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NASA NTRS2019

Simulated Weightlessness Alters Cardiomyocyte Structure and Transcriptional Regulation of Mediators Related to Immunity and Cardiovascular Disease

Spaceflight and the ensuing fluid shifts, together with an overall reduction in physical activity, lead to acute and latent effects on the cardiovascular system. This current study makes use of the rodent hindlimb unloading (HU) model to determine how factors such as sex, age, and duration of exposure impact cardiac responses to weightlessness. We hypothesize that extended exposure to simulated weightlessness and the ensuing recovery alters cardiac structure and expression of select genes, including those involved in redox signaling which together, negatively impact long-term cardiac tissue health. To begin to test this hypothesis, male and female rats underwent HU at various durations up to 90 days, with a subset reambulated after 90 days of HU. Physiological stress or contractility changes lead to alterations in ventricular cardiomyocyte size and ventricular wall thickness to adapt to greater functional demand and mitigate mechanical stress to ventricular tissue; under certain conditions, these changes also may mark progression to cardiac failure. Hence, left ventricular cardiomyocyte size (cardiomyocyte cross sectional area, CSA) was quantified to determine if HU leads to structural adaptation responses in cardiac tissue and if age and sex had any impact on this outcome. Cardiomyocyte CSA of older males (9 months) were altered by HU in a time-dependent manner, where HU led to decreases in CSA at 14 days and increases at 90 days. In contrast, younger males (3 months) did not show any changes at day 14 of HU. CSA of females (3 months) was increased in response to short-term HU (14 days) suggesting sex-dependence of structural changes. In older HU males, cardiomyocyte CSA was comparable to controls after 90 days of re-ambulation. Levels of the DNA oxidative damage marker, 8-hydroxydeoxyguanosine (8-OHdG) were greater in left ventricular tissue of females that underwent HU compared to sex-matched controls, while there were no such differences in older or younger males. To gain insight into the signals that drive cardiac adaptations to HU, global transcriptomic analysis (RNAseq) was performed on left ventricular tissue of older males that underwent 14 days of HU. Short-term simulated weightlessness led to differential expression of genes involved in immune and pro-inflammatory signaling. A subset of these genes play a role in autoimmune and cardiovascular disease and are targets of current drugs used to treat bradycardia, hypertension, atherosclerosis and rheumatoid arthritis, amongst others. Oxidative damage/redox signaling pathways were not enriched at the timepoint tested in older males. Since young females displayed greater oxidative damage to DNA, activation of oxidative stress responses at earlier or later time points cannot be ruled out. In summary, simulated weightlessness in adult rats caused changes in cardiomyocyte structure in a sex and age-dependent manner, and the transcriptional regulation of key mediators of immunity and cardiovascular disease, meriting further study to define cardiac risks for interplanetary travel of human crew. Our findings also confirm the value of the rat HU model for cardiac health and countermeasure research.

Tahimic, Candice↗

NASA NTRS2018

Aging and Spaceflight: Catalase Targeted to Mitochondria Alters Skeletal Structure and Responses to Musculoskeletal Disuse

Microgravity and ionizing radiation in the spaceflight environment pose multiple challenges to homeostasis and may contribute to cellular stress. Effects may include increased generation of reactive oxygen species (ROS), DNA damage and repair error, cell cycle arrest, cell senescence or death. Our central hypothesis is that prolonged exposure to the spaceflight environment leads to excess production of ROS and oxidative damage, culminating in accelerated tissue degeneration which resembles aging. The main goal of this project is to determine the importance of cellular redox defense for physiological adaptations and tissue degeneration in the space environment. To accomplish this, we will use both wildtype (WT) mice and a well-established, genetically-engineered animal model (mCAT mice) which displays extended lifespan (Schriner et al. 2005). The animal model selected to test these ideas is engineered to quench ROS in mitochondria by targeted over-expression of the human catalase gene to the mitochondrial matrix. We showed previously that mCAT mice express the catalase transgene in skeletal tissues, bone forming osteoblasts, and bone resorbing osteoclasts. In addition, mCAT mice also display increased catalase activity in bone. Our findings revealed that exposure of adult, male, C57Bl/6J mice to simulated spaceflight (hindlimb unloading and gamma radiation) led to an increase in markers of oxidative damage (malondialdehyde, 4-hydroxynonenol) in skeletal tissue of WT mice but not mCAT mice. To extend our hypothesis to other, spaceflight-relevant tissues, we are performing a ground-based study simulating 30 days of spaceflight by hindlimb unloading to determine potential protective effects of mitochondrial catalase activity on aging of multiple tissues (cardiovascular, nervous and skeletal).

