The largest known mass exposure to arsenic is presently occurring due to ground water contamination of well water throughout the Ganges-Brahmaputra Delta There is significant inter-individual variability in susceptibility to progression from arsenic exposure to clinical manifestations of arsenic toxicity (e g skin, lung, liver and bladder cancers) Several observational as well as biochemical studies have led to a prevalent hypothesis that nutritional status may account for a substantial portion of this variability, though no controlled clinical studies have addressed this important hypothesis. Methylation of inorganic arsenic (InAs) is generally considered to be a detoxification pathway InAs and DNA are both methylated via one-carbon metabolism, a biochemical pathway which is dependent on folate for de novo generation of one-carbon groups, and also uses vitamins B12 and B6 as cofactors The primary hypothesis of this proposal is that nutritional regulation of one-carbon metabolism, specifically folate availability, contributes substantially to the large inter-individual variability observed in InAs and DNA methylation, and thus progression from arsenic exposure to toxicity This hypothesis will first be tested in cross-sectional studies of adults and children chronically exposed to arsenic-contaminated drinking water in Bangladesh Other nutritional deficiencies, including those of retinol, carotenoids and protein, have also been implicated as possibly influencing progression from arsenic exposure to toxicity, although the mechanistic bases for these interactions are somewhat less clear Exploratory studies will address these possibilities as secondary objectives in children, who are more likely to be deficient in these nutrients A third objective will test whether, in adults or children, arsenic exposure is correlated with lymphocyte DNA hypomethylation, an early event in some cancers. Finally, a 12-week double blind placebo controlled folate supplementation trial of adults with elevated plasma homocysteine concentrations and low plasma folate concentrations will be conducted to determine if folate supplementation results in improved arsenic and/or lymphocyte DNA methylation.
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