About THREE
The Health Risks of Extraterrestrial Environments (THREE), is an encyclopedic site whose goal is to present a discussion of the space radiation environment and its health risks to humans. The intent is to make this a good starting point for researchers new to either space, radiation, or both; a source of useful information for established investigators; and a teaching tool for students. Show More
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Current Research Citations
Wang E, Shuryak I, Brenner DJ. Quantifying the effects of neutron dose, dose protraction, age and sex on mouse survival using parametric regression and machine learning on a 21,000-mouse data set. Sci Rep. 2023 Dec 9;13(1):21841. doi: 10.1038/s41598-023-49262-3. PMID: 38071393; PMCID: PMC10710496.
[12/08/2023]Summary:
The biological effects of densely-ionizing radiations such as neutrons and heavy ions encountered in space travel, nuclear incidents, and cancer radiotherapy, significantly differ from those of sparsely-ionizing photons and necessitate a comprehensive understanding for improved protection measures. Data on lifespan studies of laboratory rodents exposed to fission neutrons, accumulated in the Janus archive, afford unique insights into the impact of densely ionizing radiation on mortality from cancers and various organ dysfunction. We extracted and analyzed data for 21,308 individual B6CF1 mice to investigate the effects of neutron dose, fractionation, protraction, age, and sex on mortality. As Cox regression encountered limitations owing to assumption violations, we turned to Random Survival Forests (RSF), a machine learning algorithm adept at modeling nonlinear relationships. RSF interpretation using Shapley Additive Explanations revealed a dose response for mortality risk that curved upwards at low doses < 20 cGy, became nearly-linear over 20-150 cGy, and saturated at high doses. The response was enhanced by fractionation/protraction of irradiation (exhibiting an inverse dose rate effect), and diminished by older age at exposure. Somewhat reduced mortality was predicted for males vs females. This research expands our knowledge on the long-term effects of densely ionizing radiations on mammal mortality.
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Andrade MR, Azeez TA, Montgomery MM, Caldwell JT, Park H, Kwok AT, Borg AM, Narayanan SA, Willey JS, Delp MD, La Favor JD. Neurovascular dysfunction associated with erectile dysfunction persists after long-term recovery from simulations of weightlessness and deep space irradiation. FASEB J. 2023 Dec;37(12):e23246. doi: 10.1096/fj.202300506RR. PMID: 37990646.
[11/30/2023]Summary:
There has been growing interest within the space industry for long-duration manned expeditions to the Moon and Mars. During deep space missions, astronauts are exposed to high levels of galactic cosmic radiation (GCR) and microgravity which are associated with increased risk of oxidative stress and endothelial dysfunction. Oxidative stress and endothelial dysfunction are causative factors in the pathogenesis of erectile dysfunction, although the effects of spaceflight on erectile function have been unexplored. Therefore, the purpose of this study was to investigate the effects of simulated spaceflight and long-term recovery on tissues critical for erectile function, the distal internal pudendal artery (dIPA), and the corpus cavernosum (CC). Eighty-six adult male Fisher-344 rats were randomized into six groups and exposed to 4-weeks of hindlimb unloading (HLU) or weight-bearing control, and sham (0Gy), 0.75 Gy, or 1.5 Gy of simulated GCR at the ground-based GCR simulator at the NASA Space Radiation Laboratory. Following a 12-13-month recovery, ex vivo physiological analysis of the dIPA and CC tissue segments revealed differential impacts of HLU and GCR on endothelium-dependent and -independent relaxation that was tissue type specific. GCR impaired non-adrenergic non-cholinergic (NANC) nerve-mediated relaxation in the dIPA and CC, while follow-up experiments of the CC showed restoration of NANC-mediated relaxation of GCR tissues following acute incubation with the antioxidants mito-TEMPO and TEMPOL, as well as inhibitors of xanthine oxidase and arginase. These findings indicate that simulated spaceflight exerts a long-term impairment of neurovascular erectile function, which exposes a new health risk to consider with deep space exploration.
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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.
[11/30/2023]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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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.
[11/27/2023]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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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.
[11/26/2023]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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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.
[11/19/2023]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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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.
[10/31/2023]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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Cannon AE, Vanegas DC, Sabharwal T, Salmi ML, Wang J, Clark G, McLamore ES, Roux SJ. Polarized distribution of extracellular nucleotides promotes gravity-directed polarization of development in spores of Ceratopteris richardii. Front Plant Sci. 2023 Oct 3;14:1265458. doi: 10.3389/fpls.2023.1265458. PMID: 37854113; PMCID: PMC10579945.
[10/02/2023]Summary:
Gravity directs the polarization of Ceratopteris fern spores. This process begins with the uptake of calcium through channels at the bottom of the spore, a step necessary for the gravity response. Data showing that extracellular ATP (eATP) regulates calcium channels led to the hypothesis that extracellular nucleotides could play a role in the gravity-directed polarization of Ceratopteris spores. In animal and plant cells ATP can be released from mechanosensitive channels. This report tests the hypothesis that the polarized release of ATP from spores could be activated by gravity, preferentially along the bottom of the spore, leading to an asymmetrical accumulation of eATP. In order to carry out this test, an ATP biosensor was used to measure the [eATP] at the bottom and top of germinating spores during gravity-directed polarization. The [eATP] along the bottom of the spore averaged 7-fold higher than the concentration at the top. All treatments that disrupted eATP signaling resulted in a statistically significant decrease in the gravity response. In order to investigate the source of ATP release, spores were treated with Brefeldin A (BFA) and gadolinium trichloride (GdCl3). These treatments resulted in a significant decrease in gravity-directed polarization. An ATP biosensor was also used to measure ATP release after treatment with both BFA and GdCl3. Both of these treatments caused a significant decrease in [ATP] measured around spores. These results support the hypothesis that ATP could be released from mechanosensitive channels and secretory vesicles during the gravity-directed polarization of Ceratopteris spores.
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Radiation cataract in Heterogeneous Stock mice after γ-ray or HZE ion exposure
Kleiman N, Edmondson EF, Weil MM, Fallgren CM, King A, Schmidt C, Hall EJ. Life Sci Space Res. 2023.
[09/15/2023]Summary:
Health effects of space radiation are a serious concern for astronauts on long-duration missions. The lens of the eye is one of the most radiosensitive tissues in the body and, therefore, ocular health risks for astronauts is a significant concern. Studies in humans and animals indicate that ionizing radiation exposure to the eye produces characteristic lens changes, termed “radiation cataract,” that can affect visual function. Animal models of radiation cataractogenesis have previously utilized inbred mouse or rat strains. These studies were essential for determining morphological changes and dose-response relationships between radiation exposure and cataract. However, the relevance of these studies to human radiosensitivity is limited by the narrow phenotypic range of genetically homogeneous animal models. To model radiation cataract in genetically diverse populations, longitudinal cataract phenotyping was nested within a lifetime carcinogenesis study in male and female heterogeneous stock (HS/Npt) mice exposed to 0.4 Gy HZE ions (n = 609) or 3.0 Gy γ-rays (n = 602) and in unirradiated controls (n = 603). Cataractous change was quantified in each eye for up to 2 years using Merriam-Focht grading criteria by dilated slit lamp examination. Virtual Optomotry™ measurement of visual acuity and contrast sensitivity was utilized to assess visual function in a subgroup of mice. Prevalence and severity of posterior lens opacifications were 2.6-fold higher in HZE ion and 2.3-fold higher in γ-ray irradiated mice compared to unirradiated controls. Male mice were at greater risk for spontaneous and radiation associated cataracts. Risk for cataractogenesis was associated with family structure, demonstrating that HS/Npt mice are well-suited to evaluate genetic determinants of ocular radiosensitivity. Last, mice were extensively evaluated for cataract and tumor formation, which revealed an overlap between individual susceptibility to both cancer and cataract.
