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NASA NTRS2012

Combined Effects of Gamma Radiation and High Dietary Iron on Peripheral Leukocyte Distribution and Function

Both radiation and increased iron stores can independently increase oxidative damage, resulting in protein, lipid and DNA oxidation. Oxidative stress increases the risk of many health problems including cancer, cataracts, and heart disease. This study, a subset of a larger interdisciplinary investigation of the combined effect of iron overload on sensitivity to radiation injury, monitored immune parameters in the peripheral blood of rats subjected to gamma radiation, high dietary iron or both. Specific immune measures consisted of: (1) peripheral leukocyte distribution, (2) plasma cytokine levels and (3) cytokine production profiles following whole blood mitogenic stimulation

Crucian, Brian E.↗

NASA NTRS2011

Assessment of Resistance of Bacillus Horneckiae Endospores to UV Radiation and Function of Their Extraneous Layer in Resistance

Spore-forming microbes are highly resistant to various physical and chemical conditions, which include ionizing and UV radiation, desiccation and oxidative stress, and the harsh environment of outer space or planetary surfaces. The spore's resistance might be due to their metabolically dormant state, and/or by the presence of a series of protective structures that encase the interior-most compartment, the core, which houses the spore chromosome. These spores have multiple layers surrounding the cell that are not found in vegetative cells, and some species have an outer layer of proteins and glycoproteins termed the "exosporium" or a fibrous "extraneous layer" (EL). Bacillus horneckiae is an EL-producing novel sporeformer isolated from a Phoenix spacecraft assembly clean room, and it has previously demonstrated resistance to UV radiation up to 1000 J/m(sup 2). The EL appears to bind B. horneckiae spores into large aggregations, or biofilms, and may confer some UV resistance to the spores. Multiple culturing and purification schemes were tried to achieve high purity spores because vegetative cells would skew UV resistance results. An ethanol-based purification scheme produced high purity spores. Selective removal of the EL from spores was attempted with two schemes: a chemical extraction method and physical extraction (sonication). Results from survival rates in the presence and absence of the external layer will provide a new understanding of the role of biofilms and passive resistance that may favor survival of biological systems in aggressive extra-terrestrial environments. The chemical extraction method decreased viable counts of spores and lead to an inconclusive change UV resistance relative to non-extracted spores. The physical extraction method lead to non-aggregated spores and did not alter viability; however, it produced UV resistance profiles similar to non-extracted spores. In addition to the EL-removal study, samples of B. horneckiae spores dried on aluminum coupons and exposed to increasing UV (200-400 nm range) levels (0 to 8.0 x 105 kJ/m(sup 2)) were tested for viability, which indicated that the maximum UV exposure level that still resulted in viable spores was 5.0 x 10? kJ/m(sup 2).

resistance↗

NASA NTRS2013

Spaceflight and the Mouse Eye: Results from Experiments on Shuttle Missions STS-133 and STS-135

Vision alterations associated with globe flattening, chorodial folds and papilledema, shown in some crew members returning from long duration missions. Hypothesis: Ocular neuroanatomical changes observed in the VIIP syndrome are accompanied by retinal changes at the molecular and cellular level that may affect retinal health and physiology. Objective: Investigate evidence of ocular (retinal) changes associated with spaceflight: (1) histological markers of cellular death and damage (2) molecular markers of oxidative stress (3) gene expression markers of stress

Zanello, Susana B.↗

NASA NTRS2013

NASA Models of Space Radiation Induced Cancer, Circulatory Disease, and Central Nervous System Effects

