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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Nutrition Study Section (NTN)
Program Officer
Balshaw, David M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Schools of Medicine
New York
United States
Zip Code
Niedzwiecki, Megan M; Liu, Xinhua; Hall, Megan N et al. (2015) Sex-specific associations of arsenic exposure with global DNA methylation and hydroxymethylation in leukocytes: results from two studies in Bangladesh. Cancer Epidemiol Biomarkers Prev 24:1748-57
Peters, Brandilyn A; Liu, Xinhua; Hall, Megan N et al. (2015) Arsenic exposure, inflammation, and renal function in Bangladeshi adults: effect modification by plasma glutathione redox potential. Free Radic Biol Med 85:174-82
Niedzwiecki, Megan M; Hall, Megan N; Liu, Xinhua et al. (2014) Interaction of plasma glutathione redox and folate deficiency on arsenic methylation capacity in Bangladeshi adults. Free Radic Biol Med 73:67-74
Peters, Brandilyn A; Hall, Megan N; Liu, Xinhua et al. (2014) Creatinine, arsenic metabolism, and renal function in an arsenic-exposed population in Bangladesh. PLoS One 9:e113760
Lawley, Sean D; Yun, Jina; Gamble, Mary V et al. (2014) Mathematical modeling of the effects of glutathione on arsenic methylation. Theor Biol Med Model 11:20
Chen, Yu; McClintock, Tyler R; Segers, Stephanie et al. (2013) Prospective investigation of major dietary patterns and risk of cardiovascular mortality in Bangladesh. Int J Cardiol 167:1495-501
Liu, Xinhua (2012) Classification accuracy and cut pointýýýselection. Stat Med 31:2676-86
Pilsner, J Richard; Hall, Megan N; Liu, Xinhua et al. (2011) Associations of plasma selenium with arsenic and genomic methylation of leukocyte DNA in Bangladesh. Environ Health Perspect 119:113-8
Lawley, Sean D; Cinderella, Molly; Hall, Megan N et al. (2011) Mathematical model insights into arsenic detoxification. Theor Biol Med Model 8:31
Hall, Megan N; Liu, Xinhua; Slavkovich, Vesna et al. (2009) Folate, Cobalamin, Cysteine, Homocysteine, and Arsenic Metabolism among Children in Bangladesh. Environ Health Perspect 117:825-31

Showing the most recent 10 out of 18 publications