transgenic mice↗

NASA NTRS2010

Monte-Carlo Simulation of Radiation Track Structure and Calculation of Dose Deposition in Nanovolumes

INTRODUCTION: The radiation track structure is of crucial importance to understand radiation damage to molecules and subsequent biological effects. Of a particular importance in radiobiology is the induction of double-strand breaks (DSBs) by ionizing radiation, which are caused by clusters of lesions in DNA, and oxidative damage to cellular constituents leading to aberrant signaling cascades. DSB can be visualized within cell nuclei with gamma-H2AX experiments. MATERIAL AND METHODS: In DSB induction models, the DSB probability is usually calculated by the local dose obtained from a radial dose profile of HZE tracks. In this work, the local dose imparted by HZE ions is calculated directly from the 3D Monte-Carlo simulation code RITRACKS. A cubic volume of 5 micron edge (Figure 1) is irradiated by a (Fe26+)-56 ion of 1 GeV/amu (LET approx.150 keV/micron) and by a fluence of 450 H+ ions, 300 MeV/amu (LET approx. 0.3 keV/micron). In both cases, the dose deposited in the volume is approx.1 Gy. The dose is then calculated into each 3D pixels (voxels) of 20 nm edge and visualized in 3D. RESULTS AND DISCUSSION: The dose is deposited uniformly in the volume by the H+ ions. The voxels which receive a high dose (orange) corresponds to electron track ends. The dose is deposited differently by the 56Fe26+ ion. Very high dose (red) is deposited in voxels with direct ion traversal. Voxels with electron track ends (orange) are also found distributed around the path of the track. In both cases, the appearance of the dose distribution looks very similar to DSBs seen in gammaH2AX experiments, particularly when the visualization threshold is applied. CONCLUSION: The refinement of the dose calculation to the nanometer scale has revealed important differences in the energy deposition between high- and low-LET ions. Voxels of very high dose are only found in the path of high-LET ions. Interestingly, experiments have shown that DSB induced by high-LET radiation are more difficult to repair. Therefore, this new approach may be useful to understand the nature of DSB and oxidative damage induced by ionizing radiation.

Plante, I.↗

NASA NTRS2005

The nutritional status of astronauts is altered after long-term space flight aboard the International Space Station

Defining optimal nutrient requirements is critical for ensuring crew health during long-duration space exploration missions. Data pertaining to such nutrient requirements are extremely limited. The primary goal of this study was to better understand nutritional changes that occur during long-duration space flight. We examined body composition, bone metabolism, hematology, general blood chemistry, and blood levels of selected vitamins and minerals in 11 astronauts before and after long-duration (128-195 d) space flight aboard the International Space Station. Dietary intake and limited biochemical measures were assessed during flight. Crew members consumed a mean of 80% of their recommended energy intake, and on landing day their body weight was less (P = 0.051) than before flight. Hematocrit, serum iron, ferritin saturation, and transferrin were decreased and serum ferritin was increased after flight (P < 0.05). The finding that other acute-phase proteins were unchanged after flight suggests that the changes in iron metabolism are not likely to be solely a result of an inflammatory response. Urinary 8-hydroxy-2'-deoxyguanosine concentration was greater and RBC superoxide dismutase was less after flight (P < 0.05), indicating increased oxidative damage. Despite vitamin D supplement use during flight, serum 25-hydroxycholecalciferol was decreased after flight (P < 0.01). Bone resorption was increased after flight, as indicated by several markers. Bone formation, assessed by several markers, did not consistently rise 1 d after landing. These data provide evidence that bone loss, compromised vitamin D status, and oxidative damage are among critical nutritional concerns for long-duration space travelers.

