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Mary V. Gamble,¹ Xinhua Liu,² Habibul Ahsan,³ J. Richard Pilsner,¹ Vesna Ilievski,¹ Vesna Slavkovich,¹ Faruque Parvez,¹ Diane Levy,² Pam Factor-Litvak,³ and Joseph H. Graziano^1,4

¹Department of Environmental Health Sciences, ²Department of Biostatistics, and ³Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA; ⁴Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY, USA

Abstract
Chronic exposure to arsenic is occurring throughout South and East Asia due to groundwater contamination of well water. Variability in susceptibility to arsenic toxicity may be related to nutritional status. Arsenic is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via one-carbon metabolism, a biochemical pathway that is dependent on folate. The majority of one-carbon metabolism methylation reactions are devoted to biosynthesis of creatine, the precursor of creatinine. Our objectives of this cross-sectional study were to characterize the relationships among folate, cobalamin, homocysteine, and arsenic metabolism in Bangladeshi adults. Water arsenic, urinary arsenic, urinary creatinine, plasma folate, cobalamin, and homocysteine were assessed in 1,650 adults ; urinary arsenic metabolites were analyzed for a subset of 300 individuals. The percentage of DMA in urine was positively associated with plasma folate (r = 0.14, p = 0.02) and negatively associated with total homocysteine (tHcys ; r = -0.14, p = 0.01) . Conversely, percent MMA was negatively associated with folate (r = -0.12, p = 0.04) and positively associated with tHcys (r = 0.21, p = 0.0002) ; percent inorganic arsenic (InAs) was negatively associated with folate (r = -0.12, p = 0.03) . Urinary creatinine was positively correlated with percent DMA (r = 0.40 for males, p < 0.0001 ; 0.25 for females, p = 0.001) , and with percent InAs (r = -0.45 for males, p < 0.0001 ; -0.20 for females, p = 0.01) . Collectively, these data suggest that folate, tHcys, and other factors involved in one-carbon metabolism influence arsenic methylation. This may be particularly relevant in Bangladesh, where the prevalence of hyperhomocysteinemia is extremely high. Key words: arsenic, arsenicosis, Bangladesh, creatinine, dimethylarsinic acid, folate, homocysteine, hyperhomocysteinemia, micronutrient deficiency, monomethylarsonic acid, one-carbon metabolism, S-adenosylmethionine, vitamin B₁₂, well water. Environ Health Perspect 113: 1683-1688 (2005) . doi:10.1289/ehp.8084 available via http://dx.doi.org/ [Online 21 July 2005]

Address correspondence to M.V. Gamble, Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 60 Haven Ave., B1, New York, NY 10032, USA. Telephone: (212) 305-7949. Fax: (212) 305-3857. E-mail: mvg7@columbia.edu

We thank S. Alam for overseeing laboratory operations in Araihazar, and our staff, field workers, and study participants in Bangladesh, without whom this work would not have been possible.

This work was supported by grants RO1 ES011601, 5P30ES09089, and 1 P42 ES10349 from the National Institutes of Health.

The authors declare they have no competing financial interests.

Received 3 March 2005 ; accepted 21 July 2005.