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Tichy ED, Lee J, Li G, Estep KN, Brad Johnson F, Mourkioti F. NPJ Microgravity. 2023; 9(1):76.
[09/15/2023]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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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.
[09/13/2023]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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Sex differences in muscle health in simulated micro- and partial-gravity environments in rats
Rosa-Caldwell ME, Motreux M, Wadhwa A, Kaiser UB, Sung D, Bouxsein ML, Rutkove SB. Sports Med Health Sci. 2023.
[09/12/2023]Summary:
Skeletal muscle size and strength are important for overall health for astronauts. However, how male and female muscle may respond differently to micro- and partial-gravity environments is not fully understood. The purpose of this study was to determine how biological sex and sex steroid hormones influence the progression of muscle atrophy after long term exposure to micro and partial gravity environments in male and female rats. Male and female Fisher rats (n = 120) underwent either castration/ovariectomy or sham surgeries. After two weeks recovery, animals were divided into microgravity (0g), partial-gravity (40% of weight bearing, 0.4g), or full weight bearing (1g) interventions for 28 days. Measurements of muscle size and strength were evaluated prior to and after interventions. At 0g, females lost more dorsiflexion strength, plantar flexion strength, and other metrics of muscle size compared to males; castration/ovariectomy did not influence these differences. Additionally, at 0.4g, females lost more dorsiflexion strength, plantar flexion strength, and other metrics of muscle strength compared to males; castration/ovariectomy did not influence these differences. Females have greater musculoskeletal aberrations during exposure to both microgravity and partial-gravity environments; these differences are not dependent on the presence of sex steroid hormones. Correspondingly, additional interventions may be necessary to mitigate musculoskeletal loss in female astronauts to protect occupational and overall health.
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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.
[09/10/2023]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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Clonal Hematopoiesis in Clinical and Experimental Heart Failure With Preserved Ejection Fraction
Cochran J, Yura Y, Thel MC, Doviak H, Polizio AH, Arai Y, Arai Y, Horitani K, Park E, Chavkin NW, Kour A, Sano S, Mahajan N, Evans M, Huba M, Naya NM, Sun H, Ban Y, Hirschi KK, Toldo S, Abbate A, Druley TE, Ruberg FL, Maurer MS, Ezekowitz JA, Dyck JRB, Walsh K. Circulation. 2023; 148:1165-1178.
[09/08/2023]Summary:
BACKGROUND: Clonal hematopoiesis (CH), which results from an array of nonmalignant driver gene mutations, can lead to altered immune cell function and chronic disease, and has been associated with worse outcomes in patients with heart failure (HF) with reduced ejection fraction. However, the role of CH in the prognosis of HF with preserved ejection fraction (HFpEF) has been understudied. This study aimed to characterize CH in patients with HFpEF and elucidate its causal role in a murine model. METHODS: Using a panel of 20 candidate CH driver genes and a variant allele frequency cutoff of 0.5%, ultradeep error-corrected sequencing identified CH in a cohort of 81 patients with HFpEF (mean age, 71±6 years; ejection fraction, 63±5%) and 36 controls without a diagnosis of HFpEF (mean age, 74±7 years; ejection fraction, 61.5±8%). RESULTS: Compared with controls, there was an enrichment of TET2-mediated CH in the HFpEF patient cohort (12% versus 0%, respectively; P=0.02). In the HFpEF cohort, patients with CH exhibited exacerbated diastolic dysfunction in terms of E/e' (14.9 versus 11.7, respectively; P=0.0096) and E/A (1.69 versus 0.89, respectively; P=0.0206) compared with those without CH. The association of CH with exacerbated diastolic dysfunction was corroborated in a validation cohort of 59 individuals with HFpEF. In accordance, patients with HFpEF with CH and age ≥70 years exhibited worse prognosis in terms of 5-year cardiovascular-related hospitalization rate (hazard ratio, 5.06; P=0.042) compared with patients with HFpEF without CH and age ≥70 years. To investigate the causal role of CH in HFpEF, nonconditioned mice underwent adoptive transfer with Tet2-wild-type or Tet2-deficient bone marrow and were subsequently subjected to a high-fat diet/L-NAME (Nω-nitro-l-arginine methyl ester) combination treatment to induce features of HFpEF. This model of Tet2-CH exacerbated cardiac hypertrophy by heart weight/tibia length and cardiomyocyte size, diastolic dysfunction by E/e' and left ventricular end-diastolic pressure, and cardiac fibrosis compared with the Tet2-wild-type condition. CONCLUSIONS: CH is associated with worse heart function and prognosis in patients with HFpEF, and a murine experimental model of Tet2-mediated CH displays greater features of HFpEF.
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Updates to the NASA human system risk management process for space exploration
Antonsen EL, Connell E, Anton W, Reynolds RJ, Buckland DM, Van Baalen M. NPJ Microgravity. 2023; 9(1):72.
[09/07/2023]Summary:
This paper describes updates to NASA's approach for assessing and mitigating spaceflight-induced risks to human health and performance. This approach continues to evolve to meet dynamically changing risk environments: lunar missions are currently being designed and the ultimate destination will be Mars. Understanding the risks that astronauts will face during a Mars mission will depend on building an evidence base that informs not only how the humans respond to the challenges of the spaceflight environment, but also how systems and vehicles can be designed to support human capabilities and limitations. This publication documents updates to the risk management process used by the Human System Risk Board at NASA and includes changes to the likelihood and consequence matrix used by the board, the design reference mission categories and parameters, and the standardized evaluation of the levels of evidence that the board accepts when setting risk posture. Causal diagramming, using directed acyclic graphs, provides all stakeholders with the current understanding of how each risk proceeds from a spaceflight hazard to a mission-level outcome. This standardized approach enables improved communication among stakeholders and delineates how and where more knowledge can improve perspective of human system risks and which countermeasures can best mitigate these risks.
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Time-integrated radiation risk metrics and interpopulation variability of survival
Ulanowski A, Ban N, Ozasa K, Ruhm W, Semones E, Shavers M, Vaillant L. Z Med Phys. 2023.
[09/03/2023]Summary:
Task Group 115 of the International Commission on Radiological Protection is focusing on mission-related exposures to space radiation and concomitant health risks for space crew members including, among others, risk of cancer development. Uncertainties in cumulative radiation risk estimates come from the stochastic nature of the considered health outcome (i.e., cancer), uncertainties of statistical inference and model parameters, unknown secular trends used for projections of population statistics and unknown variability of survival properties between individuals or population groups. The variability of survival is usually ignored when dealing with large groups, which can be assumed well represented by the statistical data for the contemporary general population, either in a specific country or world averaged. Space crew members differ in many aspects from individuals represented by the general population, including, for example, their lifestyle and health status, nutrition, medical care, training and education. The individuality of response to radiation and lifespan is explored in this modelling study. Task Group 115 is currently evaluating applicability and robustness of various risk metrics for quantification of radiation-attributed risks of cancer for space crew members. This paper demonstrates the impact of interpopulation variability of survival curves on values and uncertainty of the estimates of the time-integrated radiation risk of cancer.
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Alwood JS, Mulavara AP, Iyer J, Mhatre SD, Rosi S, Shelhamer M, Davis C, Jones CW, Mao XW, Desai RI, Whitmire AM, Williams TJ. Life. 2023; 13(9):1852.
[08/31/2023]Summary:
Biomarkers, ranging from molecules to behavior, can be used to identify thresholds beyond which performance of mission tasks may be compromised and could potentially trigger the activation of countermeasures. Identification of homologous brain regions and/or neural circuits related to operational performance may allow for translational studies between species. Three discussion groups were directed to use operationally relevant performance tasks as a driver when identifying biomarkers and brain regions or circuits for selected constructs. Here we summarize small-group discussions in tables of circuits and biomarkers categorized by (a) sensorimotor, (b) behavioral medicine and (c) integrated approaches (e.g., physiological responses). In total, hundreds of biomarkers have been identified and are summarized herein by the respective group leads. We hope the meeting proceedings become a rich resource for NASA’s Human Research Program (HRP) and the community of researchers.