Space Flight↗

NASA NTRS2005

Nutrition for Space Exploration

Nutrition has proven to be critical throughout the history of human exploration, on both land and water. The importance of nutrition during long-duration space exploration is no different. Maintaining optimal nutritional status is critical for all bodily systems, especially in light of the fact that that many are also affected by space flight itself. Major systems of concern are bone, muscle, the cardiovascular system, the immune system, protection against radiation damage, and others. The task ahead includes defining the nutritional requirements for space travelers, ensuring adequacy of the food system, and assessing crew nutritional status before, during, and after flight. Accomplishing these tasks will provide significant contributions to ensuring crew health on long-duration missions. In addition, development and testing of nutritional countermeasures to effects of space flight is required, and assessment of the impact of other countermeasures (such as exercise and pharmaceuticals) on nutrition is also critical for maintaining overall crew health. Vitamin D stores of crew members are routinely low after long-duration space flight. This occurs even when crew members take vitamin D supplements, suggesting that vitamin D metabolism may be altered during space flight. Vitamin D is essential for efficient absorption of calcium, and has numerous other benefits for other tissues with vitamin D receptors. Protein is a macronutrient that requires additional study to define the optimal intake for space travelers. Administration of protein to bed rest subjects can effectively mitigate muscle loss associated with disuse, but too much or too little protein can also have negative effects on bone. In another bed rest study, we found that the ratio of protein to potassium was correlated with the level of bone resorption: the higher the ratio, the more bone resorption. These relationships warrant further study to optimize the beneficial effect of protein on both bone and muscle during space flight. Omega3 fatty acids are currently being studied as a means of protecting against radiation-induced cancer. They have also recently been implicated as having a role in mitigating the physical wasting, or cachexia, caused by cancer. The mechanism of muscle loss associated with this type of cachexia is similar to the mechanism of muscle loss during disuse or space flight. Omega3 fatty acids have already been shown to have protective effects on bone and cardiovascular function. Omega3 fatty acids could be an ideal countermeasure for space flight because they have protective effects on multiple systems. A definition of optimal nutrient intake requirements for long-duration space travel should also include antioxidants. Astronauts are exposed to numerous sources of oxidative stress, including radiation, elevated oxygen exposure during extravehicular activity, and physical and psychological stress. Elevated levels of oxidative damage are related to increased risk for cataracts, cardiovascular disease, and cancer. Many groundbased studies show the protective effects of antioxidants against oxidative damage induced by radiation or oxygen. Balancing the diet with foods that have high levels of antioxidants would be another ideal countermeasure because it should have minimal side effects on crew health. Antioxidant supplements, however, are often used without having data on their effectiveness or side effects. High doses of supplements have been associated with bone and cardiovascular problems, but research on antioxidant effects during space flight has not been conducted. Much work must be done before we can send crews on exploration missions. Nutrition is often assumed to be the simple provision of food items that will be stable throughout the mission. As outlined briefly above, the situation is much more complex than food provision. As explorers throughout history have found, failure to truly understand the role of nutrition can be catastrophic. When huns are in environments unlike any they have seen before, this is more true than ever.

Smith, Scott M.↗

NASA NTRS2014

Oxidative Stress Responses to Simulated Spaceflight in Mineralized and Marrow Compartments of Bone and Associated Vasculature

