Knockout of arsenic (+3 oxidation state) methyltransferase is associated with adverse metabolic phenotype in mice: the role of sex and arsenic exposure
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.
KeywordsArsenic Metabolic phenotype As3mt-knockout mice Obesity Insulin resistance
The authors thank Dr. David Thomas (US EPA) for his continuous support and advice regarding the establishment and maintenance of As3mt-KO mouse colony at UNC Chapel Hill.
This work was supported by grants from the National Institute of Health (R01ES022697 and DK 056350) and in part by National Research Service Award from the National Institute of Environmental Health Sciences, NIH (T32 ES007126).
- Chen Y, Parvez F, Gamble M, Islam T, Ahmed A, Argos M, Graziano JH, Ahsan H (2009) Arsenic exposure at low-to-moderate levels and skin lesions, arsenic metabolism, neurological functions, and biomarkers for respiratory and cardiovascular diseases: review of recent findings from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh. Toxicol Appl Pharmacol 239:184–192CrossRefPubMedPubMedCentralGoogle Scholar
- Del Razo LM, García-Vargas GG, Valenzuela OL, Hernandez-Castellanos E, Sánchez-Peña LC, Drobná Z, Loomis D, Stýblo M (2011) Exposure to arsenic in drinking water is associated with increased prevalence of diabetes: a cross-sectional study in the Zimapán and Lagunera Regions in Mexico. Environ Health 10:73CrossRefPubMedPubMedCentralGoogle Scholar
- Dodmane PR, Arnold LL, Pennington KL, Thomas DJ, Cohen SM (2013) Effect of dietary treatment with dimethylarsinous acid (DMA(III)) on the urinary bladder epithelium of arsenic (+3 oxidation state) methyltransferase (As3mt) knockout and C57BL/6 wild type female mice. Toxicology 305:130–135CrossRefPubMedGoogle Scholar
- Drobná Z, Naranmandura H, Kubachka KM, Edwards BC, Herbin-Davis K, Styblo M, Le XC, Creed JT, Maeda N, Hughes MF et al (2009) Disruption of the arsenic (+3 oxidation state) methyltransferase gene in the mouse alters the phenotype for methylation of arsenic and affects distribution and retention of orally administered arsenate. Chem Res Toxicol 22:1713–1720CrossRefPubMedPubMedCentralGoogle Scholar
- Fu J, Woods CG, Yehuda-Shnaidman E, Zhang Q, Wong V, Collins S, Sun G, Andersen ME, Pi J (2010) Low-level arsenic impairs glucose-stimulated insulin secretion in pancreatic beta cells: involvement of cellular adaptive response to oxidative stress. Environ Health Perspect 118:864–870CrossRefPubMedPubMedCentralGoogle Scholar
- Hernández-Zavala A, Matoušek T, Drobná Z, Adair BM, Dĕdina J, Thomas DJ, Stýblo M (2008) Speciation of arsenic in biological matrices by automated hydride generation-cryotrapping-atomic absorption spectrometry with multiple microflame quartz tube atomizer (multiatomizer). J Anal At Spectrom 23:342–351CrossRefPubMedPubMedCentralGoogle Scholar
- Huang MC, Douillet C, Su M, Zhou K, Wu T, Chen W, Galanko JA, Drobná Z, Saunders RJ, Martin E, Fry RC, Jia W, Stýblo M (2016a) Metabolomic profiles of arsenic (+3 oxidation state) methyltransferase knockout mice: effect of sex and arsenic exposure. Arch Toxicol. doi: 10.1007/s00204-016-1676-0 PubMedCentralGoogle Scholar
