Polymorphisms in arsenic(+III oxidation state) methyltransferase (AS3MT) predict gene expression of AS3MT as well as arsenic metabolism

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From: Environmental Health Perspectives(Vol. 119, Issue 2)
Publisher: National Institute of Environmental Health Sciences
Document Type: Report
Length: 6,217 words
Lexile Measure: 1350L

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BACKGROUND: Arsenic (As) occurs as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in humans, and the methylation pattern demonstrates large interindividual differences. The fraction of urinary MMA is a marker for susceptibility to As-related diseases.

OBJECTIVES: We evaluated the impact of polymorphisms in five methyltransferase genes on As metabolism in two populations, one in South America and one in Southeast Asia. The methyltransferase genes were arsenic(+III oxidation state) methyltransferase (AS3MT), DNA-methyltransferase la and 3b (DNMT1a and DNMT3b, respectively), phosphatidylethanolamine N-methyltransferase (PEMT), and betaine-homocysteine methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood.

METHODS: Subjects were women exposed to As in drinking water in the Argentinean Andes [n = 172; median total urinary As (U-As), 200 [micro]g/L] and in rural Bangladesh (n = 361; U-As, 100 [micro]g/L; all in early pregnancy). Urinary As metabolites were measured by high-pressure liquid chromatography/inductively coupled plasma mass spectrometry. Polymorphisms (n = 22) were genotyped with Sequenom, and AS3MT expression was measured by quantitative real-time polymerase chain reaction using TaqMan expression assays.

RESULTS: Six AS3MT polymorphisms were significantly associated with As metabolite patterns in both populations (p [less than or equal to] 0.01). The most frequent AS3MT haplotype in Bangladesh was associated with a higher percentage of MMA (%MMA), and the most frequent haplotype in Argentina was associated with a lower %MMA and a higher percentage of DMA. Four polymorphisms in the DNMT genes were associated with metabolite patterns in Bangladesh. Noncoding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of A453M7 polymorphisms may be altered levels of gene expression.

CONCLUSIONS: Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide.

KEY WORDS: arsenic, AS3MT, BHMT, DNMT1a, DNMT3b, gene expression, methylation, one-carbon metabolism, PEMT, polymorphism. Environ Health Perspect 119:182-188 (2011). doi:10.1289/ehp.1002471 [Online 24 September 2010]

Millions of people around the world are exposed to high concentrations of arsenic (As) in drinking water, and these exposures are associated with a number of adverse health effects (International Agency for Research on Cancer 2004; National Research Council 2001). There is a marked individual variability in As metabolism, as measured by the distribution of inorganic As (iAs) and the main methylated metabolites monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in urine (Vahter 2002). Several studies have shown an association between an increased fraction of MMA in urine, probably reflecting the highly toxic [MMA.sup.III] in the tissues, and an increased risk of various As-related adverse health effects (Chen et al. 2005; Chung et al. 2009; Lindberg et al. 2008; Tseng 2007). As is metabolized by a series of reduction and methylation reactions. S-Adenosyl methionine (SAM) is the main methyl donor, implying that As methylation is dependent on factors influencing one-carbon metabolism (Vahter 2002). As(+III oxidation state) methyltransferase (AS3MT) methylates As (Lin et al. 2002). We previously reported an unusual metabolism of As in a mainly indigenous population in the Argentinean Andes, with a lower percentage of MMA...

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Gale Document Number: GALE|A255971176