoking history and individual life styles. Because the Japanese life span study (LSS) reports women to be at 2 to 3 times greater lifetime risk of developing cancer than men, female astronauts are allowed less time in space. Another concern is the potential behavioral and cognitive impairments from galactic cosmic radiation (GCR) impinging on the nervous system that might jeopardize the mission, and, possibly, lead to dementia later in life. GCR are high-velocity heavy ions traveling through space. There are no human circumstances/analogs similar to GCR that can provide direct information on the possible effects of such high-LET exposure to brain tissue.
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Hibernation and Radioprotection: Gene Expression in the Liver and Testicle of Rats Irradiated under Synthetic Torpor
Tinganelli W, Hitrec T, Romani F, Simoniello P, Squarcio F, Stanzani A, Piscitiello E, Marchesano V, Luppi M, Sioli M, Helm A, Compagnone G, Morganti AG, Amici R, Negrini M, Zoccoli A, Durante M and Cerri M. Int J Mol Sci. 2019, 20, 352-364.
Summary:

Hibernation has been proposed as a tool for human space travel. In recent years, a procedure to induce a metabolic state known as "synthetic torpor" in non-hibernating mammals was successfully developed. Synthetic torpor may not only be an efficient method to spare resources and reduce psychological problems in long-term exploratory-class missions, but may also represent a countermeasure against cosmic rays. Here we show the preliminary results from an experiment in rats exposed to ionizing radiation in normothermic conditions or synthetic torpor. Animals were irradiated with 3 Gy X-rays and organs were collected 4 h after exposure. Histological analysis of liver and testicle showed a reduced toxicity in animals irradiated in torpor compared to controls irradiated at normal temperature and metabolic activity. The expression of ataxia telangiectasia mutated (ATM) in the liver was significantly downregulated in the group of animals in synthetic torpor. In the testicle, more genes involved in the DNA damage signaling were downregulated during synthetic torpor. These data show for the first time that synthetic torpor is a radioprotector in non-hibernators, similarly to natural torpor in hibernating animals. Synthetic torpor can be an elective strategy to protect humans during long term space exploration of the solar system.

