Although mice are widely used to study adverse effects of inorganic arsenic (iAs), higher rates of iAs methylation in mice than in humans may limit their utility as a model organism. A recently created 129S6 mouse strain in which the Borcs7/As3mt locus replaces the human BORCS7/AS3MT locus exhibits a human-like pattern of iAs metabolism. Here, we evaluate dosage dependency of iAs metabolism in humanized (Hs) mice. We determined tissue and urinary concentrations and proportions of iAs, methylarsenic (MAs), and dimethylarsenic (DMAs) in male and female Hs and wild-type (WT) mice that received 25- or 400-ppb iAs in drinking water. At both exposure levels, Hs mice excrete less total arsenic (tAs) in urine and retain more tAs in tissues than WT mice. Tissue tAs levels are higher in Hs females than in Hs males, particularly after exposure to 400-ppb iAs. Tissue and urinary fractions of tAs present as iAs and MAs are significantly greater in Hs mice than in WT mice. Notably, tissue tAs dosimetry in Hs mice resembles human tissue dosimetry predicted by a physiologically based pharmacokinetic model. These data provide additional support for use of Hs mice in laboratory studies examining effects of iAs exposure in target tissues or cells.

Chemical Characterization and Exposure Division Center for Computational Toxicology and Exposure Office of Research and Development U S Environmental Protection Agency Research Triangle Park NC 27709 USA

Department of Genetics School of Medicine University of North Carolina Chapel Hill NC 27599 USA

Department of Nutrition Gillings School of Global Public Health University of North Carolina at Chapel Hill Chapel Hill NC 27599 7461 USA

Dinkey Creek Consulting LLC Chapel Hill NC 27517 USA

Institute of Analytical Chemistry of the Czech Academy of Sciences v v i Veveří 97 602 00 Brno Czech Republic

Zobrazit více v PubMed

ATSDR. Agency for Toxic Substances and Disease Registry. Toxicological Profile for Arsenic. (U.S. DHHS, Public Health Service, 2007). PubMed

Cubadda F, et al. Human exposure to dietary inorganic arsenic and other arsenic species: State of knowledge, gaps and uncertainties. Sci. Total Environ. 2017;579:1228–1239. doi: 10.1016/j.scitotenv.2016.11.108. PubMed DOI PMC

IARC International Agency for Research on Cancer . Arsenic in Drinking Water. IARC Press; 2004. pp. 269–477.

Naujokas MF, et al. The broad scope of health effects from chronic arsenic exposure: Update on a worldwide public health problem. Environ. Health Perspect. 2013;121:95–302. doi: 10.1289/ehp.1205875. PubMed DOI PMC

Lin S, et al. A novel S-adenosyl-l-methionine: Arsenic(III) methyltransferase from rat liver cytosol. J. Biol. Chem. 2002;277:10795–10803. doi: 10.1074/jbc.M110246200. PubMed DOI

Thomas DJ, et al. Arsenic (+3 oxidation state) methyltransferase and the methylation of arsenicals. Exp. Biol. Med. 2007;232:3–13. PubMed PMC

Hughes MF, Beck BD, Chen Y, Lewis AS, Thomas DJ. Arsenic exposure and toxicology: A historical perspective. Toxicol. Sci. 2011;123:305–332. doi: 10.1093/toxsci/kfr184. PubMed DOI PMC

Ahsan H, et al. Arsenic metabolism, genetic susceptibility, and risk of premalignant skin lesions in Bangladesh. Cancer Epidemiol. Biomark. Prev. 2007;16:1270–1278. doi: 10.1158/1055-9965.EPI-06-0676. PubMed DOI

Pierce BL, et al. Genome-wide association study identifies chromosome 10q24.32 variants associated with arsenic metabolism and toxicity phenotypes in Bangladesh. PLoS Genet. 2012;8:e1002522. doi: 10.1371/journal.pgen.1002522. PubMed DOI PMC

Pierce BL, et al. Arsenic metabolism efficiency has a causal role in arsenic toxicity: Mendelian randomization and gene-environment interaction. Int. J. Epidemiol. 2013;42:1862–1871. doi: 10.1093/ije/dyt182. PubMed DOI PMC

