Project Summary (2006-2011)

Two overarching themes of this project relate to a) the metabolism of arsenic (As) and b) As-induced oxidative stress. There is significant variability in progression from As exposure to clinical manifestations of disease. Several studies have led to the hypothesis that nutritional status may account for a substantial portion of this variability. Inorganic As is methylated via one-carbon metabolism, a biochemical pathway that is dependent on folate for recruitment of one-carbon groups. This project is characterizing the impact of nutritional regulation of one-carbon metabolism on the inter-individual variability in As methylation. Glutathione (GSH), a key component of the primary antioxidant defense mechanism, and the electron donor for As reduction, is synthesized from homocysteine, and this synthesis is regulated by intermediates of one carbon metabolism. A great deal of basic research, including salient work from members of this group, points to the growing belief that As depletes glutathione (GSH) and induces oxidative stress. However, the relationship between As exposure and oxidative stress has not been rigorously examined in human populations. Dr. Gamble's team is utilizing the repository of biological samples established by the Cohort Study to conduct a nested case-control study to identify modifiable risk factors (e.g. oxidative stress and/or hyperhomocysteinemia) related to increased susceptibility to As-induced skin lesions. Project investigators are taking advantage of the expansion of the study area (and installation of Asfree tube wells) in other Columbia SBRP projects to recruit 375 new adults who are currently exposed to As. Dr. Gamble is addressing a fundamental question: To what extent do urinary As metabolites reflect As metabolites in the circulation? They are also conducting a cross-sectional study to test the hypotheses that higher concentrations of s-adenosylhomocysteine (SAH) and lower concentrations of GSH are associated with reduced As methylation. Additionally, the investigators are examining dose-response relationships between As exposure and oxidative stress. Finally, Dr. Gamble's team is testing the hypothesis that reduction of As exposure alleviates oxidative stress. This project has the potential to a) substantiate that As induces oxidative stress and depletes GSH in a human population, b) link As-induced oxidative stress and/or nutritional status to an arsenic-related clinical outcome, and c) expand our understanding of the mechanisms underlying these processes. Such findings would have significant implications for the identification of potential targeted interventions for preventing As-toxicity.