The risks of late effects from galactic cosmic rays (GCR) and solar particle events (SPE) are potentially a limitation to long-term space travel. The late effects of highest concern have significant lethality including cancer, effects to the central nervous system (CNS), and circulatory diseases (CD). For cancer and CD the use of age and gender specific models with uncertainty assessments based on human epidemiology data for low LET radiation combined with relative biological effectiveness factors (RBEs) and dose- and dose-rate reduction effectiveness factors (DDREF) to extrapolate these results to space radiation exposures is considered the current "state-of-the-art". The revised NASA Space Risk Model (NSRM-2014) is based on recent radio-epidemiology data for cancer and CD, however a key feature of the NSRM-2014 is the formulation of particle fluence and track structure based radiation quality factors for solid cancer and leukemia risk estimates, which are distinct from the ICRP quality factors, and shown to lead to smaller uncertainties in risk estimates. Many persons exposed to radiation on earth as well as astronauts are life-time never-smokers, which is estimated to significantly modify radiation cancer and CD risk estimates. A key feature of the NASA radiation protection model is the classification of radiation workers by smoking history in setting dose limits. Possible qualitative differences between GCR and low LET radiation increase uncertainties and are not included in previous risk estimates. Two important qualitative differences are emerging from research studies. The first is the increased lethality of tumors observed in animal models compared to low LET radiation or background tumors. The second are Non- Targeted Effects (NTE), which include bystander effects and genomic instability, which has been observed in cell and animal models of cancer risks. NTE's could lead to significant changes in RBE and DDREF estimates for GCR particles, and the potential effectiveness of radiation mitigator's. The NSRM- 2014 approaches to model radiation quality dependent lethality and NTE's will be described. CNS effects include both early changes that may occur during long space missions and late effects such as Alzheimer's disease (AD). AD effects 50% of the population above age 80-yr, is a degenerative disease that worsens with time after initial onset leading to death, and has no known cure. AD is difficult to detect at early stages and the small number of low LET epidemiology studies undertaken have not identified an association with low dose radiation. However experimental studies in mice suggest GCR may lead to early onset AD. We discuss modeling approaches to consider mechanisms whereby radiation would lead to earlier onset of occurrence of AD. Biomarkers of AD include amyloid beta (A(Beta)) plaques, and neurofibrillary tangles (NFT) made up of aggregates of the hyperphosphorylated form of the micro-tubule associated, tau protein. Related markers include synaptic degeneration, dentritic spine loss, and neuronal cell loss through apoptosis. Radiation may affect these processes by causing oxidative stress, aberrant signaling following DNA damage, and chronic neuroinflammation. Cell types to be considered in multi-scale models are neurons, astrocytes, and microglia. We developed biochemical and cell kinetics models of DNA damage signaling related to glycogen synthase kinase-3(Beta) (GSK3(Beta)) and neuroinflammation, and considered multi-scale modeling approaches to develop computer simulations of cell interactions and their relationships to A(Beta) plaques and NFTs. Comparison of model results to experimental data for the age specific development of A(Beta) plaques in transgenic mice will be discussed.

Cucinotta, Francis A.↗

NASA NTRS2013

Biological Effects of Particles with Very High Energy Deposition on Mammalian Cells Utilizing the Brookhaven Tandem Van de Graaff Accelerator

High LET radiation from GCR (Galactic Cosmic Rays) consisting mainly of high charge and energy (HZE) nuclei and secondary protons and neutrons, and secondaries from protons in SPE (Solar Particle Event) pose a major health risk to astronauts due to induction of DNA damage and oxidative stress. Experiments with high energy particles mimicking the space environment for estimation of radiation risk are being performed at NASA Space Radiation Laboratory at BNL. Experiments with low energy particles comparing to high energy particles of similar LET are of interest for investigation of the role of track structure on biological effects. For this purpose, we report results utilizing the Tandem Van de Graaff accelerator at BNL. The primary objective of our studies is to elucidate the influence of high vs low energy deposition on track structure, delta ray contribution and resulting biological responses. These low energy ions are of special relevance as these energies may occur following absorption through the spacecraft and shielding materials in human tissues and nuclear fragments produced in tissues by high energy protons and neutrons. This study will help to verify the efficiency of these low energy particles and better understand how various cell types respond to them.

Saha, Janapriya↗

NASA NTRS2014

Effects of Radiation and Dietary Iron on Expression of Genes and Proteins Involved in Drug Metabolism

Liver function, especially the rate of metabolic enzyme activities, determines the concentration of circulating drugs and the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand any effects of spaceflight on the enzymes of the liver. Dietary factors and exposure to radiation are aspects of spaceflight that are potential oxidative stressors and both can be modeled in ground experiments. In this experiment, we examined the effects of high dietary iron and low dose gamma radiation (individually and combined) on the gene expression of enzymes involved in drug metabolism, redox homeostasis, and DNA repair. METHODS All procedures were approved by the JSC Animal Care and Use Committee. Male Sprague-Dawley rats were divided into 4 groups (n=8); control, high Fe diet (650 mg iron/kg), radiation (fractionated 3 Gy exposure from a Cs- 137 source) and combined high Fe diet + radiation exposure. Animals were euthanized 24h after the last treatment of radiation; livers were removed immediately and flash -frozen in liquid nitrogen. Expression of genes thought to be involved in redox homeostasis, drug metabolism and DNA damage repair was measured by RT-qPCR. Where possible, protein expression of the same genes was measured by western blotting. All data are expressed as % change in expression normalized to reference gene expression; comparisons were then made of each treatment group to the sham exposed/ normal diet control group. Data was considered significant at p< 0.5. RESULTS Among the redox homeostasis genes examined, metallothionein showed a significant down regulation in the radiation treated group (-3.85 fold) and a trend toward down regulation in the high Fe + rad group. Metallothionein is involved in the regulation of physiological metals and also has antioxidant activities. Among the drug metabolism genes examined, ATP binding cassette subfamily B (Abcb1b) gene expression increased more than 10-fold in both groups that received radiation treatments. This increased expression was also seen at the protein level. This ABC transporter carries many different compounds across cell membranes, including administered medications. The cytochrome P450 2E1 enzyme, a mixed-function oxidase that deactivates some medications and activates others, showed about a 2-fold increase in gene expression in both radiation-treated groups, with a trend toward increased expression at the protein level. Expression of epoxide hydrolase, which detoxifies polycyclic aromatic hydrocarbons, showed similar 2-fold increases. Among the DNA repair genes examined, expression of RAD51 was significantly down regulated (1.5 fold) in the radiation treated group. RAD51 is involved in repair of double-stranded DNA breaks. CONCLUSION This experiment used 2 different sources of physiological oxidative stress, administered separately and together, and examined their impacts on liver gene and protein expression. It is clear that significant changes occurred in expression of several genes and proteins in the radiation-treated animals. If the results from this ground analog of portions of the spaceflight environment hold true for the spaceflight environment itself, the physiological roles of the affected enzymes (drug transport and metabolism, redox homeostasis) could mean consequences in redox homeostasis or the pharmacokinetics of administered medications

