Effects of antioxidant supplementation on bone mineral density, bone mineral content and bone structure in healthy men during 60 days of 6° head-down tilt bed rest: Results from a randomised controlled trial.

Dietary countermeasures to mitigate detrimental spaceflight-induced effects on bone health would alleviate the requirements and the consequences imposed by other types of countermeasures for this risk. We hypothesised that antioxidant supplementation during 60 days of 6° head-down tilt bed rest (HDBR), an analogue of spaceflight, would have a protective effect on bone mineral density (BMD), content (BMC) and bone structure parameters. An exploratory, randomised, controlled, single-blind intervention trial was conducted in a parallel design with 20 healthy male volunteers (age 34 ± 8 y, weight 74 ± 6 kg). The study included 14 days of baseline data collection (BDC) before bed rest, followed by 60 days of HDBR and a 14-day recovery period. Ten subjects in the antioxidant group received a supplement (741 mg/d polyphenols, 2.1 g/d omega-3 fatty acids, 168 mg/d vitamin E and 80 µg/d selenium) daily. Ten subjects in the control group received no supplement. The diet was consistent with dietary reference intakes, individually tailored based on the subject's bodyweight and strictly controlled. We measured whole-body, lumbar spine and femur BMD and BMC, as well as BMD of the cortical and trabecular compartments of the distal radius and tibia, and cortical and trabecular thickness during BDC, HDBR and recovery. Data were analysed using linear mixed models. The supplementation of an antioxidant cocktail did not mitigate the deteriorating effects of HDBR on BMD, BMC and bone structure parameters. Our findings do not support a recommendation for antioxidant supplementation for astronauts.

Dermatitis during Spaceflight Associated with HSV-1 Reactivation.

Human alpha herpesviruses herpes simplex virus (HSV-1) and varicella zoster virus (VZV) establish latency in various cranial nerve ganglia and often reactivate in response to stress-associated immune system dysregulation. Reactivation of Epstein Barr virus (EBV), VZV, HSV-1, and cytomegalovirus (CMV) is typically asymptomatic during spaceflight, though live/infectious virus has been recovered and the shedding rate increases with mission duration. The risk of clinical disease, therefore, may increase for astronauts assigned to extended missions (>180 days). Here, we report, for the first time, a case of HSV-1 skin rash (dermatitis) occurring during long-duration spaceflight. The astronaut reported persistent dermatitis during flight, which was treated onboard with oral antihistamines and topical/oral steroids. No HSV-1 DNA was detected in 6-month pre-mission saliva samples, but on flight day 82, a saliva and rash swab both yielded 4.8 copies/ng DNA and 5.3 × 104 copies/ng DNA, respectively. Post-mission saliva samples continued to have a high infectious HSV-1 load (1.67 × 107 copies/ng DNA). HSV-1 from both rash and saliva samples had 99.9% genotype homology. Additional physiological monitoring, including stress biomarkers (cortisol, dehydroepiandrosterone (DHEA), and salivary amylase), immune markers (adaptive regulatory and inflammatory plasma cytokines), and biochemical profile markers, including vitamin/mineral status and bone metabolism, are also presented for this case. These data highlight an atypical presentation of HSV-1 during spaceflight and underscore the importance of viral screening during clinical evaluations of in-flight dermatitis to determine viral etiology and guide treatment.

Antioxidant Supplementation Does Not Affect Bone Turnover Markers During 60 Days of 6° Head-Down Tilt Bed Rest: Results from an Exploratory Randomized Controlled Trial.

BACKGROUND: Immobilization and related oxidative stress are associated with bone loss. Antioxidants like polyphenols, omega-3 fatty acids, vitamins, and micronutrients may mitigate these negative effects on bone metabolism through scavenging of free radicals. OBJECTIVES: We hypothesized that antioxidant supplementation during 60 days of 6° head-down tilt bed rest (HDBR) would reduce bone resorption and increase bone formation compared to nonsupplemented controls. METHODS: This exploratory randomized, controlled, single-blind intervention study conducted in a parallel design included 20 healthy male volunteers (age, 34 ± 8 years; weight, 74 ± 6 kg). The study consisted of a 14-day adaptation phase [baseline data collection (BDC)], followed by 60 days of HDBR and a 14-day recovery period (R). In the antioxidant group, volunteers received an antioxidant cocktail (741 mg/d polyphenols, 2.1 g/d omega-3 fatty acids, 168 mg/d vitamin E, and 80 µg/d selenium) with their daily meals. In the control group, volunteers received no supplement. Based on their body weight, all volunteers received an individually tailored and strictly controlled diet, consistent with DRIs. We analyzed biomarkers of calcium homeostasis, bone formation, and bone resorption during BDC, HDBR, and R, as well as for 30 days after the end of HDBR. Data were analyzed by linear mixed models. RESULTS: The antioxidant supplement did not affect serum calcium, parathyroid hormone, urinary C-telopeptide of type I collagen (CTX), urinary N-telopeptide of type I collagen, serum ß-C-telopeptide of type I collagen (ß-CTX), bone alkaline phosphatase, aminoterminal propeptide of type I collagen, osteocalcin, or urinary calcium excretion. In both groups, typical bed rest-related changes were observed. CONCLUSIONS: Supplementation of an antioxidant cocktail to a diet matching the DRIs did not affect bone resorption or formation during 60 days of HDBR in healthy young men. This trial was registered at clinicaltrials.gov as NCT03594799.