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The importance of time-resolved personal Dosimetry in space: The ISS Crew Active Dosimeter
Gaza R, Johnson SA, Hayes B, Campbell-Ricketts T, Rakkola J, Abdelmelek M, Zeitlin C, George S, Stoffle N, Castro A, Amberboy C, Semones E. Life Sci Space Res. 2023.
[08/25/2023]Summary:
Monitoring space radiation is of vital importance for risk reduction strategies in human space exploration. Radiation protection programs on Earth and in space rely on personal and area radiation monitoring instruments. Crew worn radiation detectors are crucial for successful crew radiation protection programs since they measure what each crewmember experiences in different shielding configurations within the space habitable volume. The Space Radiation Analysis Group at NASA Johnson Space Center investigated several compact, low power, real-time instruments for personal dosimetry. Following these feasibility studies, the Crew Active Dosimeter (CAD) has been chosen as a replacement for the legacy crew passive radiation detectors. The CAD device, based on direct ion storage technology, was developed by Mirion Dosimetry Services to meet the specified NASA design requirements for the International Space Station (ISS) and Artemis programs. After a successful Technology demonstration on ISS, the CAD has been implemented for ISS Crew operations since 2020. The current paper provides an overview of the CAD development, ISS results and comparison with the ISS Radiation Assessment Detector (RAD) and the Radiation Environment Monitor 2 (REM2) instruments.
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Gastrointestinal Dysfunction in Neurological and Neurodegenerative Disorders
Raber J, Sharpton TJ. Semin Neurol. 2023; 43(4):634-644.
[08/22/2023]Summary:
Increasing research links the gut microbiome to neurodegenerative disorders. The gut microbiome communicates with the central nervous system via the gut–brain axis and affects behavioral and cognitive phenotypes. Dysbiosis (a dysfunctional microbiome) drives increased intestinal permeability and inflammation that can negatively affect the brain via the gut–brain axis. Healthier metabolic and lipid profiles and cognitive phenotypes are observed in individuals with more distinct microbiomes. In this review, we discuss the role of the gut microbiome and gut–brain axis in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease and related animal models, in cancer and cancer treatments, and in metabolic syndrome. We also discuss strategies to improve the gut microbiome and ultimately brain function. Because healthier cognitive phenotypes are observed in individuals with more distinct microbiomes, increased efforts are warranted to develop therapeutic strategies for those at increased risk of developing neurological disorders and patients diagnosed with those disorders.
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Faddegon B, Blakely EA, Burigo L, Censor Y, Dokic I, Dominguez Kondo N, Ortiz R, Ramos Mendez J, Rucinski A, Schubert K, Wahl N, Schulte R. Phys Med Biol. 2023; 68(17):175013.
[08/14/2023]Summary:
Objective. To propose a mathematical model for applying ionization detail (ID), the detailed spatial distribution of ionization along a particle track, to proton and ion beam radiotherapy treatment planning (RTP). Approach. Our model provides for selection of preferred ID parameters (Ip) for RTP, that associate closest to biological effects. Cluster dose is proposed to bridge the large gap between nanoscopic Ip and macroscopic RTP. Selection of Ip is demonstrated using published cell survival measurements for protons through argon, comparing results for nineteen Ip:Nk, k= 2, 3, …, 10, the number of ionizations in clusters of k or more per particle, and Fk, k= 1, 2, …, 10, the number of clusters of k or more per particle. We then describe application of the model to ID-based RTP and propose a path to clinical translation. Main results. The preferred Ip were N4 and F5 for aerobic cells, N5 and F7 for hypoxic cells. Significant differences were found in cell survival for beams having the same LET or the preferred Nk. Conversely, there was no significant difference for F5 for aerobic cells and F7 for hypoxic cells, regardless of ion beam atomic number or energy. Further, cells irradiated with the same cluster dose for these Ip had the same cell survival. Based on these preliminary results and other compelling results in nanodosimetry, it is reasonable to assert that Ip exist that are more closely associated with biological effects than current LET-based approaches and microdosimetric RBE-based models used in particle RTP. However, more biological variables such as cell line and cycle phase, as well as ion beam pulse structure and rate still need investigation. Significance. Our model provides a practical means to select preferred Ip from radiobiological data, and to convert Ip to the macroscopic cluster dose for particle RTP.
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Chaklai A, Canaday P, O'Niel A, Cucinotta FA, Sloop A, Gladstone D, Pogue B, Zhang R, Sunnerberg J, Kheirollah A, Thomas CR, Hoopes PJ, Raber J Int. J. Mol. Sci. 2023 Aug 6;24(15):12497
[08/06/2023]Summary:
We assessed the effects of conventional and ultra-high dose rate (UHDR) electron irradiation on behavioral and cognitive performance one month following exposure and assessed whether these effects were associated with alterations in the number of immune cells in the hippocampus using flow cytometry. Two-month-old female and male C57BL/6J mice received whole-brain conventional or UHDR irradiation. UHDR mice were irradiated with 9 MeV electrons, delivered by the Linac-based/modified beam control. The mice were irradiated or sham-irradiated at Dartmouth, the following week shipped to OHSU, and behaviorally and cognitively tested between 27 and 41 days after exposure. Conventional- and UHDR-irradiated mice showed impaired novel object recognition. During fear learning, conventional- and UHDR-irradiated mice moved less during the inter-stimulus interval (ISI) and UHDR-irradiated mice also moved less during the baseline period (prior to the first tone). In irradiated mice, reduced activity levels were also seen in the home cage: conventional- and UHDR-irradiated mice moved less during the light period and UHDR-irradiated mice moved less during the dark period. Following behavioral and cognitive testing, infiltrating immune cells in the hippocampus were analyzed by flow cytometry. The percentage of Ly6G+ CD45+ cells in the hippocampus was lower in conventional- and UHDR-irradiated than sham-irradiated mice, suggesting that neutrophils might be particularly sensitive to radiation. The percentage of Ly6G+ CD45+ cells in the hippocampus was positively correlated with the time spent exploring the novel object in the object recognition test. Under the experimental conditions used, cognitive injury was comparable in conventional and UHDR mice. However, the percentage of CD45+ CD11b+ Ly6+ and CD45+ CD11b+ Ly6G- cells in the hippocampus cells in the hippocampus was altered in conventional- but not UHDR-irradiated mice and the reduced percentage of Ly6G+ CD45+ cells in the hippocampus might mediate some of the detrimental radiation-induced cognitive effects.