Faust, K. M.↗

NASA NTRS2014

Chronic Lunar Dust Exposure on Rat Cornea: Evaluation by Gene Expression Profiling

Lunar dust is capable of entering habitats and vehicle compartments by sticking to spacesuits or other objects that are transferred into the spacecraft from the lunar surface and has been reported to cause irritation upon exposure. During the Apollo missions, crewmembers reported irritation specifically to the skin and eyes after contamination of the lunar and service modules. It has since been hypothesized that ocular irritation and abrasion might occur as a result of such exposure, impairing crew vision. Recent work has shown that both ultrafine and unground lunar dust exhibited minimal irritancy of the ocular surface (i.e., cornea); however, the assessment of the severity of ocular damage resulting from contact of lunar dust particles to the cornea has focused only on macroscopic signs of mechanical irritancy and cytotoxicity. Given the chemical reactive properties of lunar dust, exposure of the cornea may contribute to detrimental effects at the molecular level including but not limited to oxidative damage. Additionally, low level chronic exposures may confound any results obtained in previous acute studies. We report here preliminary results from a tissue sharing effort using 10‐week‐old Fischer 344 male rats chronically exposed to filtered air or jet milled lunar dust collected during Apollo 14 using a Jaeger‐NYU nose‐only chamber for a total of 120 hours (6 hours daily, 5 days a week) over a 4‐week period. RNA was isolated from corneas collected from rats at 1 day and 7 days after being exposed to concentrations of 0, 20, and 60 mg/m3 of lunar dust. Microarray analysis was performed using the Affymetrix GeneChip Rat Genome 230 2.0 Array with Affymetrix Expression Console and Transcriptome Analysis Console used for normalization and secondary analysis. An Ingenuity iReport"TM" was then generated for canonical pathway identification. The number of differentially expressed genes identified increases with dose compared to controls suggesting a more severe response to the lunar dust insult at higher levels. Pathways of interests that have been identified in all exposed samples include oxidative stress response, mitochondrial dysfunction, fibrosis, epithelial healing, TGF-Beta signaling, and extracellular matrix remodeling. Several biological processes related to cell migration, cellular proliferation, and eye development were also identified to be altered by exposure to lunar dust. Our preliminary results suggest that even a chronic insult of lunar dust as low as 20 mg/m(exp 3) elicits a molecular response in cornea tissue. Lunar dust on the surface of the moon would have the added properties of ionization and activation potentially leading to further damage to the cornea and greater sensitivity to any other environmental insult such as exposure to radiation. Additional studies are required to fully assess the risk of vision impairment and the mechanistic responses initiated in cornea exposed to lunar dust as well as the potential for long‐term effects to astronaut health

Theriot, C. A.↗

NASA NTRS2014

Protecting Neural Structures and Cognitive Function During Prolonged Space Flight by Targeting the Brain Derived Neurotrophic Factor Molecular Network