Vahter M. Genetic polymorphism in the biotransformation of inorganic arsenic and its role in toxicity. Toxicol. Lett. 2000;112–113:209–217. doi: 10.1016/S0378-4274(99)00271-4. PubMed DOI

Vahter M. Methylation of inorganic arsenic in different mammalian species and population groups. Sci. Prog. 1999;82:69–88. doi: 10.1177/003685049908200104. PubMed DOI PMC

Vahter M, Concha G. Role of metabolism in arsenic toxicity. Pharmacol. Toxicol. 2001;89:1–5. doi: 10.1034/j.1600-0773.2001.d01-128.x. PubMed DOI

Stýblo M, et al. Differential metabolism of inorganic arsenic in mice from genetically diverse collaborative cross strains. Arch. Toxicol. 2019;93:2811–2822. doi: 10.1007/s00204-019-02559-7. PubMed DOI PMC

Kalman DA, et al. Occurrence of trivalent monomethyl arsenic and other urinary arsenic species in a highly exposed juvenile population in Bangladesh. J. Expo. Sci. Environ. Epidemiol. 2014;24:113–120. doi: 10.1038/jes.2013.14. PubMed DOI

Yanez J, et al. Urinary arsenic speciation profile in ethnic group of the Atacama desert (Chile) exposed to variable arsenic levels in drinking water. J. Environ. Sci. Health A. 2015;50:1–8. doi: 10.1080/10934529.2015.964594. PubMed DOI

El-Masri HA, Kenyon EM. Development of a human physiologically based pharmacokinetic (PBPK) model for inorganic arsenic and its mono- and di-methylated metabolites. J. Pharmacokinet. Pharmacodyn. 2008;35:31–68. doi: 10.1007/s10928-007-9075-z. PubMed DOI

Koller BH, et al. Arsenic metabolism in mice carrying a BORCS7/AS3MT locus humanized by syntenic replacement. Environ. Health Perspect. 2020;28:87003. doi: 10.1289/EHP6943. PubMed DOI PMC

Threadgill DW, Miller DR, Churchill GA, de Villena FP. The collaborative cross: A recombinant inbred mouse population for the systems genetic era. ILAR J. 2011;52:24–31. doi: 10.1093/ilar.52.1.24. PubMed DOI

Drobna Z, et al. 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. 2009;22:1713–1720. doi: 10.1021/tx900179r. PubMed DOI PMC

Hughes MF, et al. Arsenic (+3 oxidation state) methyltransferase genotype affects steady-state distribution and clearance of arsenic in arsenate-treated mice. Toxicol. Appl. Pharmacol. 2010;249:217–223. doi: 10.1016/j.taap.2010.09.017. PubMed DOI

Drobná Z, Walton FS, Harmon AW, Thomas DJ, Stýblo M. Interspecies differences in metabolism of arsenic by cultured primary hepatocytes. Toxicol. Appl. Pharmacol. 2010;45:47–56. doi: 10.1016/j.taap.2010.01.015. PubMed DOI PMC

Pomroy C, Charbonneau SM, McCullough RS, Tam GK. Human retention studies with 74As. Toxicol. Appl. Pharmacol. 1980;53:550–556. doi: 10.1016/0041-008X(80)90368-3. PubMed DOI

Buchet JP, Lauwerys R, Roels H. Comparison of the urinary excretion of arsenic metabolites after a single oral dose of sodium arsenite, monomethylarsonate, or dimethylarsinate in man. Int. Arch. Occup. Environ. Health. 1981;48:71–79. doi: 10.1007/BF00405933. PubMed DOI

Buchet JP, Lauwerys R, Roels H. Urinary excretion of inorganic arsenic and its metabolites after repeated ingestion of sodium metaarsenite by volunteers. Int. Arch. Occup. Environ. Health. 1981;48:111–118. doi: 10.1007/BF00378431. PubMed DOI

Hughes MF, et al. Accumulation and metabolism of arsenic in mice after repeated oral administration of arsenate. Toxicol. Appl. Pharmacol. 2003;191:202–210. doi: 10.1016/S0041-008X(03)00249-7. PubMed DOI