Long-term spaceflight causes profound changes to the musculoskeletal system attributable to unloading and fluid shifts in microgravity. Future space explorations beyond the earth’s magnetosphere will expose astronauts to space radiation, which may cause additional skeletal deficits that are not yet fully understood. Our long-term goals are twofold: to define the mechanisms and risk of bone loss in the spaceflight environment and to facilitate the development of effective countermeasures if necessary. Our central hypothesis is that oxidative stress plays a key role in progressive bone loss and vascular dysfunction caused by spaceflight. In animal’s models, overproduction of free radicals is associated with increased bone resorption, lower bone formation, and decrements in bone mineral density and structure which can ultimately lead to skeletal fragility. Evidence in support of a possible causative role for oxidative stress in spaceflight-induced bone loss derive from knockout and transgenic mouse studies and the use of pharmacological interventions with known anti-oxidant properties. In our studies to simulate spaceflight, 16-wk old, male C56Bl/6J mice were assigned to one of four groups: hind limb unloading to simulate weightlessness (HU), normally loaded Controls (‘NL’) (sham irradiated, no hind limb unloading), irradiated at NASA Space Radiation Laboratory ‘IR’ with 1-2Gy of (600MeV/n) alone, or in combination with protons (0.5Gy Protons/0.5Gy 56Fe), (IR) or both hind limb unloaded and irradiated, ‘HU+IR’. Mice were exposed to radiation 3 days after initiating HU and tissues harvested were 1-14 days after initiating treatments for analyses. Results from our laboratories, which employ various biochemical, gene expression, functional, and transgenic animal model methods, implicate dynamic regulation of redox-related pathways by spaceflight-related environmental factors. As one example, we found that combined HU and radiation exposure caused oxidative damage in skeletal tissues (lipid peroxidation) of wildtype mice, whereas bone from transgenic mice that overexpress human catalase in mitochondria were protected. Interestingly, marrow cells grown under culture conditions that select for endothelial progenitor cells (EPC), showed that HU but not IR reduced EPC cell migration; in contrast HU and IR each inhibited growth of marrow-derived osteoblast progenitors. Taken together, these results indicate that unloading and ionizing elicit distinct effects on progenitor and mature cells of vascular and skeletal tissue, and that oxidative damage may contribute to skeletal and vascular deficits that may emerge during extended space travel.

Globus, R. K.↗

NASA NTRS2005

Nutrititional Status Assessment of International Space Station Crew Members

Defining optimal nutrient requirements is imperative to ensure crew health on long-duration space exploration missions. To date, nutrient requirement data have been extremely limited because of small sample sizes and difficulties associated with collecting biological samples. In this study, we examined changes in body composition, bone metabolism, hematology, general blood chemistry, and blood levels of selected vitamins and minerals after long-duration (128-195 d) space flight aboard the International Space Station. Crew members consumed an average of 80% of the recommended energy intakes, and on landing day their body weight had decreased (P=0.051). After flight, hematocrit was less, and serum femtin was greater than before flight (P<0.01). Serum iron, ferritin saturation, and transferrin had decreased after flight. The finding that other acute-phase proteins, including ceruloplasmin, retinol binding protein, transthyretin, and albumin were not changed after flight suggests that the changes in iron metabolism may not be strictly due to an inflammatory response. Urinary 8- hydroxy-2'-deoxyguanosine concentration was greater and superoxide dismutase was less after flight, indicating that oxidative damage had increased (P<0.05). Despite the reported use of vitamin D supplements during flight, serum 25-hydroxyvitamin D was significantly decreased after flight (P<0.01). Bone resorption was increased after flight, as indicated by several urinary markers of bone resorption. Bone formation, assessed by serum concentration of bone-specific alkaline phosphatase, was elevated only in crew members who landed in Russia, probably because of the longer time lapse between landing and sample collection. These data provide evidence that bone loss, compromised vitamin D status, and oxidative damage remain critical concerns for long-duration space flight.

Smith, S. M.↗

NASA NTRS2017

Chronic Hypergravity Induces Changes in the Dopaminergic Neuronal System in Drosophila Melanogaster