Brain derived neurotrophic factor (BDNF) is the main activity-dependent neurotrophin in the human nervous system. BDNF is implicated in production of new neurons from dentate gyrus stem cells (hippocampal neurogenesis), synapse formation, sprouting of new axons, growth of new axons, sprouting of new dendrites, and neuron survival. Alterations in the amount or activity of BDNF can produce significant detrimental changes to cortical function and synaptic transmission in the human brain. This can result in glial and neuronal dysfunction, which may contribute to a range of clinical conditions, spanning a number of learning, behavioral, and neurological disorders. There is an extensive body of work surrounding the BDNF molecular network, including BDNF gene polymorphisms, methylated BDNF gene promoters, multiple gene transcripts, varied BDNF functional proteins, and different BDNF receptors (whose activation differentially drive the neuron to neurogenesis or apoptosis). BDNF is also closely linked to mitochondrial biogenesis through PGC-1alpha, which can influence brain and muscle metabolic efficiency. BDNF AS A HUMAN SPACE FLIGHT COUNTERMEASURE TARGET Earth-based studies reveal that BDNF is negatively impacted by many of the conditions encountered in the space environment, including oxidative stress, radiation, psychological stressors, sleep deprivation, and many others. A growing body of work suggests that the BDNF network is responsive to a range of diet, nutrition, exercise, drug, and other types of influences. This section explores the BDNF network in the context of 1) protecting the brain and nervous system in the space environment, 2) optimizing neurobehavioral performance in space, and 3) reducing the residual effects of space flight on the nervous system on return to Earth

Schmidt, M. A.↗

NASA NTRS2015

Evidence Report: Risk Factor of Inadequate Nutrition

The importance of nutrition in exploration has been documented repeatedly throughout history, where, for example, in the period between Columbus' voyage in 1492 and the invention of the steam engine, scurvy resulted in more sailor deaths than all other causes of death combined. Because nutrients are required for the structure and function of every cell and every system in the body, defining the nutrient requirements for spaceflight and ensuring provision and intake of those nutrients are primary issues for crew health and mission success. Unique aspects of nutrition during space travel include the overarching physiological adaptation to weightlessness, psychological adaptation to extreme and remote environments, and the ability of nutrition and nutrients to serve as countermeasures to ameliorate the negative effects of spaceflight on the human body. Key areas of clinical concern for long-duration spaceflight include loss of body mass (general inadequate food intake), bone and muscle loss, cardiovascular and immune system decrements, increased radiation exposure and oxidative stress, vision and ophthalmic changes, behavior and performance, nutrient supply during extravehicular activity, and general depletion of body nutrient stores because of inadequate food supply, inadequate food intake, increased metabolism, and/or irreversible loss of nutrients. These topics are reviewed herein, based on the current gap structure.

Smith, Scott M.↗

NASA NTRS2012

Survival of B. Horneckiae Spores Under Ground-simulated Space Conditions

To prevent forward contamination and maintain the scientific integrity of future life detection missions, it is important to characterize and attempt to eliminate terrestrial microorganisms associated with exploratory spacecraft and landing vehicles. Among the organisms isolated from spacecraft-associated habitats, spore-forming microbes are highly resistant to various physical and chemical conditions, which include ionizing and UV radiation, desiccation and oxidative stress, and the harsh environment of outer space or planetary surfaces. Recently a radiation resistant, spore forming bacterial isolate, Bacillus horneckiae, was isolated from a clean room of the Kennedy Space Center where the Phoenix spacecraft was assembled. The exceptionally high tolerance of extreme conditions demonstrated by sporeforming bacteria highlighted the need to assess the viability of these microbes in situ (in real) space. The proposed BOSS (Biofilm Organisms Surfing Space) project aims to understand the mechanisms by which biofilm forming organisms, such as B. horneckiae, will potentially be able to withstand harsh space conditions. As previously stated, the spore producing ability of these species gives them increased survivability to harsh conditions. Some of the spores will have the protective exosporium layer artificially removed before the test to determine if the existence of this layer significantly changes the survivability during the mission. In preparation for that experiment, we analyzed spores which were exposed during a ground simulation, the EXPOSE R2 Biofilm Organisms Surfing Space (BOSS). Previous to exposure, spores were deposited onto spacecraft grade aluminum coupons in a spore suspension calculated to contain between 10(exp 7) and 10(exp 8) spores. This precursor series will be used to establish a baseline survivability function for comparison with the future flight tests during EXPOSE-R. For each coupon, a 10% polyvinyl alcohol (PVA) film was applied and peeled from the coupon to recover the spores. One hundred μl of sterile 10% PVA was applied to the surface of the coupon and allowed to dry for 1 hour at 37 C. The films were then removed using sterile scalpel and forceps and placed into a glass test tube containing 2 milliliters of sterile deionized water. The PVA film process was then repeated on each coupon one additional time to ensure recovery of the majority of spores. The second PVA film was added in the same glass tube as in the previous round. If the spores remained 100% viable, the test tubes should now contain between 5 X 10(exp 6) and 5 X 10(exp 7) spores per millimeter; however, it is expected that some loss of viability has occurred. In order to assess this loss, the number of colony forming, viable spores was counted. To count the colony forming units (CFUs), the spore containing solution was diluted in a process of 10-fold serial dilution by mixing successive solutions in a 100 microliter spore suspension to 900 microliter deionized H2O ratio. A sample dilution series revealed that 10(exp -3) and 10(exp -4) concentrations would be necessary for an accurate CFU count to be taken. For those two concentrations, a spread on a TSA plate was prepared and incubated at 32 C. For the samples exposed to UV radiation, the cell survivability was too low to establish a count from 100 microliter spread plating. Instead, no dilutions were performed and the entire 2 milliliter spore suspension was plated and incubated at 32 C. The plate's CFU counts were taken at 24 hours and 48 hours from the time of plating. At the end of the CFU counting the total surviving spores in each sample were calculated based on the number of CFUs that were observed per 100 microliters, or per 2 milliliters for the UV irradiated samples. The results of these calculations are shown in Figures 1 and 2.

