|Human Research Program Gaps:
(1) FN-401:Food as a Physiological CM - Understand and develop strategies for use of food as a physiological countermeasure (for aspects such as radiation/oxidative stress, cardiovascular health, bone, SANS, exercise, immune, MicroHost) (IRP Rev M)
(2) SANS-202:Determine if genetic/metabolic/anatomic dispositions and biomarkers, and sex differences have a contributing role in the development of ocular manifestations (IRP Rev L)
|| Some astronauts on International Space Station (ISS) missions have experienced ophthalmic pathologies including optic disc edema, part of what is characterized as Spaceflight Associated Neuro-ocular Syndrome (SANS). While the precise cause for the optic disc edema is not known, it is likely that there are multiple contributing factors, including genetic and environmental factors that may affect the response to headward fluid shifts. Biochemical evidence reveals that crewmembers with optic disc edema have higher circulating concentrations of at least 4 metabolites from the one-carbon metabolic pathway before, during, and after flight compared to astronauts that did not develop optic disc edema. B-vitamin status at landing and the presence of specific one-carbon pathway single nucleotide polymorphism (SNP) alleles were significant predictors for the incidence of astronaut ophthalmic pathologies, including optic disc edema, choroidal folds, and cotton wool spots. When looking at the individual SNPs, the G allele of methionine synthase reductase (MTRR, rs1801394) A66G, and the C allele of serine hydroxymethyltransferase-1 (SHMT1, rs1979277) C1420T, were associated with higher incidence of ophthalmic findings after flight compared to those with the A or T alleles.
In ground analog studies, end-tidal CO2, a reflection of arterial CO2, response to acute head-down tilt (HDT) bed rest and CO2 exposure was related to G and C alleles of MTRR A66G and SHMT1 C1420T and B-vitamin status. Supportive of this, these same alleles were related to the presence of optic disc edema in different bed rest subjects. Subjects were exposed to strict 6°-HDT bed rest and 0.5% CO2 for 30 days and 5 out of 11 subjects developed optic disc edema. The number of G and C alleles were found to be associated with the change in total retina thickness (ΔTRT), a quantitative measure of optic disc edema. Based on our data, differences in genetics and altered one-carbon biochemistry before flight support that one-carbon metabolism may be involved.
We hypothesize that genetics and B-vitamin status are indispensable elements of this phenomenon, along with other potential factors. Dietary B-vitamin insufficiencies and variants in genes involved in the one-carbon metabolic pathway can contribute to lower B-vitamin status and pathway inefficiency, which can affect numerous outcomes, including nitric oxide (NO) production and endothelial function.
To that end, we propose a nutraceutical containing bioactive B-vitamins as a countermeasure to optimize function of the one-carbon pathway and prevent or mitigate optic disc edema during spaceflight.
This proposal aims to test the hypotheses that one-carbon pathway genetics can predispose an individual to SANS pathologies during flight, and that this effect may be prevented or mitigated through supplementation of vitamins that can affect one-carbon pathway function.
The hypothesis will be tested in the following specific aims:
1. Determine whether provision of a daily nutraceutical containing 5-methyltetrahydrofolate (5-MTHF), pyridoxine, methylcobalamin (vitamin B12), and riboflavin prevents or mitigates SANS pathology (significant ΔTRT) compared to astronauts who did not take the supplement in previously flown astronauts with available TRT data.
2. Determine one-carbon pathway SNP profiles in all participating astronauts being supplemented, and assess whether individuals with 3-4 risk alleles for MTRR A66G and SHMT1 C1420T polymorphisms have greater mitigation of ΔTRT during and after spaceflight.
3. Determine whether subjects with 3-4 risk alleles exhibit differences in biomarkers of endothelial function, compared to subjects with 0-2 risk alleles.
We propose to provide the nutraceutical countermeasure to all participating crewmembers before and during flight, and we will assess whether the supplement provides greater mitigation of changes in TRT in individuals with 3-4 risk alleles. We will include assessments of ocular health, along with determinants of vascular endothelial function, advanced glycation end products, and nutritional status and one carbon biochemistry. These additional measures will be critical for the further definition of the causes of SANS, and in understanding the effect of the countermeasure. Finally, the supplemented subjects in this study will be compared against TRT data from previously flown astronauts known to have not taken supplements during their missions.