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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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Loss of Cognitive Flexibility Practice Effects in Female Rats Exposed to Simulated Space Radiation
Britten RA, Fesshaye A, Tidmore A, Liu A, Blackwell A. Radiat Res. 2023; 200(3):256-265
[08/01/2023]Summary:
During the planned missions to Mars, astronauts will be faced with many potential health hazards including prolonged exposure to space radiation. Ground-based studies have shown that exposure to space radiation impairs the performance of male rats in cognitive flexibility tasks which involve processes that are essential to rapidly and efficiently adapting to different situations. However, there is presently a paucity of information on the effects of space radiation on cognitive flexibility in female rodents. This study has determined the impact that exposure to a low (10 cGy) dose of ions from the simplified 5-ion galactic cosmic ray simulation [ https://www.bnl.gov/nsrl/userguide/SimGCRSim.php (07/2023)] (GCRSim) beam or 250 MeV/n 4He ions has on the ability of female Wistar rats to perform in constrained [attentional set shifting (ATSET)] and unconstrained cognitive flexibility (UCFlex) tasks. Female rats exposed to GCRSim exhibited multiple decrements in ATSET performance. Firstly, GCRSim exposure impaired performance in the compound discrimination (CD) stage of the ATSET task. While the ability of rats to identify the rewarded cue was not compromised, the time the rats required to do so significantly increased. Secondly, both 4He and GCRSim exposure reduced the ability of rats to reach criterion in the compound discrimination reversal (CDR) stage. Approximately 20% of the irradiated rats were unable to complete the CDR task; furthermore, the irradiated rats that did reach criterion took more attempts to do so than did the sham-treated animals. Radiation exposure also altered the magnitude and/or nature of practice effects. A comparison of performance metrics from the pre-screen and post-exposure ATSET task revealed that while the sham-treated rats completed the post-exposure CD stage of the ATSET task in 30% less time than for completion of the pre-screen ATSET task, the irradiated rats took 30–50% longer to do so. Similarly, while sham-treated rats completed the CDR stage in ;10% fewer attempts in the post-exposure task compared to the pre-screen task, in contrast, the 4He- and GCRSim-exposed cohorts took more (;2-fold) attempts to reach criterion in the post-exposure task than in the pre-screen task. In conclusion, this study demonstrates that female rats are susceptible to radiation-induced loss of performance in the constrained ATSET cognitive flexibility task. Moreover, exposure to radiation leads to multiple performance decrements, including loss of practice effects, an increase in anterograde interference and reduced ability or unwillingness to switch attention. Should similar effects occur in humans, astronauts may have a compromised ability to perform complex tasks.
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Galactic cosmic ray environment predictions for the NASA BioSentinel mission
Rahmanian S, Slaba TC, Braby LA, Santa Maria SR, Bhattacharya S, Straume T. Life Sciences in Space Research. 2023; 38:19-28
[08/01/2023]Summary:
BioSentinel is a nanosatellite deployed from Artemis-I designed to conduct in-situ biological measurements on yeast cells in the deep space radiation environment. Along with the primary goal of measuring damage and response in cells exposed during spaceflight, on-board active dosimetry will provide measurements of the radiation field encountered behind moderate shielding provided by the BioSentinel housing and internal components. The measurements are particularly important to enable interpretation of biological observations but also provide an opportunity to validate integrated computational models used to calculate radiation environments. In this work, models are used to predict the galactic cosmic ray exposure anticipated for the BioSentinel payload and on-board dosimeter. The model calculations presented herein were completed prior to the Artemis-I launch on November 16, 2022, and therefore represent actual predictions (i.e., unbiased by a priori knowledge of on-board measurements). Such time-forward predictions are rarely performed for space radiation applications due to limitations of environmental models, but truly independent model validation will be possible in the future when on-board measurements become available. The method used to facilitate future projections within an existing GCR (galactic cosmic ray) environmental model is described, and projection uncertainties are quantified and contextualized.
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Ong J, Waisberg E, Masalkhi M, Kamran SA, Lowry K, Sarker P, Zaman N, Paladugu P, Tavakkoli A, Lee AG. Brain Sci. 2023; 13(8):1148.
[07/30/2023]Summary:
Spaceflight associated neuro-ocular syndrome (SANS) is a unique phenomenon that has been observed in astronauts who have undergone long-duration spaceflight (LDSF). The syndrome is characterized by distinct imaging and clinical findings including optic disc edema, hyperopic refractive shift, posterior globe flattening, and choroidal folds. SANS serves a large barrier to planetary spaceflight such as a mission to Mars and has been noted by the National Aeronautics and Space Administration (NASA) as a high risk based on its likelihood to occur and its severity to human health and mission performance. While it is a large barrier to future spaceflight, the underlying etiology of SANS is not well understood. Current ophthalmic imaging onboard the International Space Station (ISS) has provided further insights into SANS. However, the spaceflight environment presents with unique challenges and limitations to further understand this microgravity-induced phenomenon. The advent of artificial intelligence (AI) has revolutionized the field of imaging in ophthalmology, particularly in detection and monitoring. In this manuscript, we describe the current hypothesized pathophysiology of SANS and the medical diagnostic limitations during spaceflight to further understand its pathogenesis. We then introduce and describe various AI frameworks that can be applied to ophthalmic imaging onboard the ISS to further understand SANS including supervised/unsupervised learning, generative adversarial networks, and transfer learning. We conclude by describing current research in this area to further understand SANS with the goal of enabling deeper insights into SANS and safer spaceflight for future missions.
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Shavers M, Semones E, Tomi L, Chen J, Straube U, Komiyama T, Shurshakov V, Li C, Ruhm W. Z Med Phys. 2023.
[07/27/2023]Summary:
The Partner Agencies of the International Space Station (ISS) maintain separate career exposure limits and shared Flight Rules that control the ionising radiation exposures that crewmembers can experience due to ambient environments throughout their space missions. In low Earth orbit as well as further out in space, energetic ions referred to as galactic cosmic radiation (GCR) easily penetrate spacecraft and spacecraft contents and consequently are always present at low dose rates. Protons and electrons that are trapped in the Earth's geomagnetic field are encountered intermittently, and a rare energetic solar particle event (SPE) may expose crew to (mostly) energetic protons. Space radiation protection goals are to optimize radiation exposures to maintain deleterious late effects at known and acceptable levels and to prevent any early effects that might compromise crew health and mission success. The conventional radiation protection metric effective dose provides a basic framework for limiting exposures associated with human spaceflight and can be communicated to all stakeholders. Additional metrics and uncertainty analyses are required to understand more completely and to convey nuanced information about potential impacts to an individual astronaut or to a space mission. Missions to remote destinations well beyond low Earth orbit (BLEO) are upcoming and bestow additional challenges that shape design and radiation protection needs. NASA has recently adopted a more permissive career exposure limit based upon effective dose and new restrictions on mission exposures imposed by nuclear technologies. This manuscript reviews the exposure limits that apply to the ISS crewmembers. This work was performed in collaboration with the advisory and guidance efforts of International Commission on Radiological Protection (ICRP) Task Group 115 and will be summarized in an upcoming ICRP Report.
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Sub-1.4 cm3 capsule for detecting labile inflammatory biomarkers in situ
Inda-Webb ME, Jimenez M, Liu Q, Phan NV, Ahn J, Steiger C, Wentworth A, Riaz A, Zirtiloglu T, Wong K, Ishida K, Fabian N, Jenkins J, Kuosmanen J, Madani W, McNally R, Lai Y, Hayward A, Mimee M, Nadeau P, Chandrakasan AP, Traverso G, Yazicigil RT, Lu TK. Nature. 2023; 620:386-392.
[07/26/2023]Summary:
Transient molecules in the gastrointestinal tract such as nitric oxide and hydrogen sulfide are key signals and mediators of inflammation. Owing to their highly reactive nature and extremely short lifetime in the body, these molecules are difficult to detect. Here we develop a miniaturized device that integrates genetically engineered probiotic biosensors with a custom-designed photodetector and readout chip to track these molecules in the gastrointestinal tract. Leveraging the molecular specificity of living sensors1, we genetically encoded bacteria to respond to inflammation-associated molecules by producing luminescence. Low-power electronic readout circuits2 integrated into the device convert the light emitted by the encapsulated bacteria to a wireless signal. We demonstrate in vivo biosensor monitoring in the gastrointestinal tract of small and large animal models and the integration of all components into a sub-1.4 cm3 form factor that is compatible with ingestion and capable of supporting wireless communication. With this device, diseases such as inflammatory bowel disease could be diagnosed earlier than is currently possible, and disease progression could be more accurately tracked. The wireless detection of short-lived, disease-associated molecules with our device could also support timely communication between patients and caregivers, as well as remote personalized care.