- IARC Monographs on the Evaluation of Carcinogenic Risks to Humans (2004) Volume 84, some drinking-water disinfectants and contaminants, including arsenic. WHO-International Agency for Research on Cancer, LyonGoogle Scholar
- Matoušek T, Hernández-Zavala A, Svoboda M, Langerová L, Adair BM, Drobná Z, Thomas DJ, Stýblo M, Dĕdina J (2008) Oxidation state specific generation of arsines from methylated arsenicals based on l-cysteine treatment in buffered media for speciation analysis by hydride generation—automated cryotrapping—gas chromatography-atomic absorption spectrometry with the multiatomizer. Spetrochim Acta Part B 63:396–406CrossRefGoogle Scholar
- Maull EA, Ahsan H, Cooper G, Edwards J, Longnecker M, Navas-Acien A, Pi J, Silbergeld E, Styblo M, Tseng C-H, Thayer K, Loomis D (2012) Evaluation of the association be-tween arsenic and diabetes: a National Toxicology Program workshop review. Environ Health Perspect 120:1658–1670CrossRefPubMedPubMedCentralGoogle Scholar
- Mendez MA, González-Horta C, Sánchez-Ramírez B, Ballinas-Casarrubias L, Hernández Cerón R, Viniegra Morales D, Baeza Terrazas FA, Ishida MC, Gutiérrez-Torres DS, Saunders RJ, Drobná Z, Fry RC, Buse JB, Loomis D, García-Vargas GG, Del Razo LM, Stýblo M (2016) Chronic exposure to arsenic and markers of cardiometabolic risk: a cross-sectional study in Chihuahua, Mexico. Environ Health Perspect 124:104–111PubMedGoogle Scholar
- Paul DS, Hernández-Zavala A, Walton FS, Adair BM, Dĕdina J, Matoušek T, Styblo M (2007b) Examination of the effects of arsenic on glucose homeostasis in cell culture and animal studies: development of a mouse model for arsenic-induced diabetes. Toxicol Appl Pharmacol 222:305–314CrossRefPubMedPubMedCentralGoogle Scholar
- Thomas DJ, Li J, Waters SB, Xing W, Adair BM, Drobna Z, Devesa V, Styblo M (2007) Arsenic (+3 oxidation state) methyltransferase and the methylation of arsenicals. Exp Biol Med (Maywood) 232:3–13Google Scholar
- Wnek SM, Kuhlman CL, Camarillo JM, Medeiros MK, Liu KJ, Lau SS, Gandolfi AJ (2011) Interdependent genotoxic mechanisms of monomethylarsonous acid: role of ROS-induced DNA damage and poly(ADP-ribose) polymerase-1 inhibition in the malignant transformation of urothelial cells. Toxicol Appl Pharmacol 257:1–13CrossRefPubMedPubMedCentralGoogle Scholar
- Wu F, Jasmine F, Kibriya MG, Liu M, Wójcik O, Parvez F, Rahaman R, Roy S, Paul-Brutus R, Segers S, Slavkovich V, Islam T, Levy D, Mey JL, van Geen A, Graziano JH, Ahsan H, Chen Y (2012) Association between arsenic exposure from drinking water and plasma levels of cardiovascular markers. Am J Epidemiol 175:1252–1261CrossRefPubMedPubMedCentralGoogle Scholar
- Yokohira M, Arnold LL, Pennington KL, Suzuki S, Kakiuchi-Kiyota S, Herbin-Davis K, Thomas DJ, Cohen SM (2010) Severe systemic toxicity and urinary bladder cytotoxicity and regenerative hyperplasia induced by arsenite in arsenic (+3 oxidation state) methyltransferase knockout mice. A preliminary report. Toxicol Appl Pharmacol 246:1–7CrossRefPubMedGoogle Scholar
- Yokohira M, Arnold LL, Pennington KL, Suzuki S, Kakiuchi-Kiyota S, Herbin-Davis K, Thomas DJ, Cohen SM (2011) Effect of sodium arsenite dose administered in the drinking water on the urinary bladder epithelium of female arsenic (+3 oxidation state) methyltransferase knockout mice. Toxicol Sci 121:257–266CrossRefPubMedGoogle Scholar