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Evaluation of statistical modeling approaches for epidemiologic studies of low dose radiation health effects
Golden AP, Cohen SS, Chen H, Ellis ED, Boice JD Jr. Int J Radiat Biol. 2018 Nov 30. [Epub ahead of print]
Summary:
This study compares radiation risk estimates for leukemia other than chronic lymphocytic leukemia (non-CLL) and ischemic heart disease (IHD) produced by both Cox and Poisson regression models for time-dependent dose-response analyses of occupational exposure. The results from one cohort, the Nuclear Power Plant workers (NPP) are presented, although the evaluation considered five cohorts of varying size and exposure as part of the Million Worker Study. Cox Proportional Hazards models, with age as the underlying timescale for hazard, were conducted using three computer software programs: SAS, R, and Epicure. Doses lagged 2 years for non-CLL and 10 years for ischemic heart disease were treated as time-dependent exposures at the annual level and were examined both in categories and as a continuous term. Hazard ratios (HR) and 95% confidence intervals (CI) were reported for each model in SAS and R, while the Peanuts program of Epicure was utilized to produce Excess Relative Risk (ERR) estimates and 95% CI. All models were adjusted for gender and year of birth. Four piece-wise exponential Poisson models (log-linear regression for rate) were developed with varying cutpoints for age strata from very fine to broad categories using both R and the Amfit program in Epicure for ERR estimates. Comparable estimates of risk (both RR and ERR) were observed from Cox and Poisson models, regardless of software utilized, as long as appropriately narrow categories of age were utilized to control the confounding of age in Poisson models. The ERR estimates produced in Epicure tended to agree very closely with the HR or RR estimates, and the statistical software program used had no impact to risk estimates for the same model. The results of this evaluation support the use of the Cox proportional hazards or the ungrouped Poisson approach to analyzing time-dependent dose-response relationships to ensure that maximum control over the confounding of age is achieved in studies of mortality for cohorts occupationally exposed to radiation.
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Non-Targeted Effects Lead To A Paridigm Shift In Risk Assessment For A Mission To The Earth's Moon Or Martian Moon Phobos
Francis A. Cucinotta, Eliedonna Cacao, Myung-Hee Y. Kim and Premkumar B. Saganti. Radiation Protection Dosimetry (2018), pp. 1-6.
Summary:
Many studies suggest non-targeted effects (NTEs) occur for low doses of high-linear energy transfer (LET) radiation, leading to deviation from the linear dose response model used in radiation protection. We investigate corrections to quality factors (QF) for NTEs, which are used in predictions of fatal cancer risks for exploration missions. Prediction of fatal cancer risks for missions to the Martian moon, Phobos of 500-d and the Earth's moon of 365-d for average solar minimum condition show increases of 2- to 4-fold higher in the NTE model compared with the conventional model. Limitations in estimating uncertainties in NTE model parameters due to sparse radiobiology data at low doses are discussed.
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How Safe Is Safe Enough? Radiation Risk for a Human Mission to Mars
Francis A. Cucinotta, Myung-Hee Y. Kim, Lori J. Chappell, Janice L. Huff. PLoS ONE 8(10):e74988, 10/16/2013.
Summary:
Astronauts on a mission to Mars would be exposed for up to 3 years to galactic cosmic rays (GCR) - made up of high-energy protons and high charge (Z) and energy (E) (HZE) nuclei. GCR exposure rate increases about three times as spacecraft venture out of Earth orbit into deep space where protection of the Earth's magnetosphere and solid body are lost. NASA's radiation standard limits astronaut exposures to a 3% risk of exposure induced death (REID) at the upper 95% confidence interval (CI) of the risk estimate. Fatal cancer risk has been considered the dominant risk for GCR, however recent epidemiological analysis of radiation risks for circulatory diseases allow for predictions of REID for circulatory diseases to be included with cancer risk predictions for space missions. Using NASA's models of risks and uncertainties, we predicted that central estimates for radiation induced mortality and morbidity could exceed 5% and 10% with upper 95% CI near 10% and 20%, respectively for a Mars mission. Additional risks to the central nervous system (CNS) and qualitative differences in the biological effects of GCR compared to terrestrial radiation may significantly increase these estimates, and will require new knowledge to evaluate.
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Should NASA collect astronauts' genetic information for occupational surveillance and research?
Reed RD, Antonsen EL. AMA J Ethics. 2018 Sep 1;20(9):E849-56.
Summary:
Humans exploring beyond low-Earth orbit face environmental challenges coupled with isolation, remote operations, and extreme resource limitations in which personalized medicine, enabled by genetic research, might be necessary for mission success. With little opportunity to test personalized countermeasures broadly, the National Aeronautics and Space Administration (NASA) will likely need to rely instead on collection of significant amounts of genomic and environmental exposure data from individuals. This need appears at first to be in conflict with the statutes and regulations governing the collection and use of genetic data. In fact, under certain conditions, the Genetic Information Nondiscrimination Act (GINA) of 2008 allows for the use of genetic information in both occupational surveillance and research and in the development of countermeasures such as personalized pharmaceuticals.
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Cancer and circulatory disease risks for a human mission to Mars: Private mission considerations.
Cucinotta FA, Cacao E, Kim M-HY, Saganti PB. Acta Astronaut. 2018 Aug 13.
Summary:
There is growing interest in private missions to Mars and other deep space destinations within the next decade. Private missions could consider persons not restricted by radiation limits; however there remains an interest in the level of risk to be encountered. Astronauts and cosmonauts are typically above 40-y, while younger aged persons could participate in private space missions. This paper describes cancer and circulatory disease risks for a 940 d Mars mission for average solar minimum conditions for persons of varying ages from 20 to 60 years. For the first-time NTEs are considered in Mars mission cancer risk predictions. We find much higher importance of cancer risk compared to circulatory disease risks for persons participating in space missions.
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Vive la radioré sistance!: Converging research in radiobiology and biogerontology to enhance human radioresistance for deep space exploration and colonization.
Cortese F, Klokov D, Osipov A, Stefaniak J, Moskalev A, Schastnaya J, Cantor C, Aliper A, Mamoshina P, Ushakov I, Sapetsky A, Vanheaelen Q, Alchinova I, Karganov M, Kovalchuk O, Wilkins RC, Shtemberg A, Moreels M, Baatout S, Izumchenko E, de Magalhães JP, Artemov AV, Costes SV, Beheshti A, Mao XW, Pecaut MJ, Kaminskiy D, Ozerov IV, Scheibye-Knudsen M, Zhavoronkov A. Oncotarget. 2018 Feb 9.
Summary:
Roadmap proposed by an international team of researchers toward enhancing human radioresistance for space exploration and colonization. The roadmap outlines possible future research directions toward the goal of enhancing human radioresistance, including upregulation of endogenous repair and radioprotective mechanisms, possible leeways into gene therapy in order to enhance radioresistance via the translation of exogenous and engineered DNA repair and radioprotective mechanisms, the substitution of organic molecules with fortified isoforms, the coordination of regenerative and ablative technologies, and methods of slowing metabolic activity while preserving cognitive function. The paper concludes by presenting the known associations between radioresistance and longevity, and articulating the position that enhancing human radioresistance is likely to extend the healthspan of human spacefarers as well.
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Men, Women, and Space Travel: Gene-Linked Molecular Networks, Human Countermeasures, and Legal and Ethical Considerations
Schmidt MA, Bailey SM, Goodwin TJ, Jones JA, Killian JP, Legato MJ, Limoli C, Moussa S, Ploutz-Snyder L. Gend Genome. 2017 Jun 1;1(2):54-67.
Summary:
A roundtable discussion to consider the extensive differences between men and women, including both their strengths and vulnerabilities, in preparing professional astronauts for space travel.
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Solid Cancer Incidence among the Life Span Study of Atomic Bomb Survivors: 1958-2009.
Eric J. Grant, Alina Brenner, Hiromi Sugiyama, Ritsu Sakata, Atsuko Sadakane, Mai Utada, Elizabeth K. Cahoon, Caitlin M. Milder, Midori Soda, Harry M. Cullings, Dale L. Preston, Kiyohiko Mabuchi and Kotaro Ozasa. Radiation Research 187(5):513-537. 2017
Summary:

The Radiation Effects Research Foundation (RERF) and its forerunner, the Atomic Bomb Casualty Commission (ABCC), have been estimating the long-term health effects of radiation among the Life Span Study (LSS) cohort of atomic bomb survivors since that study's inception in 1950. Cancer incidence has been followed since the establishment of local cancer registries in 1958.

In the accompanying article, 105,444 LSS cohort members were followed from 1958 through 2009. The primary exposure was the radiation dose to the colon, calculated by a weighted sum of gamma and neutron doses. The primary outcome was a first primary solid cancer. Excess relative risk models (ERR) and excess absolute rate models (EAR) were constructed while adjusting for smoking consumption, the first time ABCC/RERF have made such an adjustment in one of their major reports. Radiation risks were allowed to be modified by sex, age at the time of bombing, and attained age.

The most important finding was that the effects of radiation exposure in 1945 continue to be observed more than 60 years since the time of exposure. The most notable finding was a curvilinear dose response among males, while the female response remained linear. Until this paper's publication (the previous report was made in 2007), the dose responses in both sexes had been linear. The emergence of a curved response in our study was somewhat surprising, and we are now working to ascertain if this is an artifact of the types of cancers occurring among a now elderly population or if it has underlying mechanistic implications for those exposed at young ages.

The paper also reports other findings that may be of interest to the NASA community. First, the lowest dose range for which a sex-averaged linear dose model showed a statistically increased risk in solid cancer was 0-100 mGy. Also, due to the curvilinear response in males, the female-to-male ratio of excess relative risks has increased slightly in comparison with earlier reports.

This manuscript investigated solid cancers in aggregate. We are currently in the process of writing other manuscripts looking at individual organs and organ systems. The first manuscript in that series of reports (on respiratory cancers) was recently published (http://www.bioone.org/doi/abs/10.1667/RR14583.1).