Upon atmospheric exitre-entry and during training, astronauts are subjected to temporary periods of hypergravity, which has been implicated in the activation of oxidative stress pathways contributing to mitochondrial dysfunction and neuronal degeneration. The pathogenesis of Parkinsons disease and other neurodegenerative disorders is associated with oxidative damage to neurons involved in dopamine systems of the brain. Our study aims to examine the effects of a hypergravitational developmental environment on the degeneration of dopaminergic systems in Drosophila melanogaster. Male and female flies (Gal4-UAS transgenic line) were hatched and raised to adulthood in centrifugal hypergravity (97rpm, 3g). The nuclear expression of the reporter, Green Fluorescent Protein (GFP) is driven by the dopaminergic enzyme tyrosine hydroxylase (TH) promoter, allowing for the targeted visualization of dopamine producing neurons. After being raised to adulthood and kept in hypergravity until 18 days of age, flies were dissected and the expression of TH was measured by fluorescence confocal microscopy. TH expression in the fly brains was used to obtain counts of healthy dopaminergic neurons for flies raised in chronic hypergravity and control groups. Dopaminergic neuron expression data were compared with those of previous studies that limited hypergravity exposure to late life in order to determine the flies adaptability to the gravitational environment when raised from hatching through adulthood. Overall, we observed a significant effect of chronic hypergravity exposure contributing to deficits in dopaminergic neuron expression (p 0.003). Flies raised in 3g had on average lower dopaminergic neuron counts (mean 97.7) when compared with flies raised in 1g (mean 122.8). We suspect these lower levels of TH expression are a result of oxidative dopaminergic cell loss in flies raised in hypergravity. In future studies, we hope to further elucidate the mechanism by which hypergravity-induced oxidative stress damages the dopaminergic neuronal system, as well as examining possible chemical countermeasures to the hypergravity-induced oxidative stress response in dopaminergic neurons in order to combat cell death and consequent mental and behavioral deficits.

Parkinson's Disorder↗

NASA NTRS2017

Effects of Chronic Hypergravity on the Dopaminergic Neuronal System in Drosophila Melanogaster

Pelos, Andrew↗

NASA NTRS2005

DNA Damage by Ionizing Radiation: Tandem Double Lesions by Charged Particles

Oxidative damages by ionizing radiation are the source of radiation-induced carcinogenesis, damage to the central nervous system, lowering of the immune response, as well as other radiation-induced damages to human health. Monte Carlo track simulations and kinetic modeling of radiation damages to the DNA employ available molecular and cellular data to simulate the biological effect of high and low LET radiation io the DNA. While the simulations predict single and double strand breaks and base damages, so far all complex lesions are the result of stochastic coincidence from independent processes. Tandem double lesions have not yet been taken into account. Unlike the standard double lesions that are produced by two separate attacks by charged particles or radicals, tandem double lesions are produced by one single attack. The standard double lesions dominate at the high dosage regime. On the other hand, tandem double lesions do not depend on stochastic coincidences and become important at the low dosage regime of particular interest to NASA. Tandem double lesions by hydroxyl radical attack of guanine in isolated DNA have been reported at a dosage of radiation as low as 10 Gy. The formation of two tandem base lesions was found to be linear with the applied doses, a characteristic of tandem lesions. However, tandem double lesions from attack by a charged particle have not been reported.

Huo, Winifred M.↗

NASA NTRS2011

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

NASA is concerned with the health risks to astronauts, particularly those risks related to radiation exposure. 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 (A) peripheral leukocyte distribution; (B) plasma cytokine levels; (C) cytokine production profiles following whole blood stimulation of either T cells or monocytes.

Crucian, Brian E.↗

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 NTRS2002

Opportunities for nutritional amelioration of radiation-induced cellular damage

The closed environment and limited evasive capabilities inherent in space flight cause astronauts to be exposed to many potential harmful agents (chemical contaminants in the environment and cosmic radiation exposure). Current power systems used to achieve space flight are prohibitively expensive for supporting the weight requirements to fully shield astronauts from cosmic radiation. Therefore, radiation poses a major, currently unresolvable risk for astronauts, especially for long-duration space flights. The major detrimental radiation effects that are of primary concern for long-duration space flights are damage to the lens of the eye, damage to the immune system, damage to the central nervous system, and cancer. In addition to the direct damage to biological molecules in cells, radiation exposure induces oxidative damage. Many natural antioxidants, whether consumed before or after radiation exposure, are able to confer some level of radioprotection. In addition to achieving beneficial effects from long-known antioxidants such as vitamins E and C and folic acid, some protection is conferred by several recently discovered antioxidant molecules, such as flavonoids, epigallocatechin, and other polyphenols. Somewhat counterintuitive is the protection provided by diets containing elevated levels of omega-3 polyunsaturated fatty acids, considering they are thought to be prone to peroxidation. Even with the information we have at our disposal, it will be difficult to predict the types of dietary modifications that can best reduce the risk of radiation exposure to astronauts, those living on Earth, or those enduring diagnostic or therapeutic radiation exposure. Much more work must be done in humans, whether on Earth or, preferably, in space, before we are able to make concrete recommendations.

