title: Knockout of arsenic (+3 oxidation state) methyltransferase is associated with adverse metabolic phenotype in mice: the role of sex and arsenic exposure.
abstract: Susceptibility to toxic effects of inorganic arsenic (iAs) depends, in part, on efficiency of iAs methylation by arsenic (+3 oxidation state) methyltransferase (AS3MT). As3mt-knockout (KO) mice that cannot efficiently methylate iAs represent an ideal model to study the association between iAs metabolism and adverse effects of iAs exposure, including effects on metabolic phenotype. The present study compared measures of glucose metabolism, insulin resistance and obesity in male and female wild-type (WT) and As3mt-KO mice during a 24-week exposure to iAs in drinking water (0.1 or 1 mg As/L) and in control WT and As3mt-KO mice drinking deionized water. Results show that effects of iAs exposure on fasting blood glucose (FBG) and glucose tolerance in either WT or KO mice were relatively minor and varied during the exposure. The major effects were associated with As3mt KO. Both male and female control KO mice had higher body mass with higher percentage of fat than their respective WT controls. However, only male KO mice were insulin resistant as indicated by high FBG, and high plasma insulin at fasting state and 15 min after glucose challenge. Exposure to iAs increased fat mass and insulin resistance in both male and female KO mice, but had no significant effects on body composition or insulin resistance in WT mice. These data suggest that As3mt KO is associated with an adverse metabolic phenotype that is characterized by obesity and insulin resistance, and that the extent of the impairment depends on sex and exposure to iAs, including exposure to iAs from mouse diet.
authors.affiliation: Department of Nutrition, CB# 7461, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7461, USA.
authors.forename: Christelle
authors.initials: C
authors.lastname: Douillet
authors.affiliation: Curriculum in Toxicology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Madelyn C
authors.initials: MC
authors.lastname: Huang
authors.affiliation: Department of Nutrition, CB# 7461, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7461, USA.
authors.forename: R Jesse
authors.initials: RJ
authors.lastname: Saunders
authors.affiliation: Curriculum in Toxicology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Ellen N
authors.initials: EN
authors.lastname: Dover
authors.affiliation: Department of Nutrition, CB# 7461, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7461, USA.
authors.forename: Chongben
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Nutrition, CB# 7461, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7461, USA. styblo@med.unc.edu.|Curriculum in Toxicology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. styblo@med.unc.edu.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Stýblo
mesh_terms: D000818:Animals; D001151:Arsenic / Q000493:pharmacokinetics / Q000633:toxicity* / Q000652:urine; D001823:Body Composition / Q000187:drug effects / Q000235:genetics; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D005260:Female; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism*
chemical_list: D008780:Methyltransferases; C532135:AS3MT protein, mouse; D005947:Glucose; D001151:Arsenic
keywords: Arsenic; As3mt-knockout mice; Insulin resistance; Metabolic phenotype; Obesity