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Scaling human cancer risks from low LET to high LET when dose-effect relationships are complex.
Shuryak I, Fornace AJ Jr, Datta K, Suman S, Kumar S, Sachs RK, Brenner DJ. Radiat Res. 2017 Feb 20. [Epub ahead of print]
Summary:
Reliable methods are needed for scaling low-LET to high-LET radiation risks for humans, based on animal or in vitro studies comparing these radiations. The current standard metric, relative biological effectiveness (RBE) compares iso-effect doses of two radiations. By contrast, a proposed new metric, radiation effects ratio (RER), compares effects of two radiations at the same dose. This definition of RER allows direct scaling of low-LET to high-LET radiation risks in humans at the dose or doses of interest. By contrast to RBE, RER can be used without need for detailed information about dose response shapes for compared radiations. This property of RER allows animal carcinogenesis experiments to be simplified by reducing the number of tested radiation doses. Values of RBE and RER and uncertainties are estimated for tumors in a mouse model for intestinal cancer. Since non-targeted effects and the like, particularly at low doses, may contribute to non-linear dose responses, this approach offers a direct assessment at a particular dose.
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Space: The final frontier-Research relevant to Mars.
Boice JD Jr. Health Phys. 2017 Apr;112(4):392-7.
Summary:
The National Council on Radiation Protection and Measurements (NCRP) is active in the developmment of guidance for radiation protection in the US. The author, who is president of the NCRP, discusses the relevance of the ongoing Million Person Study for reducing the uncertainty in NASA risk estimates, narrowing the 95% confidence interval, and thus allowing more time in space for astronauts.
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Ionizing radiation sensitivity of the ocular lens and its dose rate dependence.
Hamada N. Int J Radiat Biol. 2016 Nov 30:1-32. [Epub ahead of print]
Summary:
This paper reviews the current knowledge on the radiosensitivity of the lens and the dose rate dependence of radiation cataractogenesis, and discusses its mechanisms. Further biological and epidemiological studies are warranted to gain deeper knowledge on the radiosensitivity of the lens and dose rate dependence of radiation cataractogenesis.
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Hibernation for space travel: Impact on radioprotection.
Cerri M, Tinganelli W, Negrini M, Helm A, Scifoni E, Tommasino F, Sioli M, Zoccoli A, Durante M. Life Sci Space Res. 2016 Sep 13. [Article in Press]
Summary:
This article reviews the mechanisms of increased radioprotection in hibernation, and discusses its possible impact on human space exploration. The idea of exploiting hibernation for space exploration is becoming more realistic, thanks to the introduction of specific methods to induce hibernation-like conditions (synthetic torpor) in non-hibernating animals. In addition to the expected advantages in long-term exploratory-class missions in terms of resource consumptions, aging, and psychology, hibernation may provide protection from cosmic radiation damage to the crew. Data from over half century ago in animal models suggest indeed that radiation effects are reduced during hibernation.
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Evaluation of superconducting magnet shield configurations for long duration manned space missions.
Ambroglini F, Battiston R, Burger WJ. Front Oncol. 2016 Jun 8;6:97.
Summary:
A series of the three studies based on high-temperature superconductors, estimate the mass of the coils and supporting structure of engineering designs based on the current and expected near-future performance of the superconducting materials. In each case, the dose reduction was calculated with a 3-dimensional Monte Carlo simulation of the electromagnetic and hadronic interactions of the galactic-cosmic rays, and the secondary particles they produce in the materials of the shield and spacecraft.
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PMMA/MWCNT nanocomposite for proton radiation shielding applications.
Li Z, Chen S, Nambiar S, Sun Y, Zhang M, Zheng W, Yeow JT. Nanotechnology. 2016 Jun 10;27(23):234001. Epub 2016 Apr 29.
Summary:
In this study, poly(methyl-methacrylate)/multi-walled carbon nanotube (PMMA/MWCNT) nanocomposite was fabricated. The role of MWCNTs embedded in PMMA matrix, in terms of radiation shielding effectiveness, was experimentally evaluated by comparing the proton transmission properties and secondary neutron generation of the PMMA/MWCNT nanocomposite with pure PMMA and aluminum. The results showed that the addition of MWCNTs in PMMA matrix can further reduce the secondary neutron generation of the pure polymer, while no obvious change was found in the proton transmission property. On the other hand, both the pure PMMA and the nanocomposite were 18%-19% lighter in weight than aluminum for stopping the protons with the same energy and generated up to 5% fewer secondary neutrons. Furthermore, the use of MWCNTs showed enhanced thermal stability over the pure polymer, and thus the overall reinforcement effects make MWCNT an effective filler material for applications in the space industry.
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Personalized Cancer Risk Assessments for Space Radiation Exposures.
Locke PA, Weil MM. Front Oncol. 2016 Feb 22;6:38
Summary:
This article examines the effect of risk or risk reduction factors that have the potential to personalize risk estimates for individual astronauts and could influence the determination of safe days in space, and explores how the provisions of the federal Genetic Information Non-discrimination Act could impact the collection, dissemination and use of this information by NASA.
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Space Radiation Quality Factors and the Delta Ray Dose and Dose-Rate Reduction Effectiveness Factor.
Cucinotta, Francis A.; Cacao, Eliedonna; Alp, Murat, Health Physics. 110(3):262-266, March 2016.
Summary:
In this paper, the authors recommend that the dose and dose-rate effectiveness factor used for space radiation risk assessments should be based on a comparison of the biological effects of energetic electrons produced along a cosmic ray particles path in low fluence exposures to high dose-rate gamma-ray exposures of doses of about 1 Gy. Methods to implement this approach are described.
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Concepts and challenges in cancer risk prediction for the space radiation environment.
Barcellos-Hoff MH, Blakely EA, Burma S, Fornace AJ Jr, Gerson S, Hlatky L, Kirsch DG, Lederer U, Shay J, Wang Y, Weil MM. Life Sci Space Res. 2015. Epub 2015 Jul 17.
Summary:
This white paper from scientists who receive funding from the NASA Space Radiation Program addresses the current state of the cancer biology and issues related to animal models used to study the effects of space radiation on carcinogenesis. Given that inherent uncertainties limit accurate cancer risk quantification for astronauts for deep space exploration, it is important to understand the biological mechanisms that increase cancer after radiation exposure and determine whether they impact risk modeling. New experimental data suggest that radiation quality may increase the incidence of cancers with poor prognosis (e.g. metastatic); if so, determining the underlying biology may also provide routes to effective countermeasures.
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Safe days in space with acceptable uncertainty from space radiation exposure.
Francis A. Cucinotta, Murat Alp, Blake Rowedder, Myung-Hee Y. Kim. Life Sciences in Space Research. Volume 5, April 2015, Pages 31-38
Summary:
In this paper, we evaluate probability distribution functions and the number or “safe days” in space, which are defined as the mission length where risk limits are not exceeded, for several mission scenarios at different acceptable levels of uncertainty. In addition, we briefly discuss several important issues in risk assessment including non-cancer effects, the distinct tumor spectra and lethality found in animal experiments for HZE particles compared to background or low LET radiation associated tumors, and the possibility of non-targeted effects (NTE) modifying low dose responses and increasing relative biological effectiveness (RBE) factors for tumor induction.
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A New Approach to Reduce Uncertainties in Space Radiation Cancer Risk Predictions.
Cucinotta, F.S. 2015;PLOS ONE 10.1371/journal.pone.0120717
Summary:
The prediction of space radiation induced cancer risk carries large uncertainties with two of the largest uncertainties being radiation quality and dose-rate effects. In risk models the ratio of the quality factor (QF) to the dose and dose-rate reduction effectiveness factor (DDREF) parameter is used to scale organ doses for cosmic ray proton and high charge and energy (HZE) particles to a hazard rate for γ-rays derived from human epidemiology data.. Here I report on an analysis of a maximum QF parameter and its uncertainty using mouse tumor induction data. Because experimental data for risks at low doses of γ-rays are highly uncertain which impacts estimates of maximum values of relative biological effectiveness (RBEmax), I developed an alternate QF model, denoted QFγAcute where QFs are defined relative to higher acute γ-ray doses (0.5 to 3 Gy). The alternate model reduces the dependence of risk projections on the DDREF, however a DDREF is still needed for risk estimates for high-energy protons and other primary or secondary sparsely ionizing space radiation components. In addition, I discuss how a possible qualitative difference leading to increased tumor lethality for HZE particles compared to low LET radiation and background tumors remains a large uncertainty in risk estimates.
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NCRP Commentary No. 23, Radiation Protection for Space Activities: Supplement to Previous Recommendations.
National Council on Radiation Protection and Measurements. Bethesda, MD. November 18, 2014.
Summary:
This Commentary supplements previous recommendations from NCRP that underlie the current National Aeronautics and Space Administration (NASA) standards for radiation protection of crew members during space activities. This Commentary focuses on the implications of extended LEO missions in a general manner, particularly with regard to uncertainties in the knowledge of the health effects and the biological effectiveness of exposures to galactic cosmic rays in space, and includes a discussion of ethical considerations and principles that may bear on the application of NCRP advice on radiation protection for space activities. The Commentary is available from the NCRP website.
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International Commission on Radiological Protection Statement on Tissue Reactions