Review↗

NASA NTRS2012

High Dietary Iron and Radiation Exposure Increase Biomarkers of Oxidative Stress in Blood and Liver of Rats

Radiation exposure and increased iron (Fe) status independently cause oxidative damage that can result in protein, lipid, and DNA oxidation. During space flight astronauts are exposed to both increased radiation and increased Fe stores. Increased body Fe results from a decrease in red blood cell mass and the typically high Fe content of the food system. In this study we investigated the combined effects of radiation exposure (0.375 Gy of Cs-137 every other day for 16 days for a total of 3 Gy) and high dietary Fe (650 mg Fe/kg diet compared to 45 mg Fe/kg for controls) in Sprague-Dawley rats (n=8/group). Liver and serum Fe were significantly increased in the high dietary Fe groups. Likewise, radiation treatment increased serum ferritin and Fe concentrations. These data indicate that total body Fe stores increase with both radiation exposure and excess dietary Fe. Hematocrit decreased in the group exposed to radiation, providing a possible mechanism for the shift in Fe indices after radiation exposure. Markers of oxidative stress were also affected by both radiation and high dietary Fe, evidenced by increased liver glutathione peroxidase (GPX) and serum catalase as well as decreased serum GPX. We thus found preliminary indications of synergistic effects of radiation exposure and increased dietary Fe, warranting further study. This study was funded by the NASA Human Research Project.

Morgan, Jennifer L. L.↗

NASA NTRSDate not supplied

Engineered Yeast to Test Risks for Human Exploration of the Lunar Surface

Jessica W. Chau, Natalie N. Ball, Aditya Hindupur, Sandra T. Vu, Jennifer Gil Acevedo, Lauren C. Liddell, Chinmayee Govinda Raj, Gentry, Sergio R. Santa Maria, A. Mark Settles Crewed exploration of the Moon carries risks of long duration exposure to reduced gravity and to deep space radiation. The Lunar Explorer Instrument for space biology Applications (LEIA) investigates the effects of increased radiation and reduced gravity on yeast viability and growth in a Commercial Lunar Payload Services (CLPS) surface mission to the south polar region. LEIA conducts yeast genetics experiments to quantify growth, metabolism, and synthetic biology-enabled production of human nutrients, while taking real time measurements of biologically relevant radiation exposure on the lunar surface. We have engineered beta-carotene producing yeast strains to test the importance of selected DNA damage repair and reactive oxygen species (ROS) defense pathways in mitigating cellular damage from lunar surface radiation. Carotenoids are important dietary antioxidants, and beta-carotene is pro-vitamin A, which is needed for vision and immune function. Carotenoids are sensitive to ROS produced by ionizing radiation and NASA is testing on-demand production of carotenoids from yeast in the BioNutrients space flight experiments. In LEIA, we test the effects of deep space on carotenoid yield in engineered yeast strains. The LEIA team uses CRISPR-Cas9 to engineer yeast to express carotenoids as well as to generate loss-of-function mutations. We are generating mutations in the RAD51 DNA damage repair locus and three genes that function to reduce oxidative damage to the cell: SOD1, SOD2, and TSA1. These strains are tested for carotenoid production using microfluidics and LED spectroscopy to allow remote sensing of cellular growth and carotenoid levels. Keywords: synthetic biology, oxidative stress tolerance, biosensors, space radiation, beyond low Earth orbit, lunar surface, CRISPR/Cas9, gene editing, desiccation, carotenoids.

synthetic biology↗

NASA NTRS2002

Clustered DNA damages induced in human hematopoietic cells by low doses of ionizing radiation

Ionizing radiation induces clusters of DNA damages--oxidized bases, abasic sites and strand breaks--on opposing strands within a few helical turns. Such damages have been postulated to be difficult to repair, as are double strand breaks (one type of cluster). We have shown that low doses of low and high linear energy transfer (LET) radiation induce such damage clusters in human cells. In human cells, DSB are about 30% of the total of complex damages, and the levels of DSBs and oxidized pyrimidine clusters are similar. The dose responses for cluster induction in cells can be described by a linear relationship, implying that even low doses of ionizing radiation can produce clustered damages. Studies are in progress to determine whether clusters can be produced by mechanisms other than ionizing radiation, as well as the levels of various cluster types formed by low and high LET radiation.