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.

Multi-year crewed space exploration missions are now on the horizon; therefore, it is important that we understand and mitigate the physiological effects of spaceflight. The spaceflight hazards-radiation, isolation, confinement, and altered gravity-have the potential to contribute to neuroinflammation and produce long-term cognitive and behavioral effects-while the fifth hazard, distance from earth, limits capabilities to mitigate these risks. 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. Just as history has taught us the importance of nutrition in terrestrial exploration, we must understand the role of nutrition in the development and mitigation of spaceflight risks before humans can successfully explore beyond low-Earth orbit.

Red risks for a journey to the red planet: The highest priority human health risks for a mission to Mars.

NASA's plans for space exploration include a return to the Moon to stay-boots back on the lunar surface with an orbital outpost. This station will be a launch point for voyages to destinations further away in our solar system, including journeys to the red planet Mars. To ensure success of these missions, health and performance risks associated with the unique hazards of spaceflight must be adequately controlled. These hazards-space radiation, altered gravity fields, isolation and confinement, closed environments, and distance from Earth-are linked with over 30 human health risks as documented by NASA's Human Research Program. The programmatic goal is to develop the tools and technologies to adequately mitigate, control, or accept these risks. The risks ranked as "red" have the highest priority based on both the likelihood of occurrence and the severity of their impact on human health, performance in mission, and long-term quality of life. These include: (1) space radiation health effects of cancer, cardiovascular disease, and cognitive decrements (2) Spaceflight-Associated Neuro-ocular Syndrome (3) behavioral health and performance decrements, and (4) inadequate food and nutrition. Evaluation of the hazards and risks in terms of the space exposome-the total sum of spaceflight and lifetime exposures and how they relate to genetics and determine the whole-body outcome-will provide a comprehensive picture of risk profiles for individual astronauts. In this review, we provide a primer on these "red" risks for the research community. The aim is to inform the development of studies and projects with high potential for generating both new knowledge and technologies to assist with mitigating multisystem risks to crew health during exploratory missions.

Multi-omic, Single-Cell, and Biochemical Profiles of Astronauts Guide Pharmacological Strategies for Returning to Gravity.

The National Aeronautics and Space Administration (NASA) Twins Study created an integrative molecular profile of an astronaut during NASA's first 1-year mission on the International Space Station (ISS) and included comparisons to an identical Earth-bound twin. The unique biochemical profiles observed when landing on Earth after such a long mission (e.g., spikes in interleukin-1 [IL-1]/6/10, c-reactive protein [CRP], C-C motif chemokine ligand 2 [CCL2], IL-1 receptor antagonist [IL-1ra], and tumor necrosis factor alpha [TNF-α]) opened new questions about the human body's response to gravity and how to plan for future astronauts, particularly around initiation or resolution of inflammation. Here, single-cell, multi-omic (100-plex epitope profile and gene expression) profiling of peripheral blood mononuclear cells (PBMCs) showed changes to blood cell composition and gene expression post-flight, specifically for monocytes and dendritic cell precursors. These were consistent with flight-induced cytokine and immune system stress, followed by skeletal muscle regeneration in response to gravity. Finally, we examined these profiles relative to 6-month missions in 28 other astronauts and detail potential pharmacological interventions for returning to gravity in future missions.

Temporal Telomere and DNA Damage Responses in the Space Radiation Environment.