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An autonomous wearable biosensor powered by a perovskite solar cell
Min J, Demchyshyn S, Sempionatto JR, Song Y, Hailegnaw B, Xu C, Yang Y, Solomon S, Putz C, Lehner L, Schwarz J, Schwarzinger C, Scharber MC, Shirzaei Sani E, Kaltenbrunner M, Gao W. Nat Electron. 2023;6:630-641
[07/20/2023]Summary:
Wearable sweat sensors can potentially be used to continuously and non-invasively monitor physicochemical biomarkers that contain information related to disease diagnostics and fitness tracking. However, the development of such autonomous sensors faces a number of challenges including achieving steady sweat extraction for continuous and prolonged monitoring and addressing the high power demands of multifunctional and complex analysis. Here we report an autonomous wearable biosensor that is powered by a perovskite solar cell and can provide continuous and non-invasive metabolic monitoring. The device uses a flexible quasi-two-dimensional perovskite solar cell module that provides ample power under outdoor and indoor illumination conditions (power conversion efficiency exceeding 31% under indoor light illumination). We show that the wearable device can continuously collect multimodal physicochemical data—glucose, pH, sodium ion, sweat rate and skin temperature—across indoor and outdoor physical activities for over 12 h.
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Otsuka K, Cornelissen G, Kubo Y, Shibata K, Mizuno K, Aiba T, Furukawa S, Ohshima H, Mukai C. Sci. Rep. 2023; 13(1):10909
[07/05/2023]Summary:
This study was designed to examine the feasibility of analyzing heart rate variability (HRV) data from repeat-flier astronauts at matching days on two separate missions to assess any effect of repeated missions on brain plasticity and psychological resilience, as conjectured by Demertzi. As an example, on the second mission of a healthy astronaut studied about 20 days after launch, sleep duration lengthened, sleep quality improved, and spectral power (ms2) co-varying with activity of the salience network (SN) increased at night. HF-component (0.15-0.50 Hz) increased by 61.55%, and HF-band (0.30-0.40 Hz) by 92.60%. Spectral power of HRV indices during daytime, which correlate negatively with psychological resilience, decreased, HF-component by 22.18% and HF-band by 37.26%. LF-component and LF-band, reflecting activity of the default mode network, did not change significantly. During the second mission, 24-h acrophases of HRV endpoints did not change but the 12-h acrophase of TF-HRV did (P < 0.0001), perhaps consolidating the circadian system to help adapt to space by taking advantage of brain plasticity at night and psychological resilience during daytime. While this N-of-1 study prevents drawing definitive conclusions, the methodology used herein to monitor markers of brain plasticity could pave the way for further studies that could add to the present results.
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Mosaic Loss of Y Chromosome in White Blood Cells: Its Impact on Men's Health
Sano S, Thel M, Walsh K. Physiology (Bethesda). 2023; 38(4):0
Summary:
We present a brief introduction of loss of Y chromosome (LOY) in blood and describe the known risk factors for this condition. We then overview the associations between LOY and age-related disease traits. Finally, we discuss murine models and the potential mechanisms by which LOY contributes to disease.
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Applicability of the NASA galactic cosmic ray simulator for mice, rats, and minipigs
Rahmanian S, Slaba TC. Acta Astronaut. 2023; 208:111-123.
Summary:
Space radiation poses multiple health risks to astronauts including cancer, cardiovascular disease, and damage to the central nervous system. Radiation from galactic cosmic rays (GCR) is the main source of these risks for missions beyond low Earth orbit to the moon and beyond. A galactic cosmic ray simulator (GCRsim) was developed at the NASA Space Radiation Laboratory to better understand and mitigate these risks by simulating the complex mixed field of the GCR environment at a ground-based facility. The GCRsim delivers a radiation field to cell and animal models in a laboratory setting that is comparable to the shielded radiation environment within internal organs of astronauts in deep space missions. Previous verification studies using Monte Carlo simulations with mouse (Digimouse) and rat (Digirat) digital phantoms showed that the GCRsim yields acceptable dose homogeneity within the internal organs of these animals. Spectral characteristics of the intended space radiation environment are also accurately reproduced at radiosensitive sites in both phantoms. In this work, similar Monte Carlo simulations were performed in a minipig model (Digipig) to show the applicability and limitations of the current GCRsim for larger animal model systems. The results showed dose homogeneity in internal organs of the three animal models with GCRsim irradiation. While slightly lower average doses were seen in the minipig compared to the external beam dose, the individual voxel doses in slices of the phantoms were found to be within 6%–8% of the average voxel dose, establishing that the GCRsim can still provide a relatively homogeneous irradiation within larger animals. Furthermore, simulated dose and fluence spectral results across the relevant linear energy transfer (LET) range agreed well with the reference field in the most relevant regions of the spectra, further verifying that the GCRsim beam represents the reference field in larger animals.
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Kothiyal P, Eley G, Ilangovan H, Hoadley KA, Elgart SR, Mao XW, Eslami P. A multi-omics longitudinal study of the murine retinal response to chronic low-dose irradiation and simulated microgravity. Sci Rep. 2022 Oct 7;12(1):16825. doi: 10.1038/s41598-022-19360-9. PMID: 36207342; PMCID: PMC9547011.
[10/06/2022]Summary:
The space environment includes unique hazards like radiation and microgravity which can adversely affect biological systems. We assessed a multi-omics NASA GeneLab dataset where mice were hindlimb unloaded and/or gamma irradiated for 21 days followed by retinal analysis at 7 days, 1 month or 4 months post-exposure. We compared time-matched epigenomic and transcriptomic retinal profiles resulting in a total of 4178 differentially methylated loci or regions, and 457 differentially expressed genes. Highest correlation in methylation difference was seen across different conditions at the same time point. Nucleotide metabolism biological processes were enriched in all groups with activation at 1 month and suppression at 7 days and 4 months. Genes and processes related to Notch and Wnt signaling showed alterations 4 months post-exposure. A total of 23 genes showed significant changes in methylation and expression compared to unexposed controls, including genes involved in retinal function and inflammatory response. This multi-omics analysis interrogates the epigenomic and transcriptomic impacts of radiation and hindlimb unloading on the retina in isolation and in combination and highlights important molecular mechanisms at different post-exposure stages.
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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.
[04/01/2022]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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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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Race and ethnic group dependent space radiation cancer risk predictions.
Cucinotta FA, Saganti PB. Sci Rep. 2022 Feb 7;12(1):2028
[02/20/2022]Summary:
Future space missions by national space agencies and private industry, including space tourism, will include a diverse makeup of crewmembers with extensive variability in age, sex, and race or ethnic groups. The relative risk (RR) model is used to transfer epidemiology data between populations to estimate radiation risks. We apply the NSCR-2020 model to make the first predictions of age dependent space radiation cancer risks for several U.S. populations, which includes Asian-Pacific Islanders (API), Black, Hispanic (white and black), and White (non-Hispanic) populations. Results suggest that male API and Hispanic populations have the overall lowest cancer risks, while White females have the highest risk. Blacks have similar total cancer rates than Whites, however their reduced life expectancy leads to modestly lower lifetime radiation risks compared to Whites. There are diverse tissue specific cancer risk ranking across sex and race, which include sex specific organ risks, female's having larger lung, stomach, and urinary-bladder radiation risks, and male's having larger colon and brain risks.
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Mary Helen Barcellos-Hoff, Semin Cancer Biol. 2022 Feb 2;S1044-579X(22)00022-0. Online ahead of print.
Summary:
Although the therapeutic effect of radiation is attributed to induction of DNA damage that kills cancers cells, radiation also activates transforming growth factor β (TGFβ), a ubiquitously expressed cytokine that acts as biological lynchpin to promote malignancy, a permissive tumor microenvironment and immune evasion. The radiobiology of TGFβ unifies targets at the forefront of oncology—the DNA damage response and immunotherapy. This review covers the mechanisms by which radiation induces TGFβ activation, how TGFβ regulates DNA repair, and the dynamic regulation of the tumor immune microenvironment that together oppose effective cancer therapy.
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Penninckx S, Pariset E, Cekanaviciute E, Costes SV NAR Cancer. 2021 Dec 22;3(4):zcab046.