Hughes MF, et al. Tissue dosimetry, metabolism and excretion of pentavalent and trivalent monomethylated arsenic in mice after oral administration. Toxicol. Appl. Pharmacol. 2005;208:186–197. doi: 10.1016/j.taap.2005.02.008. PubMed DOI PMC

Hughes MF, et al. Tissue dosimetry, metabolism and excretion of pentavalent and trivalent dimethylated arsenic in mice after oral administration. Toxicol. Appl. Pharmacol. 2008;227:26–35. doi: 10.1016/j.taap.2007.10.011. PubMed DOI PMC

Marafante E, et al. Biotransformation of dimethylarsinic acid in mouse, hamster and man. J. Appl. Toxicol. 1987;7:111–117. doi: 10.1002/jat.2550070207. PubMed DOI

Sumi D, Himeno S. Role of arsenic (+3 oxidation state) methyltransferase in arsenic metabolism and toxicity. Biol. Pharm. Bull. 2012;35:1870–1875. doi: 10.1248/bpb.b212015. PubMed DOI

Drobná Z, Del Razo LM, García-Vargas GG, Sánchez-Peña LC, Barrera-Hernández A, Stýblo M, Loomis D. Environmental exposure to arsenic, AS3MT polymorphism and prevalence of diabetes in Mexico. J. Expo. Sci. Environ. Epidemiol. 2013;23:151–155. doi: 10.1038/jes.2012.103. PubMed DOI PMC

Das N, Giri A, Chakraborty S, Bhattacharjee P. Association of single nucleotide polymorphism with arsenic-induced skin lesions and genetic damage in exposed population of West Bengal, India. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 2016;809:50–56. doi: 10.1016/j.mrgentox.2016.09.006. PubMed DOI

Jansen RJ, et al. Determinants and consequences of arsenic metabolism efficiency among 4,794 individuals: demographics, lifestyle, genetics, and toxicity. Cancer Epidemiol. Biomark. Prev. 2016;25:381–390. doi: 10.1158/1055-9965.EPI-15-0718. PubMed DOI PMC

Li J, Packianathan C, Rossman TG, Rosen BP. Nonsynonymous polymorphisms in the human AS3MT arsenic methylation gene: Implications for arsenic toxicity. Chem. Res. Toxicol. 2017;30:1481–1491. doi: 10.1021/acs.chemrestox.7b00113. PubMed DOI PMC

Song Y, Jin D, Chen J, Liang W, Liu X. Effects of arsenic (+3 oxidation state) methyltransferase gene polymorphisms and expression on bladder cancer: Evidence from a systematic review, meta-analysis and TCGA dataset. Toxicol. Sci. 2020;177:27–40. doi: 10.1093/toxsci/kfaa087. PubMed DOI

Delgado DA, et al. Rare, protein-altering variants in AS3MT and arsenic metabolism efficiency: A multi-population association study. Environ. Health Perspect. 2021;129:47007. doi: 10.1289/EHP8152. PubMed DOI PMC

Stýblo M, Venkatratnam A, Fry RC, Thomas DJ. Origins, fate, and actions of methylated trivalent metabolites of inorganic arsenic: Progress and prospects. Arch. Toxicol. 2021;95:1547–1572. doi: 10.1007/s00204-021-03028-w. PubMed DOI PMC

Vahter M. Species differences in the metabolism of arsenic compounds. Appl. Organomet. Chem. 1994;8:175–182. doi: 10.1002/aoc.590080304. DOI

Tseng CH. Arsenic methylation, urinary arsenic metabolites and human diseases: current perspective. J. Environ. Sci. Health. C. 2007;25:1–22. doi: 10.1080/10590500701201695. PubMed DOI

Vahter M. Mechanisms of arsenic biotransformation. Toxicology. 2002;181–182:211–217. doi: 10.1016/S0300-483X(02)00285-8. PubMed DOI

Chernoff M, et al. Genetic determinants of reduced arsenic metabolism efficiency in the 10q24.32 region are associated with reduced AS3MT expression in multiple human tissue types. Toxicol. Sci. 2020;176:382–395. doi: 10.1093/toxsci/kfaa075. PubMed DOI PMC