Telomeres, repetitive terminal features of chromosomes essential for maintaining genome integrity, shorten with cell division, lifestyle factors and stresses, and environmental exposures, and so they provide a robust biomarker of health, aging, and age-related diseases. We assessed telomere length dynamics (changes over time) in three unrelated astronauts before, during, and after 1-year or 6-month missions aboard the International Space Station (ISS). Similar to our results for National Aeronautics and Space Administration's (NASA's) One-Year Mission twin astronaut (Garrett-Bakelman et al., 2019), significantly longer telomeres were observed during spaceflight for two 6-month mission astronauts. Furthermore, telomere length shortened rapidly after return to Earth for all three crewmembers and, overall, telomere length tended to be shorter after spaceflight than before spaceflight. Consistent with chronic exposure to the space radiation environment, signatures of persistent DNA damage responses were also detected, including mitochondrial and oxidative stress, inflammation, and telomeric and chromosomal aberrations, which together provide potential mechanistic insight into spaceflight-specific telomere elongation.

Countermeasures-based Improvements in Stress, Immune System Dysregulation and Latent Herpesvirus Reactivation onboard the International Space Station - Relevance for Deep Space Missions and Terrestrial Medicine.

The International Space Station (ISS) has continued to evolve from an operational perspective and multiple studies have monitored both stress and the immune system of ISS astronauts. Alterations were ascribed to a potentially synergistic array of factors, including microgravity, radiation, psychological stress, and circadian misalignment. Comparing similar data across 12 years of ISS construction and operations, we report that immunity, stress, and the reactivation of latent herpesviruses have all improved in ISS astronauts. Major physiological improvements seem to have initiated approximately 2012, a period coinciding with improvements onboard ISS including cargo delivery and resupply frequency, personal communication, exercise equipment and protocols, food quality and variety, nutritional supplementation, and schedule management. We conclude that spaceflight associated immune dysregulation has been positively influenced by operational improvements and biomedical countermeasures onboard ISS. Although an operational challenge, agencies should therefore incorporate, within vehicle design limitations, these dietary, operational, and stress-relieving countermeasures into deep space mission planning. Specific countermeasures that have benefited astronauts could serve as a therapy augment for terrestrial acquired immunodeficiency patients.

Dietary acid load and bone turnover during long-duration spaceflight and bed rest.

Background: Bed rest studies document that a lower dietary acid load is associated with lower bone resorption. Objective: We tested the effect of dietary acid load on bone metabolism during spaceflight. Design: Controlled 4-d diets with a high or low animal protein-to-potassium (APro:K) ratio (High and Low diets, respectively) were given to 17 astronauts before and during spaceflight. Each astronaut had 1 High and 1 Low diet session before flight and 2 High and 2 Low sessions during flight, in addition to a 4-d session around flight day 30 (FD30), when crew members were to consume their typical in-flight intake. At the end of each session, blood and urine samples were collected. Calcium, total protein, energy, and sodium were maintained in each crew member's preflight and in-flight controlled diets. Results: Relative to preflight values, N-telopeptide (NTX) and urinary calcium were higher during flight, and bone-specific alkaline phosphatase (BSAP) was higher toward the end of flight. The High and Low diets did not affect NTX, BSAP, or urinary calcium. Dietary sulfur and age were significantly associated with changes in NTX. Dietary sodium and flight day were significantly associated with urinary calcium during flight. The net endogenous acid production (NEAP) estimated from the typical dietary intake at FD30 was associated with loss of bone mineral content in the lumbar spine after the mission. The results were compared with data from a 70-d bed rest study, in which control (but not exercising) subjects' APro:K was associated with higher NTX during bed rest. Conclusions: Long-term lowering of NEAP by increasing vegetable and fruit intake may protect against changes in loss of bone mineral content during spaceflight when adequate calcium is consumed, particularly if resistive exercise is not being performed. This trial was registered at clinicaltrials.gov as NCT01713634.

Comprehensive genomic analysis reveals FLT3 activation and a therapeutic strategy for a patient with relapsed adult B-lymphoblastic leukemia.