Summary:
Radiation-induced foci (RIF), which are nuclear puncta visualized by immunostaining of proteins, have been used as a surrogate marker of DNA double strand breaks (DSB) for the past 25 years. RIF formation and foci baseline have great potential to predict in vivo responses to ionizing radiation, predisposition to cancer and probability of adverse reactions to radiotherapy. In this review, we discuss the spatiotemporal characteristics of RIF after irradiation, addressing the common confounding factors, including cell proliferation and foci merging. We also summarize mathematical models to interpret RIF formation and resolution. This article was intended to guide the scientific community design radiobiology experiments using RIF as a key metric and to provide the necessary background for accurate biological interpretation.
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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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Shuryak I, Loucas BD, Cornforth MN. Radiat Res. 2021 Aug 1;196(2):147-55. [1/29/2022]
Summary:
The large majority of chromosome damage produced by ionizing radiations takes the form of exchange aberrations. For simple exchanges between two chromosomes, multi-fluor fluorescence in situ hybridization (mFISH) studies confirm that the dose response to X rays or gamma rays is quasilinear with dose. This result is in seeming conflict with generalized theories of radiation action that depend on the interaction of lesions as the source of curvature in dose-response relationships. A qualitative explanation for such "linearization" had been previously proposed but lacked quantitative support. The essence of this explanation is that during the rejoining of radiogenic chromosome breaks, competition for breaks (CFB) between different aberration types often results in formation of complex exchange aberrations at the expense of simple reciprocal exchange events. This process becomes more likely at high radiation doses, where the number of contemporaneous breaks is high and complex exchanges involving multiple breaks become possible. Here we provide mathematical support for this CFB concept under the assumption that the mean and variance for exchange complexity increase with radiation dose.
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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.
[01/18/2022]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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Ferroptosis, a new form of cell death defined after radiation exposure.
Zhang X, Li X, Zheng C, Yang C, Zhang R, Wang A, Feng J, Hu X, Chang S, Zhang H. Int J Radiat Biol. 2022 Jan 4;1-9. Online ahead of print. [1/18/2022]
Summary:
Ionizing radiation induces an increase in hydroxyl radicals, free iron, and lipid metabolic enzymes, which subsequently synergistically initiate a high level of lipid peroxidation, making ionizing radiation an exogenous inducer of ferroptosis. In addition, ferroptosis may be the primary form of cell death in the bone marrow under hematopoietic acute radiation syndrome. Ionizing radiation can also induce changes in iron metabolism, which may be a target for regulating ferroptosis. Finally, ionizing radiation-induced ferroptosis initiates from the cytoplasm and ends on the membrane, and is independent of DNA damage.
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Pengwei Luo, Xiaoping Zhang, Shuai Fu, Yong Li, Cunhui Li, Jinbin Cao and published in SCIENCE ADVANCES • 14 Jan 2022 • Vol 8, Issue 2
[01/18/2022]Summary:
The radiation environment on the lunar surface is strongly affected by cosmic rays and the albedo particles produced by their interactions with the lunar surface. However, the data of the cosmic ray energy spectra is still absent to date. To better evaluate the radiation level, measurements of the cosmic ray energy spectra on the lunar surface are paramount. In this work, we obtained the energy spectra of cosmic ray protons, alpha particles, CNO, and heavy ions with energies ranging from ~10 MeV/nuc to ~100 MeV/nuc based on the data collected by the Lunar Lander Neutron and Dosimetry (LND) instrument onboard the Chang’E-4 (CE-4) lander around the solar minimum 24/25.
The comparisons of the CE-4/LND measurements to those observations from several near-earth spacecraft, such as the ACE, the SOHO, and the STEREO-A, show that they were consistent within 1.7 standard deviations, indicating that the influence of the lunar surroundings, like magnetic anomalies, on these energy spectra is negligible. Considering that the higher energy particles are less sensitive to the lunar surroundings, this conclusion can be further extended to the higher energy spectra of these particles. We also extracted the He isotope ratios and a prominent enhancement was observed at ~12 MeV/nuc. In addition, the dawn-dusk symmetry of the energy spectrum was confirmed, which will guide the selections of landing times for future crewed lunar missions and extravehicular activities on the lunar surface. In short, the above findings will promote human understanding of the lunar radiation environment and benefit future lunar explorations.
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Mitochondrial effects in the liver of C57BL/6 mice by low dose, high energy, high charge irradiation
Barnette BL, Yu Y, Ullrich RL, Emmett MR. Int J Mol Sci. 2021 Nov;22(21):11806. [12/20/2021]
[12/20/2021]Summary:
This publication is the first full multi-omics, systems biological study (encompassing transcriptomics, proteomics, lipidomics, metabolomics and specific biological assays) to monitor the microenvironmental changes induced by low-dose high-charge, high-energy (HZE) exposure in C57BL/6 mouse liver. These studies were performed to study microenviromental changes induced by low-dose HZE leading to hepatocellular carcinoma (HCC). The C57BL/6 mouse is relatively resistant to low-dose HZE induced HCC and thus, it was unexpected to observe the mitochondrial dysfunction in their livers after low-dose HZE exposure. The HZE induced mitochondrial dysfunction was exhibited in all omics datasets (transcriptomics, proteomics, lipidomics & metabolomics) and was also validated through mitochondrial Complex I biochemical assays. Mitochondria effects induced by HZE irradiation are novel, real, and important to the health and safety of the astronauts. Not only in liver but these effects could also be very detrimental in brain and cardiac tissue that have high levels of mitochondria. The systems biological approach identified possible countermeasures that are targeted to specific biological pathways that are discussed as possible mediators of exposure to low-dose HZE.
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Plante I, Poignant F, Slaba T., Life (Basel). 2021 Oct 20;11(11):1112. [12/16/2021]
[12/16/2021]Summary:
To understand the biological effects of radiation, it is important to determine how ionizing radiation deposits energy in micrometric targets. The energy deposited in a target located in an irradiated tissue is a function of several factors such as the radiation type and the irradiated volume size. We simulated the energy deposited by energetic ions in spherical targets of 1, 2, 4, and 8 µm radii encompassed in irradiated parallelepiped volumes of various sizes using the stochastic radiation track structure code Relativistic Ion Tracks (RITRACKS). Because cells are usually part of a tissue when they are irradiated, electrons originating from radiation tracks in neighboring volumes also contribute to energy deposition in the target. To account for this contribution, we used periodic boundary conditions in the simulations. We found that the single-ion spectra of energy deposition in targets comprises two components: the direct ion hits to the targets, which is identical in all irradiation conditions, and the contribution of hits from electrons from neighboring volumes, which depends on the irradiated volume. We also calculated an analytical expression of the indirect hit contributions using the local effect model, which showed results similar to those obtained with RITRACKS.
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Francesco G. Cordoni; Marta Missiaggia; Emanuele Scifoni; Chiara La Tessa Radiat Res (2022) 197 (3): 218–232.
[12/02/2021]Summary:
This article presents the Generalized Stochastic Microdosimetric Model (GSM2) for computing explicitly a cell survival curve. GSM2 is a general probabilistic model that predicts the kinetic evolution of DNA damages taking full advantage of a microdosimetric description of a radiation energy deposition.
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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.
[11/13/2021]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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Rühle A, Ping D, Lopez Perez R, Strack M, Brons S, Yijia Q, Debus J, Wuchter P, Grosu AL, Huber PE, Nicolay NH. and published in Cancer Lett. 2022 Jan;524:172-81. Available online 21 October 2021.
