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Differential methylation of the arsenic (III) methyltransferase promoter according to arsenic exposure

  • Inorganic Compounds
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Abstract

Inorganic arsenic is methylated in the body by arsenic (III) methyltransferase (AS3MT). Arsenic methylation is thought to play a role in arsenic-related epigenetic phenomena, including aberrant DNA and histone methylation. However, it is unclear whether the promoter of the AS3MT gene, which codes for AS3MT, is differentially methylated as a function of arsenic exposure. In this study, we evaluated AS3MT promoter methylation according to exposure, assessed by urinary arsenic excretion in a stratified random sample of 48 participants from the Strong Heart Study who had urine arsenic measured at baseline and DNA available from 1989 to 1991 and 1998–1999. For this study, all data are from the 1989–1991 visit. We measured AS3MT promoter methylation at its 48 CpG loci by bisulphite sequencing. We compared mean  % methylation at each CpG locus by arsenic exposure group using linear regression adjusted for study centre, age and sex. A hypomethylated region in the AS3MT promoter was associated with higher arsenic exposure. In vitro, arsenic induced AS3MT promoter hypomethylation, and it increased AS3MT expression in human peripheral blood mononuclear cells. These findings may suggest that arsenic exposure influences the epigenetic regulation of a major arsenic metabolism gene.

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Acknowledgments

Supported by grants from the National Heart Lung and Blood Institute (R01HL090863 and by Strong Heart Study grants HL41642, HL41652, HL41654 and HL65520) and the National Institute of Environmental Health Sciences (R01ES021367, R00ES016817 and P30ES03819). M. Gribble was supported by T32 training grants from the National Heart, Lung, and Blood Institute (5T32HL007024) and the National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK062707-10).

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Authors and Affiliations

  1. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Matthew O. Gribble, Eliseo Guallar, M. Daniele Fallin & Ana Navas-Acien

  2. Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, 615 N. Wolfe Street Office W7513D, Baltimore, MD, 21205, USA

    Matthew O. Gribble, Wan-yee Tang, Yan Shang, Jonathan Pollak, Ellen K. Silbergeld & Ana Navas-Acien

  3. Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA

    Matthew O. Gribble, Eliseo Guallar & Ana Navas-Acien

  4. MedStar Health Research Institute, Hyattsville, MD, USA

    Jason G. Umans

  5. Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC, USA

    Jason G. Umans

  6. Institute of Chemistry-Analytical Chemistry, Karl-Franzens University, Graz, Austria

    Kevin A. Francesconi & Walter Goessler

  7. Department of Medicine, Johns Hopkins Medical School, Baltimore, MD, USA

    Eliseo Guallar

  8. Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA

    Shelley A. Cole

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  1. Matthew O. Gribble
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  2. Wan-yee Tang
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  3. Yan Shang
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Correspondence to Ana Navas-Acien.

Electronic supplementary material

The supplemental materials illustrate the raw data used to generate individual  % methylation variables at each CpG locus (Supplement 1), the distribution of  % methylation values across individuals at each CpG locus (Supplement 2) and mean level of  % DNA methylation in a 30-CpG-loci region of the AS3MT promoter (Supplement 3).

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Gribble, M.O., Tang, Wy., Shang, Y. et al. Differential methylation of the arsenic (III) methyltransferase promoter according to arsenic exposure. Arch Toxicol 88, 275–282 (2014). https://doi.org/10.1007/s00204-013-1146-x

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