The genomic events responsible for the pathogenesis of relapsed adult B-lymphoblastic leukemia (B-ALL) are not yet clear. We performed integrative analysis of whole-genome, whole-exome, custom capture, whole-transcriptome (RNA-seq), and locus-specific genomic assays across nine time points from a patient with primary de novo B-ALL. Comprehensive genome and transcriptome characterization revealed a dramatic tumor evolution during progression, yielding a tumor with complex clonal architecture at second relapse. We observed and validated point mutations in EP300 and NF1, a highly expressed EP300-ZNF384 gene fusion, a microdeletion in IKZF1, a focal deletion affecting SETD2, and large deletions affecting RB1, PAX5, NF1, and ETV6. Although the genome analysis revealed events of potential biological relevance, no clinically actionable treatment options were evident at the time of the second relapse. However, transcriptome analysis identified aberrant overexpression of the targetable protein kinase encoded by the FLT3 gene. Although the patient had refractory disease after salvage therapy for the second relapse, treatment with the FLT3 inhibitor sunitinib rapidly induced a near complete molecular response, permitting the patient to proceed to a matched-unrelated donor stem cell transplantation. The patient remains in complete remission more than 4 years later. Analysis of this patient's relapse genome revealed an unexpected, actionable therapeutic target that led to a specific therapy associated with a rapid clinical response. For some patients with relapsed or refractory cancers, this approach may indicate a novel therapeutic intervention that could alter outcome.

Genotype, B-vitamin status, and androgens affect spaceflight-induced ophthalmic changes.

Ophthalmic changes have occurred in a subset of astronauts on International Space Station missions. Visual deterioration is considered the greatest human health risk of spaceflight. Affected astronauts exhibit higher concentrations of 1-carbon metabolites (e.g., homocysteine) before flight. We hypothesized that genetic variations in 1-carbon metabolism genes contribute to susceptibility to ophthalmic changes in astronauts. We investigated 5 polymorphisms in the methionine synthase reductase (MTRR), methylenetetrahydrofolate reductase (MTHFR), serine hydroxymethyltransferase (SHMT), and cystathionine ß-synthase (CBS) genes and their association with ophthalmic changes after flight in 49 astronauts. The number of G alleles of MTRR 66 and C alleles of SHMT1 1420 both contributed to the odds of visual disturbances. Preflight dehydroepiandrosterone was positively associated with cotton wool spots, and serum testosterone response during flight was associated with refractive change. Block regression showed that B-vitamin status and genetics were significant predictors of many of the ophthalmic outcomes that we observed. In one example, genetics trended toward improving (P = 0.10) and B-vitamin status significantly improved (P < 0.001) the predictive model for refractive change after flight. We document an association between MTRR 66 and SHMT1 1420 polymorphisms and spaceflight-induced vision changes. This line of research could lead to therapeutic options for both space travelers and terrestrial patients.

Genome Modeling System: A Knowledge Management Platform for Genomics.

In this work, we present the Genome Modeling System (GMS), an analysis information management system capable of executing automated genome analysis pipelines at a massive scale. The GMS framework provides detailed tracking of samples and data coupled with reliable and repeatable analysis pipelines. The GMS also serves as a platform for bioinformatics development, allowing a large team to collaborate on data analysis, or an individual researcher to leverage the work of others effectively within its data management system. Rather than separating ad-hoc analysis from rigorous, reproducible pipelines, the GMS promotes systematic integration between the two. As a demonstration of the GMS, we performed an integrated analysis of whole genome, exome and transcriptome sequencing data from a breast cancer cell line (HCC1395) and matched lymphoblastoid line (HCC1395BL). These data are available for users to test the software, complete tutorials and develop novel GMS pipeline configurations. The GMS is available at https://github.com/genome/gms.

Using natural, stable calcium isotopes of human blood to detect and monitor changes in bone mineral balance.

We are exploring variations in the Ca isotope composition of blood and urine as a new tool for early diagnosis and monitoring of changes in bone mineral balance for patients suffering from metabolic bone disease, cancers that originate in or metastasize to bone, and for astronauts who spend time in low gravity environments. Blood samples are often collected instead of, or in addition to, urine in clinical settings, so it is useful to know if variations in the Ca isotope composition of blood carry the same information as variations in urine. We found that the Ca isotope composition of blood shifts in the same direction and to the same magnitude (~2 parts per ten thousand--pptt) as that of urine in response to skeletal unloading during bed rest. However, the Ca isotope composition of blood is lighter than that of urine by 12 ± 2 pptt. This offset between blood and urine may result from Ca isotope fractionation occurring in the kidneys. This is the first study to confirm the suspected offset between the Ca isotope composition of blood and urine in humans, to directly quantify its magnitude, and to establish that either blood or urine can be used to detect and quantify bone loss.

Plasma cytokine concentrations indicate that in vivo hormonal regulation of immunity is altered during long-duration spaceflight.

