Arsenic Methylation, One-Carbon Metabolism, and Diabetes Incidence

PROJECT SUMMARY/ABSTRACT Over 140 million individuals worldwide are exposed to water arsenic (As) above the WHO standard of 10 ?g/L and 500 million people live with Type 2 diabetes (T2D). A current gap in knowledge is a thorough understanding of the interplay between modifiable risk factors, e.g. nutritional status and environmental exposures such as As, with diabetes outcomes. Our goal is to investigate the influence of nutritional status on the association between As methylation and diabetes risk. Once ingested, inorganic As (iAs) is methylated via one-carbon-metabolism (OCM) to form mono-methyl (MMA) and dimethyl (DMA) arsenicals; full methylation to DMA facilitates urinary As (uAs) elimination and reduces risk for numerous As-related health outcomes, e.g. cancers of the skin, bladder and lung. Higher urinary DMA% (uDMA%), and corresponding lower uMMA%, however, have been associated with increased risk for diabetes and diabetes-related outcomes in populations from the US, Mexico, and Taiwan. These findings are highly controversial as they contradict those for other As-related outcomes. OCM, which facilitates the production of the methyl donor for As methylation, depends on nutrients such as folate and choline. We hypothesize the association between As methylation and diabetes is confounded by OCM nutrients. This is supported by our preliminary analyses in Bangladesh, where an inverse association between uMMA% and body mass index among females was attenuated with adjustment for plasma choline. Similarly, in a subset (N=59) of the Strong Heart Family Study (SHFS) in American Indian (AI) communities, the association between lower uMMA% and higher waist circumference was completely attenuated after adjustment for OCM-related nutrients. To formally investigate this hypothesis, we will leverage data from the SHFS, a robust cohort with well characterized As exposure, incident diabetes and newly measured OCM nutrient data. The SHFS recruited 3,838 participants aged 14-93 (median 33) years from 12 tribes/communities in Arizona, Oklahoma, and North/South Dakota during two visits in 1998?1999 or 2001?2003 and followed them for up to 11 years. OCM nutrients, and many other metabolites, are currently being analyzed using a gas chromatography time of flight (GCTOF) mass spectrometer (MS) platform. Lipid metabolomics has been analyzed using a quadrupole time of flight (QTOF) MS. Metabolites and nutrients measured using these platforms include S-adenosylmethionine (SAM), S- adenosylhomocysteine (SAH), cysteine, glutamate, and choline metabolites. Untargeted analyses will also be conducted in an exploratory manner. Although it has been speculated that OCM nutrients may confound the relationship between As methylation and diabetes incidence, this hypothesis has never been formally and prospectively assessed using a comprehensive panel of OCM nutrients. This study will provide insight into the role OCM nutrients may play in the observed association between As methylation and diabetes incidence to allow for interventions that address As toxicity via targeted exposure remediation and dietary changes that enhance OCM nutrients.