cleanroom↗

NASA NTRS2015

Evidence Report: Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure

Occupational radiation exposure from the space environment may result in non-cancer or non-CNS degenerative tissue diseases, such as cardiovascular disease, cataracts, and respiratory or digestive diseases. However, the magnitude of influence and mechanisms of action of radiation leading to these diseases are not well characterized. Radiation and synergistic effects of radiation cause DNA damage, persistent oxidative stress, chronic inflammation, and accelerated tissue aging and degeneration, which may lead to acute or chronic disease of susceptible organ tissues. In particular, cardiovascular pathologies such as atherosclerosis are of major concern following gamma-ray exposure. This provides evidence for possible degenerative tissue effects following exposures to ionizing radiation in the form of the GCR or SPEs expected during long-duration spaceflight. However, the existence of low dose thresholds and dose-rate and radiation quality effects, as well as mechanisms and major risk pathways, are not well-characterized. Degenerative disease risks are difficult to assess because multiple factors, including radiation, are believed to play a role in the etiology of the diseases. As additional evidence is pointing to lower, space-relevant thresholds for these degenerative effects, particularly for cardiovascular disease, additional research with cell and animal studies is required to quantify the magnitude of this risk, understand mechanisms, and determine if additional protection strategies are required.The NASA PEL (Permissive Exposure Limit)s for cataract and cardiovascular risks are based on existing human epidemiology data. Although animal and clinical astronaut data show a significant increase in cataracts following exposure and a reassessment of atomic bomb (A-bomb) data suggests an increase in cardiovascular disease from radiation exposure, additional research is required to fully understand and quantify these adverse outcomes at lower doses (less than 0.5 gray (SI unit for ionizing radiation dosage, i.e. one joule of radiation energy per one kilogram of matter)) to facilitate risk prediction. This risk has considerable uncertainty associated with it, and no acceptable model for projecting degenerative tissue risk is currently available. In particular, risk factors such as obesity, alcohol, and tobacco use can act as confounding factors that contribute to the large uncertainties. The PELs could be violated under certain scenarios, including following a large SPE (solar proton event) or long-term GCR (galactic cosmic ray) exposure. Specifically, for a Mars mission, the accumulated dose is sufficiently high that epidemiology data and preliminary risk estimates suggest a significant risk for cardiovascular disease. Ongoing research in this area is intended to provide the evidence base for accurate risk quantification to determine criticality for extended duration missions. Data specific to the space radiation environment must be compiled to quantify the magnitude of this risk to decrease the uncertainty in current PELs and to determine if additional protection strategies are required. New research results could lead to estimates of cumulative radiation risk from CNS and degenerative tissue diseases that, when combined with the cancer risk, may have major negative impacts on mission design, costs, schedule, and crew selection. The current report amends an earlier report (Human Research Program Requirements Document, HRP-47052, Rev. C, dated Jan 2009) in order to provide an update of evidence since 2009.

Patel, Zarana↗

NASA NTRS2016

Mitigating HZE Radiation-Induced Deficits in Marrow-Derived Mesenchymal Progenitor Cells and Skeletal Structure

Future long-duration space exploration beyond the earths magnetosphere will increase human exposure to space radiation and associated risks to skeletal health. We hypothesize that oxidative stress resulting from radiation exposure causes progressive bone loss and dysfunction in associated tissue. In animal studies, increased free radical formation is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility.