Aspects of immune system dysregulation associated with long-duration spaceflight have yet to be fully characterized and may represent a clinical risk to crewmembers during deep space missions. Plasma cytokine concentration may serve as an indicator of in vivo physiological changes or immune system mobilization. The plasma concentrations of 22 cytokines were monitored in 28 astronauts during long-duration spaceflight onboard the International Space Station. Blood samples were collected 3 times before flight, 3-5 times during flight (depending on mission duration), at landing, and 30 days after landing. Analysis was performed by bead array immunoassay. With few exceptions, minimal detectable mean plasma concentrations were observed at baseline (launch minus 180) for innate inflammatory cytokines or adaptive regulatory cytokines; however, interleukin (IL)-1ra and several chemokines and growth factors were constitutively present. An increase in the plasma concentration, tumor necrosis factor-α (TNFα), IL-8, IL-1ra, thrombopoietin (Tpo), vascular endothelial growth factor (VEGF), C-C motif chemokine ligand 2 (CCL2), chemokine ligand 4/macrophage inhibitory protein 1b (CCL4), and C-X-C motif chemokine 5/epithelial neutrophil-activating protein 78 (CXCL5) was observed associated with spaceflight. No significant alterations were observed during or following spaceflight for the inflammatory or adaptive/T-regulatory cytokines: IL-1α, IL-1ß, IL-2, interferon-gamma (IFN-γ), IL-17, IL-4, IL-5, IL-10, G-CSF, GM-CSF, FGF basic, CCL3, or CCL5. This pattern of cytokine dysregulation suggests multiple physiological adaptations persist during flight, including inflammation, leukocyte recruitment, angiogenesis, and thrombocyte regulation.

Increased dietary iron and radiation in rats promote oxidative stress, induce localized and systemic immune system responses, and alter colon mucosal environment.

Astronauts are exposed to increased body iron stores and radiation, both of which can cause oxidative damage leading to negative health effects. The purpose of this study was to investigate combined effects of high dietary iron (650 mg/kg diet) and radiation exposure (0.375 Gy cesium-137 every other day for 16 d) on markers of oxidative stress, immune system function, and colon mucosal environment in male Sprague-Dawley rats (n=8/group). Control rats consumed adequate iron (45 mg/kg diet) and were not irradiated. Combined treatments increased liver glutathione peroxidase, serum catalase, and colon myeloperoxidase while decreasing total fecal short-chain fatty acid concentrations. The high-iron diet alone increased leukocyte count. Radiation decreased the T-cell CD4:CD8 ratio. Plasma iron was negatively correlated with cytokine production in activated monocytes. Genes involved in colon microbial signaling, immune response, and injury repair were altered by radiation. Genes involved with injury repair and pathogen recognition changed with dietary iron. These data demonstrate that dietary iron and radiation, alone and combined, contribute to oxidative stress that is related to immune system alterations in circulation and the colon. The model presented may help us better understand the changes to these systems that have been identified among astronauts.

DGIdb: mining the druggable genome.

The Drug-Gene Interaction database (DGIdb) mines existing resources that generate hypotheses about how mutated genes might be targeted therapeutically or prioritized for drug development. It provides an interface for searching lists of genes against a compendium of drug-gene interactions and potentially 'druggable' genes. DGIdb can be accessed at http://dgidb.org/.

Iron status and its relations with oxidative damage and bone loss during long-duration space flight on the International Space Station.

BACKGROUND: Increases in stored iron and dietary intake of iron during space flight have raised concern about the risk of excess iron and oxidative damage, particularly in bone. OBJECTIVES: The objectives of this study were to perform a comprehensive assessment of iron status in men and women before, during, and after long-duration space flight and to quantify the association of iron status with oxidative damage and bone loss. DESIGN: Fasting blood and 24-h urine samples were collected from 23 crew members before, during, and after missions lasting 50 to 247 d to the International Space Station. RESULTS: Serum ferritin and body iron increased early in flight, and transferrin and transferrin receptors decreased later, which indicated that early increases in body iron stores occurred through the mobilization of iron to storage tissues. Acute phase proteins indicated no evidence of an inflammatory response during flight. Serum ferritin was positively correlated with the oxidative damage markers 8-hydroxy-2'-deoxyguanosine (r = 0.53, P < 0.001) and prostaglandin F2α (r = 0.26, P < 0.001), and the greater the area under the curve for ferritin during flight, the greater the decrease in bone mineral density in the total hip (P = 0.031), trochanter (P = 0.006), hip neck (P = 0.044), and pelvis (P = 0.049) after flight. CONCLUSION: Increased iron stores may be a risk factor for oxidative damage and bone resorption.

Rapidly assessing changes in bone mineral balance using natural stable calcium isotopes.