Lindberg AL, et al. Metabolism of low-dose inorganic arsenic in a central European population: Influence of sex and genetic polymorphisms. Environ. Health Perspect. 2007;115:1081–1086. doi: 10.1289/ehp.10026. PubMed DOI PMC

Kile ML, et al. Variability in biomarkers of arsenic exposure and metabolism in adults over time. Environ. Health Perspect. 2009;117:455–460. doi: 10.1289/ehp.11251. PubMed DOI PMC

Shen H, et al. Factors affecting arsenic methylation in arsenic-exposed humans: A systematic review and meta-analysis. Int. J. Environ. Res. Public Health. 2016;13:205. doi: 10.3390/ijerph13020205. PubMed DOI PMC

Torres-Sánchez L, et al. Sex differences in the reduction of arsenic methylation capacity as a function of urinary total and inorganic arsenic in Mexican children. Environ. Res. 2016;151:38–43. doi: 10.1016/j.envres.2016.07.020. PubMed DOI

Jiang R, et al. Influence of combined exposure levels of total arsenic and inorganic arsenic on arsenic methylation capacity among university students: findings from Bayesian kernel machine regression analysis. Environ. Sci. Pollut. Res. Int. 2022;29:28714–28724. doi: 10.1007/s11356-021-17906-4. PubMed DOI

Vahter M, Akesson A, Lidén C, Ceccatelli S, Berglund M. Gender differences in the disposition and toxicity of metals. Environ. Res. 2007;104:85–95. doi: 10.1016/j.envres.2006.08.003. PubMed DOI

Bustaffa E, Gorini F, Bianchi F, Minichilli F. Factors affecting arsenic methylation in contaminated Italian areas. Int. J. Environ. Res. Public Health. 2020;17:5226. doi: 10.3390/ijerph17145226. PubMed DOI PMC

Murko M, Elek B, Styblo M, Thomas DJ, Francesconi KA. Dose and diet: Sources of arsenic intake in mouse in utero exposure scenarios. Chem. Res. Toxicol. 2018;31:156–164. doi: 10.1021/acs.chemrestox.7b00309. PubMed DOI PMC

Arcella D, Cascio C, Gómez Ruiz JÁ, European Food Safety Authority (EFSA) Chronic dietary exposure to inorganic arsenic. EFSA J. 2021;19:e06380. PubMed PMC

Matoušek T, et al. 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. Spectrochim. Acta B. 2008;63:396–406. doi: 10.1016/j.sab.2007.11.037. PubMed DOI PMC

Matoušek T, et al. Selective hydride generation- cryotrapping-ICP-MS for arsenic speciation analysis at picogram levels: Analysis of river and sea water reference materials and human bladder epithelial cells. J. Anal. At. Spectrom. 2013;28:1456–1465. doi: 10.1039/c3ja50021g. PubMed DOI PMC

Matoušek T, Wang Z, Douillet C, Musil S, Stýblo M. Direct speciation analysis of arsenic in whole blood and blood plasma at low exposure levels by hydride generation-cryotrapping-inductively coupled plasma mass spectrometry. Anal. Chem. 2017;89:9633–9637. doi: 10.1021/acs.analchem.7b01868. PubMed DOI PMC

Hernández-Zavala A, et al. Speciation analysis of arsenic in biological matrices by automated hydride generation-cryotrapping-atomic absorption spectrometry with multiple microflame quartz tube atomizer (multiatomizer) J. Anal. At. Spectrom. 2008;23:342–351. doi: 10.1039/B706144G. PubMed DOI PMC

Currier JM, et al. Direct analysis of methylated trivalent arsenicals in mouse liver by hydride generation-cryotrapping-atomic absorption spectrometry. Chem. Res. Toxicol. 2011;24:478–480. doi: 10.1021/tx200060c. PubMed DOI PMC

Currier J, et al. Comparative oxidation state specific analysis of arsenic species by high-performance liquid chromatography-inductively coupled plasma-mass spectrometry and hydride generation-cryotrapping-atomic absorption spectrometry. J. Anal. At. Spectrom. 2013;28:843–852. doi: 10.1039/c3ja30380b. PubMed DOI PMC