NASA Discipline Radiation Health↗

NASA NTRS2009

Development of a GCR Event-based Risk Model

A goal at NASA is to develop event-based systems biology models of space radiation risks that will replace the current dose-based empirical models. Complex and varied biochemical signaling processes transmit the initial DNA and oxidative damage from space radiation into cellular and tissue responses. Mis-repaired damage or aberrant signals can lead to genomic instability, persistent oxidative stress or inflammation, which are causative of cancer and CNS risks. Protective signaling through adaptive responses or cell repopulation is also possible. We are developing a computational simulation approach to galactic cosmic ray (GCR) effects that is based on biological events rather than average quantities such as dose, fluence, or dose equivalent. The goal of the GCR Event-based Risk Model (GERMcode) is to provide a simulation tool to describe and integrate physical and biological events into stochastic models of space radiation risks. We used the quantum multiple scattering model of heavy ion fragmentation (QMSFRG) and well known energy loss processes to develop a stochastic Monte-Carlo based model of GCR transport in spacecraft shielding and tissue. We validated the accuracy of the model by comparing to physical data from the NASA Space Radiation Laboratory (NSRL). Our simulation approach allows us to time-tag each GCR proton or heavy ion interaction in tissue including correlated secondary ions often of high multiplicity. Conventional space radiation risk assessment employs average quantities, and assumes linearity and additivity of responses over the complete range of GCR charge and energies. To investigate possible deviations from these assumptions, we studied several biological response pathway models of varying induction and relaxation times including the ATM, TGF -Smad, and WNT signaling pathways. We then considered small volumes of interacting cells and the time-dependent biophysical events that the GCR would produce within these tissue volumes to estimate how GCR event rates mapped to biological signaling induction and relaxation times. We considered several hypotheses related to signaling and cancer risk, and then performed simulations for conditions where aberrant or adaptive signaling would occur on long-duration space mission. Our results do not support the conventional assumptions of dose, linearity and additivity. A discussion on how event-based systems biology models, which focus on biological signaling as the mechanism to propagate damage or adaptation, can be further developed for cancer and CNS space radiation risk projections is given.

Cucinotta, Francis A.↗

NASA NTRS2007

Nutritional Status Assessment (SMO 016E)

It has not been possible to assess nutritional status of crew members on the ISS during flight because blood and urine could not be collected during ISS missions. Postflight observations of alterations in nutritional status for several nutrients are troubling, and we require the ability to monitor the status of these nutrients during flight to determine if there is a specific impetus or timeframe for these changes. In addition to the monitoring of crew nutritional status during flight, in-flight sample collection would allow better assessment of countermeasure effectiveness. SMO 016E is also designed to expand the current medical requirement for nutritional assessment (MR016L) to include additional normative markers for assessing crew health and countermeasure effectiveness. Additional markers of bone metabolism will be measured to better monitor bone health and the effectiveness of countermeasures to prevent bone resorption. New markers of oxidative damage will be measured to better assess the type of oxidative insults that occur during space flight. The array of nutritional assessment parameters will be expanded to include parameters that will allow us to better understand changes in folate and vitamin B6 status, and related cardiovascular risk factors during and after flight. Additionally, stress hormones and hormones that affect bone and muscle metabolism will also be measured. This additional assessment will allow us to better monitor the health of crew members and make more accurate recommendations for their rehabilitation. Several nutritional assessment parameters are altered at landing, but it is not known how long these changes persist. We extended the current protocol to include an additional postflight blood and urine sample collection 30 days after landing. Data are being collected before, during, and after flight. These data will provide a complete survey of how nutritional status and related systems are affected by space flight. Analyzing the data will help us to define nutritional requirements for long-duration missions. This expanded set of measurements will also aid in the identification of nutritional countermeasures to counteract, for example, the deleterious effects of microgravity on bone and muscle and the effects of space radiation.

Smith, S. M.↗