AS3MT, GSTO, and PNP polymorphisms: impact on arsenic methylation and implications for disease susceptibility

Ray Antonelli; Kan Shao; David J Thomas; Reeder Sams 2nd; John Cowden

doi:10.1016/j.envres.2014.03.012

AS3MT, GSTO, and PNP polymorphisms: impact on arsenic methylation and implications for disease susceptibility

Environ Res. 2014 Jul:132:156-67. doi: 10.1016/j.envres.2014.03.012. Epub 2014 May 8.

Authors

Ray Antonelli¹, Kan Shao¹, David J Thomas², Reeder Sams 2nd³, John Cowden⁴

Affiliations

¹ ORISE Fellow, Hazardous Pollutant Assessment Group, National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
² Integrated Systems Toxicology Division, National Health and Environmental Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
³ Hazardous Pollutant Assessment Group, National Center for Environmental Assessment, Research Triangle Park Division, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
⁴ Hazardous Pollutant Assessment Group, National Center for Environmental Assessment, Research Triangle Park Division, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA. Electronic address: cowden.john@epa.gov.

PMID: 24792412
DOI: 10.1016/j.envres.2014.03.012

Abstract

Background: Oral exposure to inorganic arsenic (iAs) is associated with adverse health effects. Epidemiological studies suggest differences in susceptibility to these health effects, possibly due to genotypic variation. Genetic polymorphisms in iAs metabolism could lead to increased susceptibility by altering urinary iAs metabolite concentrations.

Objective: To examine the impact of genotypic polymorphisms on iAs metabolism.

Methods: We screened 360 publications from PubMed and Web of Science for data on urinary mono- and dimethylated arsenic (MMA and DMA) percentages and polymorphic genes encoding proteins that are hypothesized to play roles in arsenic metabolism. The genes we examined were arsenic (+3) methyltransferase (AS3MT), glutathione-s-transferase omega (GSTO), and purine nucleoside phosphorylase (PNP). Relevant data were pooled to determine which polymorphisms are associated across studies with changes in urinary metabolite concentration.

Results: In our review, AS3MT polymorphisms rs3740390, rs11191439, and rs11191453 were associated with statistically significant changes in percent urinary MMA. Studies of GSTO polymorphisms did not indicate statistically significant associations with methylation, and there are insufficient data on PNP polymorphisms to evaluate their impact on metabolism.

Discussion: Collectively, these data support the hypothesis that AS3MT polymorphisms alter in vivo metabolite concentrations. Preliminary evidence suggests that AS3MT genetic polymorphisms may impact disease susceptibility. GSTO polymorphisms were not associated with iAs-associated health outcomes. Additional data are needed to evaluate the association between PNP polymorphisms and iAs-associated health outcomes. Delineation of these relationships may inform iAs mode(s) of action and the approach for evaluating low-dose health effects for iAs.

Conclusions: Genotype impacts urinary iAs metabolite concentrations and may be a potential mechanism for iAs-related disease susceptibility.

Keywords: Arsenic; Arsenic methyltransferase; Genetic polymorphisms; Glutathione-s-transferase omega; Purine nucleoside phosphorylase.

Published by Elsevier Inc.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Review

MeSH terms

Arsenic / urine*
Genetic Predisposition to Disease
Genotype
Glutathione Transferase / genetics*
Humans
Methylation
Methyltransferases / genetics*
Purine-Nucleoside Phosphorylase / genetics*

Substances

Methyltransferases
AS3MT protein, human
Purine-Nucleoside Phosphorylase
GSTO1 protein, human
Glutathione Transferase
Arsenic