The ability to rapidly detect changes in bone mineral balance (BMB) would be of great value in the early diagnosis and evaluation of therapies for metabolic bone diseases such as osteoporosis and some cancers. However, measurements of BMB are hampered by difficulties with using biochemical markers to quantify the relative rates of bone resorption and formation and the need to wait months to years for altered BMB to produce changes in bone mineral density large enough to resolve by X-ray densitometry. We show here that, in humans, the natural abundances of Ca isotopes in urine change rapidly in response to changes in BMB. In a bed rest experiment, use of high-precision isotope ratio MS allowed the onset of bone loss to be detected in Ca isotope data after about 1 wk, long before bone mineral density has changed enough to be detectable with densitometry. The physiological basis of the relationship between Ca isotopes and BMB is sufficiently understood to allow quantitative translation of changes in Ca isotope abundances to changes in bone mineral density using a simple model. The rate of change of bone mineral density inferred from Ca isotopes is consistent with the rate observed by densitometry in long-term bed rest studies. Ca isotopic analysis provides a powerful way to monitor bone loss, potentially making it possible to diagnose metabolic bone disease and track the impact of treatments more effectively than is currently possible.

Vision changes after spaceflight are related to alterations in folate- and vitamin B-12-dependent one-carbon metabolism.

Approximately 20% (7 of 38) of astronauts on International Space Station (ISS) missions have developed measurable ophthalmic changes after flight. This study was conducted to determine if the folate- and vitamin B-12-dependent 1-carbon metabolic pathway is altered in these individuals. Since 2006, we have conducted experiments on the ISS to evaluate nutritional status and related biochemical indices of astronauts before, during, and after flight. Data were modeled to evaluate differences between individuals with ophthalmic changes (n = 5) and those without them (n = 15), all of whom were on ISS missions of 48-215 d. We also determined whether mean preflight serum concentrations of the 1-carbon metabolites and changes in measured cycloplegic refraction after flight were associated. Serum homocysteine (Hcy), cystathionine, 2-methylcitric acid (2MCA), and methylmalonic acid concentrations were 25-45% higher (P < 0.001) in astronauts with ophthalmic changes than in those without them. These differences existed before, during, and after flight. Preflight serum concentrations of Hcy and cystathionine, and mean in-flight serum folate, were correlated with change (postflight relative to preflight) values in refraction (P < 0.05), and preflight serum concentrations of 2MCA tended to be associated (P = 0.06) with ophthalmic changes. The biochemical differences observed in crewmembers with vision issues strongly suggest that their folate- and vitamin B-12-dependent 1-carbon transfer metabolism was affected before and during flight. The consistent differences in markers of 1-carbon metabolism between those who did and those who did not develop changes in vision suggest that polymorphisms in enzymes of this pathway may interact with microgravity to cause these pathophysiologic changes.

Response to vitamin D supplementation during Antarctic winter is related to BMI, and supplementation can mitigate Epstein-Barr Virus Reactivation.

Maintaining vitamin D status without sunlight exposure is difficult without supplementation. This study was designed to better understand interrelationships between periodic vitamin D supplementation and immune function in Antarctic workers. The effect of 2 oral dosing regimens of vitamin D supplementation on vitamin D status and markers of immune function was evaluated in people in Antarctica with no UV light exposure for 6 mo. Participants were given a 2000-IU (50 µg) daily (n = 15) or 10,000-IU (250 µg) weekly (n = 14) vitamin D supplement for 6 mo during a winter in Antarctica. Biological samples were collected at baseline and at 3 and 6 mo. Vitamin D intake, markers of vitamin D and bone metabolism, and latent virus reactivation were determined. After 6 mo, the serum 25-hydroxyvitamin D concentration (mean ± SD) increased from 56 ± 17 to 79 ± 16 nmol/L and from 52 ± 10 to 69 ± 9 nmol/L in the 2000-IU/d and 10,000-IU/wk groups, respectively (main effect over time, P < 0.001). Participants with a greater BMI (participant BMI range = 19­43 g/m2) had a smaller increase in 25-hydroxyvitamin D after 6-mo supplementation (P < 0.05). Participants with high serum cortisol and higher serum 25-hydroxyvitamin D were less likely to shed Epstein-Barr virus in saliva (P < 0.05). The doses given raised vitamin D status in participants not exposed to sunlight for 6 mo, and the efficacy was influenced by baseline vitamin D status and BMI. The data also provide evidence that vitamin D, interacting with stress, can reduce risk of latent virus reactivation during the winter in Antarctica.