[11/13/2021]Summary:
The influence of high-linear energy transfer (LET) particle radiation on the functionalities of mesenchymal stromal cells (MSCs) is largely unknown. Here, we analyzed the effects of proton (1H), helium (4He), carbon (12C) and oxygen (16O) ions on human bone marrow-MSCs. Cell cycle distribution and apoptosis induction were examined by flow cytometry, and DNA damage was quantified using ?H2AX immunofluorescence and Western blots. Relative biological effectiveness values of MSCs amounted to 1.0–1.1 for 1H, 1.7–2.3 for 4He, 2.9–3.4 for 12C and 2.6–3.3 for 16O. Particle radiation did not alter the MSCs’ characteristic surface marker pattern, and MSCs maintained their multi-lineage differentiation capabilities. Apoptosis rates ranged low for all radiation modalities. At 24 h after irradiation, particle radiation-induced ATM and CHK2 phosphorylation as well as ?H2AX foci numbers returned to baseline levels. The resistance of human MSCs to high-LET irradiation suggests that MSCs remain functional after exposure to moderate doses of particle radiation as seen in normal tissues after particle radiotherapy or during manned space flights. In the future, in vivo models focusing on long-term consequences of particle irradiation on the bone marrow niche and MSCs are needed.
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Historical reconstruction of astronaut cancer risk: Context for recent solar minima
Slaba TC. Space Weather. 2021 Oct;19(10):e2021SW002851
Summary:
Recent observational data and model predictions have suggested an intensifying galactic cosmic ray environment. This could have an impact on mission planning and crew safety as space exploration extends beyond low Earth orbit for longer durations. Updated models and data are evaluated in this work to provide historical context for recent observations. It is shown that projected risks vary by only +10% over all historical minima since 1750. This degree of historical variation is within combined environmental and physics uncertainties already accounted for in the probabilistic cancer risk model used by NASA for crew health and safety considerations. Uncertainties for epidemiology and radiobiology models remain significantly larger than combined physics uncertainties; however, new measurement data and model development efforts should continue to be supported by NASA and international partners to improve our understanding of the space environment.
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Mortality from leukemia, cancer and heart disease among U.S. nuclear power plant workers, 1957-2011
Boice JD Jr, Cohen SS, Mumma MT, Hagemeyer DA, Chen H, Golden AP, Yoder RC, Dauer LT.
Int J Radiat Biol. 2021 Oct 20;1-67. Online ahead of print.
[11/10/2021]Summary:
The aim of the Million Person Study (MPS) of Low Dose Health Effects is to examine the level of radiation risk for chronic exposures received gradually over time and not acutely as was the case for the Japanese atomic bomb survivors. Leukemia, selected cancers, Parkinson's disease, ischemic heart disease (IHD) and other causes of death are evaluated. Prolonged exposure to radiation increased the risk of leukemia other than CLL among NPP workers. There was little evidence for a radiation-association for all solid cancers, lung cancer or ischemic heart disease. Increased precision will be forthcoming as the different cohorts within the MPS are combined, such as industrial radiographers and medical radiation workers who were assembled and evaluated in like manner.
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Improving astronaut cancer risk assessment from space radiation with an ensemble model framework
Simonsen LC, Slaba TC and published in Life Sci Space Res (Amst). 2021 Nov;31:14-28.
[11/10/2021]Summary:
A new approach to NASA space radiation risk modeling has successfully extended the current NASA probabilistic cancer risk model to an ensemble framework able to consider sub-model parameter uncertainty as well as model-form uncertainty associated with differing theoretical or empirical formalisms. Applying ensemble methodologies to space radiation risk projections offers the potential to efficiently incorporate emerging research results, allow for the incorporation of future models, improve uncertainty quantification, and reduce the impact of subjective bias. In these analyses, the ensemble forecast compares well to results from NASA’s current operational cancer risk projection model used to assess permissible mission durations for astronauts. However, a large range of projected risk values are obtained at the upper 95th confidence level where models must extrapolate beyond available biological data sets.
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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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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.
[11/08/2021]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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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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Kadhim M, Tuncay Cagatay S, Elbakrawy EM. and published in Int J Radiat Biol. 2021 Oct 18:1-39. Online ahead of print.
[11/02/2021]Summary:
Radiation-induced “non-targeted effects” (NTE) have implications in a variety of areas relevant to radiation biology. Here we evaluate the various cargoes associated with exosomal signalling and how they work synergistically to initiate and propagate the non-targeted effects including genomic instability and bystander effects. Extracellular vesicles (EV), in particular exosomes, have been shown to carry bystander signals. Exosome cargo may contain nucleic acids, both DNA and RNA, as well as proteins, lipids, and metabolites. These cargo molecules have all been considered as potential mediators of NTE. A review of current literature shows mounting evidence of a role for ionizing radiation in modulating both the numbers of exosomes released from affected cells as well as the content of their cargo, and that these exosomes can instigate functional changes in recipient cells. However, there are significant gaps in our understanding, particularly regarding modified exosome cargo after radiation exposure and the functional changes induced in recipient cells. Also, there are a number of interesting research questions relating to the whole EV field and not limited to radiation biology. Finding answers to these questions may lead to novel therapies, prognostic and diagnostic biomarkers, and an enhanced understanding of intercellular communication.
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A Geant4-DNA evaluation of radiation-induced DNA damage on a human fibroblast
Shin WG, Sakata D, Lampe N, Belov O, Tran NH, Petrovic I, Ristic-Fira A, Dordevic M, Bernal MA, Bordage MC, Francis Z, Kyriakou I, Perrot Y, Sasaki T, Villagrasa C, Guatelli S, Breton V, Emfietzoglou D, Incerti S. Cancers (Basel). 2021 Oct;13(19):4940
[10/30/2021]Summary:
Accurate modeling of the radiobiological mechanisms responsible for the induction of DNA damage remains a major scientific challenge. In this work, the assessment of DNA damage in a human fibroblast cell using the Geant4-DNA Monte Carlo toolkit is described. A validation study using a computational geometric model of human DNA was performed and the calculated DNA damage as a function of particle type and energy is presented. The results of this work showed a significant improvement over previous work and are consistent with recent radiobiological experimental data, such as damage yields. The complete simulation chain application "molecularDNA", an example for users of Geant4-DNA, will soon be distributed through Geant4.
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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
[10/30/2021]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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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
[10/30/2021]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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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.
[10/25/2021]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.
[10/18/2021]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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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
[10/04/2021]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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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. Int J Mol Sci. 2021 Sep;22(19):10507. Review.
[10/04/2021]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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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.
[10/01/2021]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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Borg AM, Baker JE. Synth Biol (Oxf). 2021 Sep 2;6(1):ysab023.
[09/27/2021]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.
[09/23/2021]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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Destabilizing effects of ionizing radiation on chromosomes: Sizing up the damage
Cornforth MN, Bedford JS, Bailey SM and published in Cytogenet Genome Res. 2021 Sep 6;1-24. Review.
[09/23/2021]Summary:
For long-term survival and evolution, all organisms have depended on a delicate balance between processes involved in maintaining stability of their genomes and opposing processes that lead toward destabilization. At the level of mammalian somatic cells in renewal tissues, events or conditions that can tip this balance toward instability have attracted special interest in connection with carcinogenesis. Mutations affecting DNA (and its subsequent repair) would, of course, be a major consideration here. These may occur spontaneously through endogenous cellular processes or as a result of exposure to mutagenic environmental agents. It is in this context that we discuss the rather unique destabilizing effects of ionizing radiation (IR) in terms of its ability to cause large-scale structural rearrangements to the genome. We present arguments supporting the conclusion that these and other important effects of IR originate largely from microscopically visible chromosome aberrations.
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Yamanouchi S, Adachi T, Yoshida Y, Rhone J, Mao J-H, Fujiwara K, Saganti PB, Takahashi A, Hada M. Biological Sciences in Space. 2021;35:15-23.
[09/23/2021]Summary:
We investigated the combined effect of µG and space radiation on human peripheral blood lymphocytes. Whole blood was irradiated with X-ray or carbon-ion (C-ion) beam while being exposed to simulated µG using a three-dimensional clinostat. The frequency of chromosome aberrations (CA) was assessed using the three-color fluorescence in situ hybridization on chromosome spreads of Colcemid-induced prematurely condensed chromosomes in lymphocytes during the first cell division post irradiation. Compared with the cells irradiated at 1G, the frequency of CA was increased in cells simultaneously exposed to simulated µG and radiation. This result is similar to those of our previous studies in which we used human lymphoblast TK6 cells and human fibroblast IBR-hTERT cells.
