Advertisement

Differential metabolism of inorganic arsenic in mice from genetically diverse Collaborative Cross strains

  • Miroslav StýbloEmail author
  • Christelle Douillet
  • Jacqueline Bangma
  • Lauren A. Eaves
  • Fernando Pardo-Manuel de Villena
  • Rebecca FryEmail author
Inorganic Compounds

Abstract

Mice have been frequently used to study the adverse effects of inorganic arsenic (iAs) exposure in laboratory settings. Like humans, mice metabolize iAs to monomethyl-As (MAs) and dimethyl-As (DMAs) metabolites. However, mice metabolize iAs more efficiently than humans, which may explain why some of the effects of iAs reported in humans have been difficult to reproduce in mice. In the present study, we searched for mouse strains in which iAs metabolism resembles that in humans. We examined iAs metabolism in male mice from 12 genetically diverse Collaborative Cross (CC) strains that were exposed to arsenite in drinking water (0.1 or 50 ppm) for 2 weeks. Concentrations of iAs and its metabolites were measured in urine and livers. Significant differences in total As concentration and in proportions of total As represented by iAs, MAs, and DMAs were observed between the strains. These differences were more pronounced in livers, particularly in mice exposed to 50 ppm iAs. In livers, large variations among the strains were found in percentage of iAs (15–48%), MAs (11–29%), and DMAs (29–66%). In contrast, DMAs represented 96–99% of total As in urine in all strains regardless of exposure. Notably, the percentages of As species in urine did not correlate with total As concentration in liver, suggesting that the urinary profiles were not representative of the internal exposure. In livers of mice exposed to 50 ppm, but not to 0.1 ppm iAs, As3mt expression correlated with percent of iAs and DMAs. No correlations were found between As3mt expression and the proportions of As species in urine regardless of exposure level. Although we did not find yet a CC strain in which proportions of As species in urine would match those reported in humans (typically 10–30% iAs, 10–20% MAs, 60–70% DMAs), CC strains characterized by low %DMAs in livers after exposure to 50 ppm iAs (suggesting inefficient iAs methylation) could be better models for studies aiming to reproduce effects of iAs described in humans.

Keywords

Arsenic Metabolism Genetically diverse mice The Collaborative Cross 

Notes

Acknowledgements

This study was supported by a UNC Systems Genetics Core Facility CC Pilot Program grant and by the following grants from NIEHS: R01ES022697 to M.S., R01ES028721 to M.S. and R.F., R01ES029925 to R.F., F.P.M.D.V., and M.S., and by the UNC Nutrition Obesity Research Center grant DK056350 from NIDDK.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

204_2019_2559_MOESM1_ESM.docx (3 mb)
Supplementary material 1 (DOCX 3106 kb)