cells↗

NASA NTRS2017

Effects of Ionizing Radiation on Murine Gene Expression in Skin and Bone

Long duration spaceflight causes a negative calcium balance and reduces bone density in astronauts. The potential for exposure to space radiation to contribute to lasting decrements in bone mass is not yet understood. Sustained changes to bone mass have a relatively long latency for development, however skin is a radiation sensitive organ and changes in skin gene expression may serve as an early radiation biomarker of exposures and may correlate with adverse effects on skeletal tissue. Previous studies have shown that FGF18 gene expression levels of hair follicles collected from astronauts on the ISS rose over time. In the hair follicle, FGF18 signaling mediates radioresistance in the telogen by arresting the cell cycle, and FGF18 has the potential to function as a radioprotector. In bone, FGF18 appears to regulate cell proliferation and differentiation positively during osteogenesis and negatively during chondrogenesis. Cellular defense responses to radiation are shared by a variety of organs, hence in this study, we examined whether radiation induced gene expression changes in skin may be predictive of the responses of skeletal tissue to radiation exposure. We have examined oxidative stress and growth arrest pathways in mouse skin and long bones by measuring gene expression levels via quantitative polymerase chain reaction (qPCR) after exposure to total body irradiation (TBI). To investigate the effects of irradiation on gene expression, we used skin and femora (cortical shaft) from the following treatment groups: control (normally loaded, sham-irradiated), and TBI (0.5 Gy Fe-56 600 MeV/n and 0.5 Gy H-1 150 MeV/n). Animals were euthanized one and 11 days post-IR. Statistical analysis was performed via a Student's ttest. In skin samples one day after IR, skin expression of FGF18 was significantly greater (3.8X) than sham-irradiated controls (3.8X), but did not differ 11 days post TBI. Expression levels of other radiation related genes (Nfe2l2, Trp53, Cdkn1a, FoxO3, Gadd45g, SOD1), was not different due to TBI at either time point. In bone (femora) TBI significantly increased (3.8X) expression of the pro-bone resorption cytokine, MCP-1, one day after TBI. FGF18 expression in skin and MCP- 1 expression in bone were found to be positively correlated (P less than 0.002, r=0.8779). Further, microcomputed tomography analysis of tibae from these animals showed reduced fractional cancellous bone volume (-21.7%) at 11 days post exposure. These results suggest that early radiation induced changes in FGF18 gene expression in skin may have value for predicting subsequent loss of cancellous bone mass.

space radiation↗

NASA NTRS2018

Pilot Study on the Investigation of Tear Fluid Biomarkers as an Indicator of Ocular, Neurological, and Immunological Health in Astronauts

The purpose of this pilot study is to investigate the collection, preparation, and analysis of tear biomarkers as a means of assessing ocular, neurological, and immunological health. At present, no published data exists on the cytokine profiles of tears from astronauts exposed to long periods of microgravity and space irradiations. In addition, no published data exist on cytokine (biomarker) profiles of tears that have been collected from irradiated non-human biological systems (primates and other animal models). A goal for the proposed pilot study is to discover novel tear biomarkers which can help inform researchers, clinicians, epidemiologist and healthcare providers about the health status of a living biological system, as well as informing them when a disease state is triggered. This would be done via analysis of the onset of expression of pro-inflammatory cytokines, leading up to the full progression of a disease (i.e. cancer, loss of vision, radiation-induced oxidative stress, cardiovascular disorders, fibrosis in major organs, bone loss). Another goal of this pilot study is to investigate the state of disease against proposed medical countermeasures, in order to determine whether the countermeasures are efficacious in preventing or mitigating these injuries. An example of an up and coming tear biomarker technology, Ascendant Dx, a clinical stage diagnostic company, is developing a screening test to detect breast cancer using proteins from tears. The team utilized Liquid Chromatography -Mass Spectrometry with Mass analysis (LC MS/MS) as a discovery platform followed by validation with ELISA to come up with a panel of protein biomarkers that can differentiate breast cancer samples from control ("cancer free") samples with results far surpassing the results of imaging techniques in use today. Continued research into additional proteins is underway to increase the sensitivity and specificity of the test and development efforts are on the way to transfer the test onto a fast, accurate and inexpensive point of care platform. In conclusion, the expected results from this proposed pilot study are to: a) establish an SOP for retrieving/storing/transporting tear fluid samples from multicentre sites b) establish a normal range for relevant biomarkers in tears; and c) establish a database (biobank) of tears of space naïve versus veteran astronauts, to establish a personal baseline for long-term ocular health monitoring

