title: Metabolomic profiles of arsenic (+3 oxidation state) methyltransferase knockout mice: effect of sex and arsenic exposure.
abstract: Arsenic (+3 oxidation state) methyltransferase (As3mt) is the key enzyme in the pathway for methylation of inorganic arsenic (iAs). Altered As3mt expression and AS3MT polymorphism have been linked to changes in iAs metabolism and in susceptibility to iAs toxicity in laboratory models and in humans. As3mt-knockout mice have been used to study the association between iAs metabolism and adverse effects of iAs exposure. However, little is known about systemic changes in metabolism of these mice and how these changes lead to their increased susceptibility to iAs toxicity. Here, we compared plasma and urinary metabolomes of male and female wild-type (WT) and As3mt-KO (KO) C57BL/6 mice and examined metabolomic shifts associated with iAs exposure in drinking water. Surprisingly, exposure to 1 ppm As elicited only small changes in the metabolite profiles of either WT or KO mice. In contrast, comparisons of KO mice with WT mice revealed significant differences in plasma and urinary metabolites associated with lipid (phosphatidylcholines, cytidine, acyl-carnitine), amino acid (hippuric acid, acetylglycine, urea), and carbohydrate (L-sorbose, galactonic acid, gluconic acid) metabolism. Notably, most of these differences were sex specific. Sex-specific differences were also found between WT and KO mice in plasma triglyceride and lipoprotein cholesterol levels. Some of the differentially changed metabolites (phosphatidylcholines, carnosine, and sarcosine) are substrates or products of reactions catalyzed by other methyltransferases. These results suggest that As3mt KO alters major metabolic pathways in a sex-specific manner, independent of iAs treatment, and that As3mt may be involved in other cellular processes beyond iAs methylation.
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: Christelle
authors.initials: C
authors.lastname: Douillet
authors.affiliation: University of Hawaii at Mãnoa Cancer Center, Honolulu, HI, 96813, USA.
authors.forename: Mingming
authors.initials: M
authors.lastname: Su
authors.affiliation: University of Hawaii at Mãnoa Cancer Center, Honolulu, HI, 96813, USA.
authors.forename: Kejun
authors.initials: K
authors.lastname: Zhou
authors.affiliation: University of Hawaii at Mãnoa Cancer Center, Honolulu, HI, 96813, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.affiliation: University of Hawaii at Mãnoa Cancer Center, Honolulu, HI, 96813, USA.
authors.forename: Wenlian
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Galanko
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: Zuzana
authors.initials: Z
authors.lastname: Drobná
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: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Martin
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fry
authors.affiliation: University of Hawaii at Mãnoa Cancer Center, Honolulu, HI, 96813, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.affiliation: Curriculum in Toxicology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. styblo@med.unc.edu.|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.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Stýblo
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001151:Arsenic / Q000097:blood / Q000378:metabolism / Q000633:toxicity* / Q000652:urine; D020261:Arsenic Poisoning / Q000097:blood / Q000201:enzymology* / Q000378:metabolism / Q000652:urine; D001152:Arsenicals / Q000097:blood / Q000378:metabolism / Q000652:urine; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001711:Biotransformation; D050260:Carbohydrate Metabolism / Q000187:drug effects; D004351:Drug Resistance; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012727:Sex Characteristics; D066007:Toxicokinetics; D014874:Water Pollutants, Chemical / Q000097:blood / Q000378:metabolism / Q000633:toxicity* / Q000652:urine
chemical_list: D000596:Amino Acids; D001152:Arsenicals; D015415:Biomarkers; D014874:Water Pollutants, Chemical; D008780:Methyltransferases; C532135:AS3MT protein, mouse; D001151:Arsenic
keywords: Arsenic; As3mt knockout; Metabolomics; Mice; Plasma; Urine