References

  1. Agusa T, Iwata H, Fujihara J, Kunito T, Takeshita H, Minh TB, Trang PT, Viet PH, Tanabe S (2010) Genetic polymorphisms in glutathione S-transferase (GST) superfamily and arsenic metabolism in residents of the Red River Delta, Vietnam. Toxicol Appl Pharmacol 242(3):352–362Google Scholar
  2. Agusa T, Fujihara J, Takeshita H, Iwata H (2011) Individual variations in inorganic arsenic metabolism associated with AS3MT genetic polymorphisms. Int J Mol Sci 12(4):2351–2382Google Scholar
  3. Agusa T, Kunito T, Tue NM, Lan VT, Fujihara J, Takeshita H, Minh TB, Trang PT, Takahashi S, Viet PH, Tanabe S, Iwata H (2012) Individual variations in arsenic metabolism in Vietnamese: the association with arsenic exposure and GSTP1 genetic polymorphism. Metallomics 4(1):91–100Google Scholar
  4. Antonelli R, Shao K, Thomas DJ, Sams R 2nd, Cowden J (2014) AS3MT, GSTO, and PNP polymorphisms: impact on arsenic methylation and implications for disease susceptibility. Environ Res 132:156–167Google Scholar
  5. ATSDR (2007) Toxicological Profile for Arsenic 2007. http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=22&tid=3. Accessed 4 Sept 2019
  6. Aylor DL, Valdar W, Foulds-Mathes W, Buus RJ, Verdugo RA, Baric RS, Ferris MT, Frelinger JA, Heise M, Frieman MB, Gralinski LE, Bell TA, Didion JD, Hua K, Nehrenberg DL, Powell CL, Steigerwalt J, Xie Y, Kelada SN, Collins FS, Yang IV, Schwartz DA, Branstetter LA, Chesler EJ, Miller DR, Spence J, Liu EY, McMillan L, Sarkar A, Wang J, Wang W, Zhang Q, Broman KW, Korstanje R, Durrant C, Mott R, Iraqi FA, Pomp D, Threadgill D, de Villena FP, Churchill GA (2011) Genetic analysis of complex traits in the emerging Collaborative Cross. Genome Res 21(8):1213–1222Google Scholar
  7. Beebe-Dimmer JL, Iyer PT, Nriagu JO, Keele GR, Mehta S, Meliker JR, Lange EM, Schwartz AG, Zuhlke KA, Schottenfeld D, Cooney KA (2012) Genetic variation in glutathione S-transferase omega-1, arsenic methyltransferase and methylene-tetrahydrofolate reductase, arsenic exposure and bladder cancer: a case–control study. Environ Health 11:43Google Scholar
  8. Caceres DD, Werlinger F, Orellana M, Jara M, Rocha R, Alvarado SA, Luis Q (2010) Polymorphism of glutathione S-transferase (GST) variants and its effect on distribution of urinary arsenic species in people exposed to low inorganic arsenic in tap water: an exploratory study. Arch Environ Occup Health 65(3):140–147Google Scholar
  9. Chen JW, Chen HY, Li WF, Liou SH, Chen CJ, Wu JH, Wang SL (2011) The association between total urinary arsenic concentration and renal dysfunction in a community-based population from central Taiwan. Chemosphere 84(1):17–24Google Scholar
  10. Chen JW, Wang SL, Wang YH, Sun CW, Huang YL, Chen CJ, Li WF (2012) Arsenic methylation, GSTO1 polymorphisms, and metabolic syndrome in an arseniasis endemic area of southwestern Taiwan. Chemosphere 88(4):432–438Google Scholar
  11. Chen X, Guo X, He P, Nie J, Yan X, Zhu J, Zhang L, Mao G, Wu H, Liu Z, Aga D, Xu P, Smith M, Ren X (2017) Interactive influence of N6AMT1 and As3MT genetic variations on arsenic metabolism in the population of Inner Mongolia, China. Toxicol Sci 155(1):124–134Google Scholar
  12. Chung CJ, Hsueh YM, Bai CH, Huang YK, Huang YL, Yang MH, Chen CJ (2009) Polymorphisms in arsenic metabolism genes, urinary arsenic methylation profile and cancer. Cancer Causes Control 20(9):1653–1661Google Scholar
  13. Chung CJ, Pu YS, Su CT, Chen HW, Huang YK, Shiue HS, Hsueh YM (2010) Polymorphisms in one-carbon metabolism pathway genes, urinary arsenic profile, and urothelial carcinoma. Cancer Causes Control 21(10):1605–1613Google Scholar
  14. Chung CJ, Pu YS, Su CT, Huang CY, Hsueh YM (2011) Gene polymorphisms of glutathione S-transferase omega 1 and 2, urinary arsenic methylation profile and urothelial carcinoma. Sci Total Environ 409(3):465–470Google Scholar