Summary:

On April 21, 2011, the International Commission on Radiological Protection (ICRP) issued new recommendations on radiological protection. The Commission has now reviewed recent epidemiological evidence suggesting that there are some tissue reaction effects, particularly those with very late manifestation, where threshold doses are or might be lower than previously considered. For the lens of the eye, the threshold in absorbed dose is now considered to be 0.5 Gy. Accordingly, (3) For occupational exposure in planned exposure situations the Commission now recommends an equivalent dose limit for the lens of the eye of 20 mSv in a year, averaged over defined periods of 5 years, with no single year exceeding 50 mSv. In part, the new recommendations are based on research reported by NASA scientists:

• Chylack LT Jr, Peterson LE, Feiveson AH, Wear ML, Manuel FK, Tung WH, Hardy DS, Marak LJ, Cucinotta FA (2009) NASA study of cataract in astronauts (NASCA). Report 1: Cross-sectional study of the relationship of exposure to space radiation and risk of lens opacity.Radiat Res 172(1) 10-20 and
• Cucinotta FA, Manuel FK, Jones J, Iszard G, Murrey J, Djojonegro, Wear ML (2001). Space radiation and cataracts in astronauts. Radiat Res 156(5) 460-466.

The full draft report may be found at

Annals of the ICRP

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Evaluating Biomarkers To Model Cancer Risk Post Cosmic Ray Exposure.
Sridharan DM, Asaithamby A, Blattnig SR, Costes SV, Doetsch PW, Dynan WS, Hahnfeldt P, Hlatky L, Kidane Y, Kronenberg A, Naidu MD, Peterson LE, Plante I, Ponomarev AL, Saha J, Snijders AM, Srinivasan K, Tang J, Werner E, Pluth JM, Life Sci Space Res. 2016 May 21. [Article in Press]
Summary:
Prediction of cancer risk from radiation exposure is a goal for NASA's HRP as astronauts are subjected to protracted cosmic ray exposure. The spectrum of doses, dose rates, radiation qualities, energies and particle flux in the space radiation environment complicate risk assessment. One approach to unravel uncertainties contributed by each of these factors is to identify sensitive biomarkers that can serve as inputs for modeling an individual's risk of cancer. To assist in these modeling efforts, a collaborative effort was undertaken by NASA scientists to critically evaluate candidate biomarkers of radiation exposure and discuss their usefulness in predicting cell fate decisions and its ultimate impact on cancer development. The authors highlight qualities and limitations of various biomarkers and assess their ability to contribute to biomarker-driven models that can be used to estimate cancer risk from radiation exposure.
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Issues for Simulation of Galactic Cosmic Ray Exposures for Radiobiological Research at Ground Based Accelerators
Kim Myung-Hee Y, Rusek Adam, Cucinotta Francis A. Frontiers in Oncology. 2015. Vol 5(00122).
Summary:
We performed extensive simulation studies using the stochastic transport code, GERMcode (GCR Event Risk Model) to define a GCR reference field using 9 HZE particle beam-energy combinations each with a unique absorber thickness to provide fragmentation and 10 or more energies of proton and 4He beams. A kinetics model of HZE particle hit probabilities suggests that experimental simulations of several weeks will be needed to avoid high fluence rate artifacts, which places limitations on the experiments to be performed. Ultimately risk estimates are limited by theoretical understanding, and focus on improving knowledge of mechanisms and development of experimental models to improve this understanding should remain the highest priority for space radiobiology research.
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Does the worsening galactic cosmic radiation environment observed by CRaTER preclude future manned deep space exploration?
N. A. Schwadron, J. B. Blake, A. W. Case, C. J. Joyce1, J. Kasper, J. Mazur, N. Petro, M. Quinn, J. A. Porter, C.W. Smith, S. Smith, H. E. Spence, L.W. Townsend, R. Turner, J. K.Wilson, and C. Zeitlin. Space Weather (online), 11, doi:10.1002/2014SW001084
Summary:

Data from a cosmic ray telescope onboard NASA's Lunar Reconnaissance Orbiter show that while increasing fluxes of cosmic rays "are not a show stopper for long duration missions (e.g., to the Moon, an asteroid, or Mars), galactic cosmic radiation remains a significant and worsening factor that limits mission durations." Cosmic rays are intensifying. Galactic cosmic rays are a mixture of high-energy photons and subatomic particles accelerated to near-light speed by violent events such as supernova explosions. Astronauts are protected from cosmic rays in part by the sun: solar magnetic fields and the solar wind combine to create a porous 'shield' that fends off energetic particles from outside the solar system. The problem is "The sun and its solar wind are currently exhibiting extremely low densities and magnetic field strengths, representing states that have never been observed during the Space Age. As a result of the remarkably weak solar activity, we have also observed the highest fluxes of cosmic rays in the Space Age." The shielding action of the sun is strongest during solar maximum and weakest during solar minimum. At the moment we are experiencing Solar Max, which should be a good time for astronauts to fly. However, the solar maximum of 2011-2014 is the weakest in a century, allowing unusual numbers of cosmic rays to penetrate the solar system. This situation could become even worse if, as some researchers suspect, the sun is entering a long-term phase of the solar cycle characterized by relatively weak maxima and deep, extended minima. In such a future, feeble solar magnetic fields would do an extra-poor job keeping cosmic rays at bay, further reducing the number of days astronauts can travel far from Earth.

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Space Radiation Cancer Risk Projections and Uncertainties - 2010
Francis A. Cucinotta, Myung-Hee Y. Kim, Lori J. Chappell
Summary:

Revisions to the NASA projection model for lifetime cancer risks from space radiation and new estimates of model uncertainties are described in NASA/TP-2011- 216155, Space Radiation Cancer Risk Projections and Uncertainties - 2010 by Francis A. Cucinotta, Myung-Hee Y. Kim, Lori J. Chappell.

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Updates to Astronaut Radiation Limits: Radiation Risks for Never-Smokers
Francis A. Cucinotta, Lori J. Chappell
Summary:

Updates to Astronaut Radiation Limits: Radiation Risks for Never-Smokers was published online by Rad Res, May 16, 2011. The article from the Space Radiation Program Laboratory at NASA Johnson Space Center recommends dose limits for astronauts that take into consideration age- and gender-specific dose limits for never-smokers.

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Environmental Radiation Effects on Mammals: A Dynamical Modeling Approach
Olga Smirnova
Summary:

A new text by Dr. Olga Smirnova, Environmental Radiation Effects on Mammals: A Dynamical Modeling Approach , has been published by Springer. Read more. Posted to the Archive, May 27, 2011.
Feature article on Radiation Risk in Technology Innovation, NASA's magazine for Business & Technology, Volume 15 Number 3, 2010. Posted to the Archive, May 17, 2011.
Mitigating Astronauts' Health Risks from Space Radiation
Francis A. Cucinotta, Ph.D.

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