title: AS3MT, GSTO, and PNP polymorphisms: impact on arsenic methylation and implications for disease susceptibility.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: ORISE Fellow, Hazardous Pollutant Assessment Group, National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Ray
authors.initials: R
authors.lastname: Antonelli
authors.affiliation: ORISE Fellow, Hazardous Pollutant Assessment Group, National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Kan
authors.initials: K
authors.lastname: Shao
authors.affiliation: Integrated Systems Toxicology Division, National Health and Environmental Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Thomas
authors.affiliation: Hazardous Pollutant Assessment Group, National Center for Environmental Assessment, Research Triangle Park Division, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Reeder
authors.initials: R
authors.lastname: Sams
authors.affiliation: 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.
authors.forename: John
authors.initials: J
authors.lastname: Cowden
mesh_terms: D001151:Arsenic / Q000652:urine*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics*; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics*
chemical_list: D008780:Methyltransferases; C505756:AS3MT protein, human; D011683:Purine-Nucleoside Phosphorylase; C490476:GSTO1 protein, human; D005982:Glutathione Transferase; D001151:Arsenic
keywords: Arsenic; Arsenic methyltransferase; Genetic polymorphisms; Glutathione-s-transferase omega; Purine nucleoside phosphorylase