  15. Currier JM, Svoboda M, de Moraes DP, Matousek T, Dĕdina J, Stýblo M (2011) Direct analysis of methylated trivalent arsenicals in mouse liver by hydride generation-cryotrapping-atomic absorption spectrometry. Chem Res Toxicol 24(4):478–480Google Scholar
  16. Currier JM, Douillet C, Drobná Z, Stýblo M (2016) Oxidation state specific analysis of arsenic species in tissues of wild-type and arsenic (+ 3 oxidation state) methyltransferase-knockout mice. J Environ Sci (China) 49:104–112Google Scholar
  17. Das N, Giri A, Chakraborty S, Bhattacharjee P (2016) Association of single nucleotide polymorphism with arsenic-induced skin lesions and genetic damage in exposed population of West Bengal, India. Mutat Res 809:50–56Google Scholar
  18. de la Rosa R, Steinmaus C, Akers NK, Conde L, Ferreccio C, Kalman D, Zhang KR, Skibola CF, Smith AH, Zhang L, Smith MT (2017) Associations between arsenic (+ 3 oxidation state) methyltransferase (AS3MT) and N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) polymorphisms, arsenic metabolism, and cancer risk in a Chilean population. Environ Mol Mutagen 58(6):411–422Google Scholar
  19. Del Razo LM, Garcia-Vargas GG, Vargas H, Albores A, Gonsebatt ME, Montero R, Ostrosky-Wegman P, Kelsh M, Cebrian ME (1997) Altered profile of urinary arsenic metabolites in adults with chronic arsenicism. A pilot study. Arch Toxicol 71:211–217Google Scholar
  20. Douillet C, Huang MC, Saunders RJ, Dover EN, Zhang C, Styblo M (2017) Knockout of arsenic (+ 3 oxidation state) methyltransferase is associated with adverse metabolic phenotype in mice: the role of sex and arsenic exposure. Arch Toxicol 91(7):2617–2627Google Scholar
  21. Drobna Z, Naranmandura H, Kubachka KM, Edwards BC, Herbin-Davis K, Styblo M, Le XC, Creed JT, Maeda N, Hughes MF, Thomas DJ (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(10):1713–1720Google Scholar
  22. Drobna Z, Del Razo LM, Garcia-Vargas GG, Sanchez-Pena LC, Barrera-Hernandez A, Styblo M, Loomis D (2013) Environmental exposure to arsenic, AS3MT polymorphism and prevalence of diabetes in Mexico. J Expo Sci Environ Epidemiol 23(2):151–155Google Scholar
  23. Engstrom KS, Vahter M, Fletcher T, Leonardi G, Goessler W, Gurzau E, Koppova K, Rudnai P, Kumar R, Broberg K (2015) Genetic variation in arsenic (+ 3 oxidation state) methyltransferase (AS3MT), arsenic metabolism and risk of basal cell carcinoma in a European population. Environ Mol Mutagen 56(1):60–69Google Scholar
  24. Faita F, Cori L, Bianchi F, Andreassi MG (2013) Arsenic-induced genotoxicity and genetic susceptibility to arsenic-related pathologies. Int J Environ Res Public Health 10(4):1527–1546Google Scholar
  25. Fu S, Wu J, Li Y, Liu Y, Gao Y, Yao F, Qiu C, Song L, Wu Y, Liao Y, Sun D (2014) Urinary arsenic metabolism in a Western Chinese population exposed to high-dose inorganic arsenic in drinking water: influence of ethnicity and genetic polymorphisms. Toxicol Appl Pharmacol 274(1):117–123Google Scholar
  26. Fujihara J, Fujii Y, Agusa T, Kunito T, Yasuda T, Moritani T, Takeshita H (2009) Ethnic differences in five intronic polymorphisms associated with arsenic metabolism within human arsenic (+ 3 oxidation state) methyltransferase (AS3MT) gene. Toxicol Appl Pharmacol 234(1):41–46Google Scholar
  27. Gribble MO, Voruganti VS, Cropp CD, Francesconi KA, Goessler W, Umans JG, Silbergeld EK, Laston SL, Haack K, Kao WH, Fallin MD, Maccluer JW, Cole SA, Navas-Acien A (2013) SLCO1B1 variants and urine arsenic metabolites in the Strong Heart Family Study. Toxicol Sci 136(1):19–25Google Scholar