Morton, Stephen↗

NASA NTRS2017

Ionizing Radiation Affects Gene Expression in Mouse Skin and Bone

Future long-duration space exploration beyond low earth orbit will increase human exposure to space radiation and microgravity conditions as well as associated risks to skeletal health. In animal studies, radiation exposure (greater than 1 Gy) is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility. Definitive measurements and detection of bone loss typically require large and specialized equipment which can make their application to long duration space missions logistically challenging. Towards the goal of developing non-invasive and less complicated monitoring methods to predict astronauts' health during spaceflight, we examined whether radiation induced gene expression changes in skin may be predictive of the responses of skeletal tissue to radiation exposure. We examined oxidative stress and growth arrest pathways in mouse skin and long bones by measuring gene expression levels via quantitative polymerase chain reaction (qPCR) after exposure to total body irradiation (IR). To investigate the effects of irradiation on gene expression, we used skin and femora (cortical shaft) from the following treatment groups: control (normally loaded, sham-irradiated), and IR (0.5 Gy 56Fe 600 MeV/n and 0.5 Gy 1H 150 MeV/n), euthanized at one and 11 days post-irradiation (IR). To determine the extent of bone loss, tibiae were harvested and cancellous microarchitecture in the proximal tibia quantified ex vivo using microcomputed tomography (microCT). Statistical analysis was performed using Student's t-test. At one day post-IR, expression of FGF18 in skin was significantly greater (3.8X) than sham-irradiated controls, but did not differ at 11 days post IR. Expression levels of other genes associated with antioxidant response (Nfe2l2, FoxO3 and Sod1) and the cell cycle (Trp53, Cdkn1a, Gadd45g) did not significantly differ between the control and IR groups at either time point. Radiation exposure resulted in a 27.0% increase in FGF18-positive hair follicles at one day post-IR and returned to basal levels at 11 days post-IR. A similar trend was observed from FGF18 gene expression analysis of skin. In bone (femora), there was an increase in the expression of the pro-osteoclastogenic cytokine, MCP-1, one day after IR compared to non-irradiated controls. FGF18 expression in skin and MCP- 1 expression in bone were found to be positively correlated (P less than 0.002, r=0.8779). Further, microcomputed tomography analysis of tibia from these animals showed reduced cancellous bone volume (-9.9%) at 11 days post- IR. These results suggest that measurements of early radiation induced changes in FGF18 gene expression in skin may have value for predicting subsequent loss of cancellous bone mass. Further research may lead to the development of a relatively simple diagnostic tool for bone loss, with the advantage that hair follicles and skin are relatively easy to acquire from human subjects.

space radiation↗

NASA NTRS2018

Potential Dietary Countermeasure Against Spaceflight-Induced Bone Loss

As humans venture further into space and beyond low Earth orbit, space radiation is one of the main challenges for astronauts' health. Radiation-induced bone loss is a potential health problem for long duration habitation in space. We showed that a dietary countermeasure prevents bone loss in mice exposed to total body irradiation (TBI). We used a range of ionizing radiation, gamma (137Cs), proton (1H), iron (56Fe), and a combination of sequential proton and iron beam (1H/56Fe/1H) to evaluate skeletal responses. These TBI cover a range of linear energy transfer (LET), from low-LET such as proton, to high-LET such as 56Fe (HZE: high Z- high energy) at doses between 1-2 Gy. The countermeasure diet, composed of 25% Dried Plum (DP) was effective at preventing radiation-induced cancellous bone loss in appendicular bone (tibia). Furthermore, exposing mice to HZE radiation, such as 56Fe (1Gy), impaired ex vivo growth of marrow-derived, bone-forming osteoblasts, which led to reduced mineralization capacity (-77%). In contrast, mice fed the DP diet did not display these deficits, showing the diet's capacity to protect marrow-derived osteoprogenitors. Dietary DP prevented the increase of bone resorbing osteoclast cells, inflammation and oxidative stress, while protecting the osteoprogenitors and mesenchymal stem cells, which few drugs against osteoporosis may achieve. Spaceflight is a combination of multiple factors including microgravity, in addition to space radiation. Therefore, we conducted additional studies to determine if the DP diet could prevent simulated spaceflight (simulated microgravity and radiation combined) bone loss. Mice were exposed to gamma (TBI, 137Cs, 2 Gy), simulated microgravity (using the hindlimb unloading system, HU) or TBI+HU. While we observed bone loss in mice fed the control diet (CD) due to both treatments (TBI=14%, HU=20%), and a worse effect with combined treatments (TBI+HU=25%), mice fed the DP diet did not sustain significant bone loss relative to untreated controls. The DP diet prevented microarchitectural decrements in both appendicular bone (tibia) and axial bone (vertebrae). In addition, the DP diet mitigated HU-induced deficits in osteoblastogenesis. Interestingly, lower doses of DP diet (5%, 10%) did not appear to prevent cancellous bone loss, which shows the importance of identifying the active component(s) of DP. Finally, we have preliminary data showing the potential of DP to prevent radiation-induced damage at a systematic level.. In summary, this novel dietary countermeasure is a promising candidate nutritional countermeasure for spaceflight-induced bone loss and tissue damage.

