Associations of Plasma Selenium with Arsenic and Genomic Methylation of Leukocyte DNA in Bangladesh
Pilsner, J. Richard, Hall, Megan N., Liu, Xinhua, Ahsan, Habibul, Ilievski, Vesna, Slavkovich, Vesna, Levy, Diane, Factor-Litvak, Pam, Graziano, Joseph H., Gamble, Mary V., Environmental Health Perspectives
BACKGROUND: Global hypomethylation of DNA is thought to constitute an early event in some cancers and occurs in response to arsenic (As) exposure and/or selenium (Se) deficiency in both in vitro and animal models. In addition, antagonism between As and Se, whereby each reduces toxicity of the other, has been well documented in animal models. Se status may therefore modify the health effects of As in As-exposed populations.
OBJECTIVE: The primary objectives of our study were to test the hypothesis that Se deficiency is associated with genomic hypomethylation of lymphocyte DNA and to determine whether Se levels are associated with blood As (bAs) and urinary As (uAs) concentrations in adults exposed to As-contaminated groundwater in Bangladesh. A secondary objective was to explore the relationships between plasma Se and As metabolites.
DESIGN: We assessed plasma Se concentrations, As metabolite profiles in blood and urine, and genomic methylation of leukocyte DNA in a cross-sectional study of 287 adults.
RESULTS: After adjustment for potential confounders, we observed an inverse association between Se (micrograms per liter) and genomic DNA methylation (disintegrations per minute per 1-[micro]g/L increase in Se): [beta] = 345.6; 95% confidence interval (CI), 59-632. Se concentrations were inversely associated with total As concentrations (micrograms per liter) in blood ([beta] = -0.04; 95% CI, -0.08 to -0.01) and urine ([beta] = -20.1; 95% CI, -29-3 to -10.9). Se levels were negatively associated with the percentage of monomethylarsinic acid ([beta] = -0.59; 95% CI, 1.04 to -0.01) and positively associated with the percentage of dimethylarsinic acid ([beta] = 0.53; 95% CI, 0.04 to 1.01) in blood.
CONCLUSIONS: Our results suggest that Se is inversely associated with genomic DNA methylation. The underlying mechanisms and implications of this observation are unclear and warrant further investigation. In addition, Se may influence bAs and uAs concentrations, as well as relative proportions of As metabolites in blood.
KEY WORDS: arsenic, Bangladesh, DNA methylation, epigenetics, folate, folic acid, selenite, selenium, thioredoxin reductase, well water. Environ Health Perspect 119:113-118 (2011). doi:10.1289/ehp.1001937 [Online 15 September 2010]
Arsenic (As) and selenium (Se) share many chemical properties and are adjacent on the periodic table of elements. The two metalloids, however, have marked differences in their biological effects (Csanaky and Gregus 2003). Although toxic at high doses, Se is an essential trace element necessary for antioxidant enzyme activity, thyroid hormone metabolism, and immune function and has been used in chemoprevention studies (Zeng et al. 2005). In contrast, As has no known biological function and displays both acute and chronic toxicity. Arsenic-contaminated groundwater is a major health concern worldwide, affecting roughly 140 million people in > 70 countries (Kinniburgh and Smedley 2001; World Bank 2005). Ingestion of inorganic As (InAs) via contaminated drinking water is associated with elevated risk of pre-malignant skin lesions and cancers of the skin, lung, bladder, liver, and kidney, as well as noncarcinogenic outcomes, including cardiovascular disease and neurological deficits (National Research Council 2001; Tseng 2008; Wasserman et al. 2004).
In drinking water, As occurs in its inorganic form, either as arsenite ([As.sup.III]) or arsenate ([As.sup.V]), the former being the primary form found in groundwater in Bangladesh. Once ingested, [As.sup.III] undergoes oxidative methylation using S-adenosylmethionine (SAM) as the methyl donor, forming monomethylarsonic acid ([MMA.sup.V]). [MMA.sup.V] can then be reduced to monomethylarsonous acid ([MMA.sup.III]), with reducing equivalents provided by thioredoxin (Trx) (Thomas et al. 2004). [MMA.sup.III] can undergo a second methylation step to form dimethylarsinic acid ([DMA.sup. …