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Singh VK, Seed TM. in Int J Radiat Biol. 2021 Aug 17;1-67. Review.
[08/30/2021]Summary:
This article reports the status of pharmaceuticals currently being developed for possible use for individuals unwantedly and acutely injured as a result of radiological/nuclear exposures. A limited number of medicinals (namely filigrastim, pegfiligrastim, sargramostim and romiplostim) have been deemed sufficiently safe and effective by the US FDA for use in treating the ‘hematopoietic acute radiation syndrome. All of these agents are recombinant growth factors that target and stimulate progenitors within bone marrow, thus serving to foster hematopoietic recovery following acute irradiation. Comparable medicinals for the other major sub-syndromes of ARS are currently lacking, but much needed. The research and development of such medicinals will undoubtedly entail some form of a polypharmaceutical strategy, or perhaps novel, bioengineered chimeric agents with multiple, radioprotective/radiomitigative functionalities.
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Protective Effects of Amino Acids on Plasmid DNA Damage Induced by Therapeutic Carbon Ions
Katsunori Yogo, Chieko Murayama, Ryoichi Hirayama, Ken-ichiro Matsumoto, Ikuo Nakanishi, Hiromichi Ishiyama, Hiroshi Yasuda Radiation Research, 196(2), 197-203, (27 May 2021)
[08/25/2021]Summary:
With the aim of finding the most effective radioprotector against heavy ions, we investigated systematically the radioprotective effects of five amino acids: tryptophan (Trp), cysteine (Cys), methionine (Met), valine (Val) and alanine (Ala) on the damage yields of plasmid DNA. The samples were irradiated with 290 MeV/u carbon-ion beams on spread-out Bragg peak at HIMAC, Japan. As results, some amino acids such as Trp, Cys and Met showed good radioprotective effects in regard to the double strand breaks of plasmid DNA. It was indicated that the radioprotective effects against carbon ions could be explained primarily based on the scavenging capacity of radiation-induced radicals.
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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
[08/16/2021]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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Kodaira S, Naito M, Uchihori Y, Hashimoto H, Yano H, Yamagishi A. Astrobiology. 2021 Aug 4.. doi: 10.1089/ast.2020.2427. Epub ahead of print. PMID: 34348047.
[08/14/2021]Summary:
Radiation dosimetry was carried out at the exposure facility (EF) and the pressurized module (PM) of the Japanese Kibo module installed in the International Space Station as one study on environmental monitoring for the Tanpopo mission. Three exposure panels and three references including biological and organic samples and luminescence dosimeters were launched to obtain data for different exposure durations during 3 years from May 2015 to July 2018. The dosimeters were equipped with additional shielding materials (0.55, 2.95, and 6.23 g/cm2 mass thickness). The relative dose variation, as a function of shielding mass thickness, was observed and compared with Monte Carlo simulations with respect to galactic cosmic rays (GCRs) and typical solar energetic particles (SEPs). The mean annual dose rates were DEF = 231 ± 5 mGy/year at the EF and DPM = 82 ± 1 mGy/year at the PM during the 3 years. The PM is well shielded, and the GCR simulation indicated that the measured mean dose reduction ratio inside the module (DPM/DEF = 0.35) required ~26 g/cm2 additional shielding mass thickness. Observed points of the dose reduction tendency could be explained by the energy ranges of protons (10-100 MeV), where the protons passed through, or were absorbed in, the shielding materials of different mass thickness that surrounded dosimeters.
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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. [07/31/2021]
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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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 [07/20/2021]
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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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. [06/29/2021]
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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Evaluating the long-term effect of space radiation on the reproductive normality of mammalian sperm preserved on the International Space Station
Wakayama S, Ito D, Kamada Y, Shimazu T, Suzuki T, Nagamatsu A, Araki R, Ishikawa T, Kamimura S, Hirose N, Kazama K, Yang L, Inoue R, Kikuchi Y, Hayashi E, Emura R, Watanabe R, Nagatomo H, Suzuki H, Yamamori T, Tada MN, Osada I, Umehara M, Sano H, Kasahara H, Higashibata A, Yano S, Abe M, Kishigami S, Kohda T, Ooga M, Wakayama T. Sci Adv. 2021 Jun 11;7(24):eabg5554. [06/28/2021]
Summary:
Space radiation may cause DNA damage to cells and concern for the inheritance of mutations in offspring after deep space exploration. However, there is no way to study the long-term effects of space radiation using biological materials. Here, we developed a method to evaluate the biological effect of space radiation and examined the reproductive potential of mouse freeze-dried spermatozoa stored on the International Space Station (ISS) for the longest period in biological research. The space radiation did not affect sperm DNA or fertility after preservation on ISS, and many genetically normal offspring were obtained without reducing the success rate compared to the ground-preserved control. The results of ground x-ray experiments showed that sperm can be stored for more than 200 years in space. These results suggest that the effect of deep space radiation on mammalian reproduction can be evaluated using spermatozoa, even without being monitored by astronauts in Gateway.
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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. [06/14/2021]
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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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. [05/18/2021]
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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The role of nutrition in space exploration: Implications for sensorimotor, cognition, behavior and the cerebral changes due to the exposure to radiation, altered gravity, and isolation/confinement hazards of spaceflight
Zwart SR, Mulavara AP, Williams TJ, George K, Smith SM. Neurosci Biobehav Rev. 2021 Apr 26;S0149-7634(21)00185-8. Review. [05/12/2021]
Summary:
Accumulated evidence suggests that nutrition has an important role in optimizing cognition and reducing the risk of neurodegenerative diseases caused by neuroinflammation. Here we review the nutritional perspective of how these spaceflight hazards affect the astronaut's brain, behavior, performance, and sensorimotor function. We also assess potential nutrient/nutritional countermeasures that could prevent or mitigate spaceflight risks and ensure that crewmembers remain healthy and perform well during their missions.
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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 [04/30/2021]
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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Observations of neutron radiation environment during Odyssey cruise to Mars
M.L. Litvak, I.G. Mitrofanov, A.B. Sanin, B. Bakhtin, D.V. Golovin, C. Zeitlin, Life Sciences in Space Research, 2021, Volume 29, May 2021, Pages 53-62 [04/23/2021]
Summary:
In April 2001, Mars Odyssey spacecraft with the High Energy Neutron Detector (HEND) onboard was launched to Mars. HEND/Odyssey was switched on measurement mode for most of transit to Mars to monitor variations of spacecraft background and solar activity. Although HEND/Odyssey was originally designed to measure Martian neutron albedo and to search for Martian subsurface water/water ice, its measurements during cruise phase to Mars are applicable to evaluate spacecraft ambient radiation background. We have modeled the spacecraft neutron spectral density and compared it with HEND measurements to estimate neutron dose equivalent rates during Odyssey cruise phase, which occurred during the maximum period of solar cycle 23. We find that the Odyssey ambient neutron environment during May - September 2001 yields 10.6 ± 2.0 µSv per day in the energy range from 0 to 15 MeV, and about 29 µSv per day when extrapolated to the 0-1000 MeV energy range during solar quiet time (intervals without Solar Particle Events, SPEs). We have also extrapolated HEND/Odyssey measurements to different periods of solar cycle and find that during solar minimum (maximum of GCR flux), the neutron dose equivalent rate during cruise to Mars could be as high as 52 µSv per day with the same shielding. These values are in good agreement with results reported for a similar measurement made with an instrument aboard the Mars Science Laboratory during its cruise to Mars in 2011-2012.
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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. [04/20/2021]
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. [04/11/2021]
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. [04/02/2021]
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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