Folate Deficiency, Hyperhomocysteinemia, Low Urinary Creatinine and Hypomethylation of Leukocyte DNA are Risk Factors for Arsenic-Induced Skin

J. Richard Pilsner, Xinhua Liu, Habibul Ahsan, Vesna Ilievski, Vesna Slavkovich, Diane Levy, Pam Factor-Litvak, Joseph H. Graziano, and Mary V. Gamble

Background: Arsenic methylation relies on folate-dependent one-carbon metabolism and facilitates urinary As elimination. Clinical manifestations of As toxicity vary considerably among individuals and populations, and poor methylation capacity is thought to confer greater susceptibility.

Objective: After determining that folate deficiency, hyperhomocysteinemia, and low urinary creatinine are associated with reduced As methylation, and that As exposure is associated with increased genomic methylation of leukocyte DNA, we asked whether these factors are associated with As-induced skin lesion risk among Bangladeshi adults.

Methods: We conducted a nested case–control study of 274 cases who developed lesions 2 years after recruitment, and 274 controls matched to cases for sex, age, and water As. results: The odds ratios and 95% confidence intervals (CIs) for development of skin lesions for participants who had low folate (< 9 nmol/L), hyperhomocysteinemia (men, > 11.4 μmol/L; women, > 10.4 μmol/L), or hypomethylated leukocyte DNA at recruitment (< median) were 1.8 (95% CI, 1.1–2.9), 1.7 (95% CI, 1.1–2.6), and 1.8 (95% CI, 1.2–2.8), respectively. Compared with the subjects in the first quartile, those in the third and fourth quartiles for urinary creatinine had a 0.4-fold decrease in the odds of skin lesions (p < 0.01).

Conclusions: These results suggest that folate deficiency, hyperhomocysteinemia, and low urinary creatinine, each associated with decreased As methylation, are risk factors for As-induced skin lesions. The increased DNA methylation associated with As exposure previously observed, and confirmed among controls in this study, may be an adaptive change because hypomethylation of leukocyte DNA is associated with increased risk for skin lesions.

Key Words: arsenic, Bangladesh, DNA methylation, epigenetics, folate, folate deficiency, global methylation, homocysteine, hyperhomocysteinemia, skin lesions. Environ Health Perspect 117:254–260 (2009). doi:10.1289/ehp.11872 available via http://dx.doi.org/ [Online 26 September 2008]