Countermeasure↗

NASA NTRS2015

Beneficial Effects of Metabolic Supression for Adoptation and Survival in Space Environment

NASA in its plans to send humans to distant destination such as Mars faces the health and physiological performance problems caused by microgravity and space radiation. While most of the environmental conditions in spacecraft during flight can be made to mimic terrestrial conditions, microgravity cannot yet be managed. This space environmental factor has a major impact on the body’s biological system forcing alterations, in order to adapt to this new environment. Most space flight and ground-based studies suggest that prolonged exposure to microgravity leads to significant skeletal muscle atrophy, bone loss, and results in suppression of total metabolism. Due to microgravity, unloaded crewmembers lose up to 1.5% of their skeletal mass and 1.8% of bone strength each month during ISS missions. Remarkably many animals, including human-size bears, which are largely inactive during the 6 to 8 months of hibernation, show no loss in bone mass and much less muscle atrophy than would be anticipated over such a prolonged period of physical inactivity. This suggests that while in a suppressed metabolic state animals have unique natural mechanisms to prevent muscle disuse and bone atrophy. The molecular mechanisms underlying these important adaptations are not yet known. Radiation exposure is the second health hazard encountered during spaceflight that can cause radiation sickness, cancer or death. This study provides new evidence that metabolic activity levels play a critical role in radioprotection. Metabolic suppression, as an adaptive response of cells to minimize damage caused by radiation, enables cells to reduce cellular dysfunction and damage, and prolong their survival despite persistent oxidative stress. Thus mechanistic understanding of metabolism offers a means for sustaining astronauts in long-duration missions. The ultimate goals of this study are to demonstrate that induced metabolic suppression in animals and humans will profoundly reduce their sensitivity to the damaging effects of radiation and microgravity as well as other kinds of stresses caused by spaceflight. The beneficial effects of suppressed metabolism induced by different factors such as temperature, nutrition, and medications, will not only mitigate the most detrimental hazards of spaceflight but also radically reduce mission life support requirements and spaceflight logistics.

Galicia, E.↗

NASA NTRS2019

Predicting Cancer Risk from Ionizing Radiation

The ability to predict cancer risk associated with exposure to low doses of high-LET ionizing radiation (IR) remains a challenge. Epidemiological methods lack the sensitivity and power to provide detailed risk estimates for cancer and ignore individual variance in IR sensitivity. We have hypothesized that DNA repair capacity can be used as a marker to evaluate and differentiate individual radiation sensitivity. More specifically, this work is based on the concept that the combined time-dose dependence of radiation-induced foci (RIF) of p53-binding protein 1 (53BP1) following low-LET exposure contains sufficient information to infer sensitivity to any other LET. Our hypothesis was tested in 15 different mouse strains as well as in primary human immune cells. We first approached individual ionizing radiation sensitivity in a mouse model by culturing primary skin fibroblasts extracted from 76 mice of 15 different genetic backgrounds and exposing them to HZE particles and X-rays. This work is one of the most extensive studies on the kinetics and possible genetic underpinnings of radiation-induced DNA damage and repair. Our results is in agreement with a DNA repair model we previously postulated, where nearby DNA double strand breaks (DSB) in the nucleus are brought together for more efficient repair, leading to RIF clustering. Such mechanism was evidenced by a specific dose and LET dependence of RIF numbers. Briefly, RIF quantification after low-LET X-ray exposure showed an asymptotic saturation for doses between 1 Gy and 4 Gy 4 hours post-irradiation across all 15 strains. The clustering of DSB across all strains also led to more RIF/Gy for lower LET (X-ray and 350 MeV/n Ar) than for higher LET (600 MeV/n Fe) 4 hours post-exposure. Considering the fact that the number of DSB/Gy should be independent of LET, our data suggest there are more DSB in individual RIF as the LET increases. RIF numbers for 24 and 48 hours post-exposure led to the inverse trend, with more remaining RIF/Gy for higher LET (by 600 MeV/n Fe). This result suggests cells have more difficulty resolving RIF from higher LET as they the number DSB/RIF increases. Note that for most conditions, the variance of RIF/Gy was small within individual animals of the same strain and large between strains, suggesting a strong genetics component. Furthermore, we present our preliminary data from an ongoing study on human genetic associations with IR sensitivity. To address the human variability in responses to HZE particle irradiation in a maximally comprehensive manner, we are in the process of collecting and isolating primary blood mononuclear cells from 768 healthy subjects of European descent, 18-75 years of age, 50/50 male/female distribution. We have analyzed 53BP1+ RIF formation as well as oxidative stress and cell death in primary cells from 192 subjects in response to the same HZE particles as used in mice: 600 MeV/n Fe, 350 MeV/n Ar and 350 MeV/n Si, 1.1 and 3 particles/100m2, 4 and 24 hours after irradiation. We will next complete the quantification of HZE particle-induced DNA and cellular damage in the remaining subjects and compare it to their responses to low-LET irradiation. Finally, we will perform GWAS analysis to identify human genomic associations with IR sensitivity and potential targets for biomarker development.

High-LET radiation↗