  28. Harari F, Engstrom K, Concha G, Colque G, Vahter M, Broberg K (2013) N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) polymorphisms and arsenic methylation in Andean women. Environ Health Perspect 121(7):797–803Google Scholar
  29. Hernandez A, Marcos R (2008) Genetic variations associated with interindividual sensitivity in the response to arsenic exposure. Pharmacogenomics 9(8):1113–1132Google Scholar
  30. Hernández-Zavala A, Matoušek T, Drobná Z, Paul DS, Walton F, Adair BM, Jiří D, Thomas DJ, Stýblo M (2008) 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 23:342–351Google Scholar
  31. Hopenhayn-Rich C, Biggs ML, Kalman DA, Moore LE, Smith AH (1996a) Arsenic methylation patterns before and after changing from high to lower concentrations of arsenic in drinking water. Environ Health Perspect 104:1200–1207Google Scholar
  32. Hopenhayn-Rich C, Biggs ML, Smith AH, Kalman DA, Moore LE (1996b) Methylation study of a population environmentally exposed to arsenic in drinking water. Environ Health Perspect 104:620–628Google Scholar
  33. Huang MC, Douillet C, Dover EN, Zhang C, Beck R, Tejan-Sie A, Krupenko SA, Stýblo M (2018a) Metabolic phenotype of wild-type and As3mt-knockout C57BL/6J mice exposed to inorganic arsenic: the role of dietary fat and folate intake. Environ Health Perspect 126(12):127003Google Scholar
  34. Huang MC, Douillet C, Dover EN, Stýblo M (2018b) Prenatal arsenic exposure and dietary folate and methylcobalamin supplementation alter the metabolic phenotype of C57BL/6J mice in a sex-specific manner. Arch Toxicol 92(6):1925–1937Google Scholar
  35. Hughes MF, Kenyon EM, Edwards BC, Mitchell CT, Thomas DJ (1999) Strain-dependent disposition of inorganic arsenic in the mouse. Toxicology 137(2):95–108Google Scholar
  36. Keane TM, Goodstadt L, Danecek P, White MA, Wong K, Yalcin B, Heger A, Agam A, Slater G, Goodson M, Furlotte NA, Eskin E, Nellåker C, Whitley H, Cleak J, Janowitz D, Hernandez-Pliego P, Edwards A, Belgard TG, Oliver PL, McIntyre RE, Bhomra A, Nicod J, Gan X, Yuan W, van der Weyden L, Steward CA, Bala S, Stalker J, Mott R, Durbin R, Jackson IJ, Czechanski A, Guerra-Assunção JA, Donahue LR, Reinholdt LG, Payseur BA, Ponting CP, Birney E, Flint J, Adams DJ (2011) Mouse genomic variation and its effect on phenotypes and gene regulation. Nature 477(7364):289–294Google Scholar
  37. Lindberg AL, Kumar R, Goessler W, Thirumaran R, Gurzau E, Koppova K, Rudnai P, Leonardi G, Fletcher T, Vahter M (2007) Metabolism of low-dose inorganic arsenic in a central European population: influence of sex and genetic polymorphisms. Environ Health Perspect 115(7):1081–1086Google Scholar
  38. Lindberg AL, Ekström EC, Nermell B, Rahman M, Lönnerdal B, Persson LA, Vahter M (2008) Gender and age differences in the metabolism of inorganic arsenic in a highly exposed population in Bangladesh. Environ Res 106(1):110–120Google Scholar
  39. Mazumder DN (2005) Effect of chronic intake of arsenic-contaminated water on liver. Toxicol Appl Pharmacol 206(2):169–175Google Scholar
  40. Naujokas MF, Anderson B, Ahsan H, Aposhian HV, Graziano JH, Thompson C, Suk WA (2013) The broad scope of health effects from chronic arsenic exposure: update on a worldwide public health problem. Environ Health Perspect 121(3):295–302Google Scholar
  41. Paul DS, Hernández-Zavala A, Walton FS, Adair BM, Dedina J, Matousek T, Stýblo M (2007) 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(3):305–314Google Scholar
  42. Paul DS, Walton FS, Saunders RJ, Styblo M (2011) Characterization of the impaired glucose homeostasis produced in C57BL/6 mice by chronic exposure to arsenic and high-fat diet. Environ Health Perspect 119(8):1104–1109Google Scholar
  43. Paul S, Majumdar S, Giri AK (2015) Genetic susceptibility to arsenic-induced skin lesions and health effects: a review. Genes Environ. 37:23Google Scholar
  44. Pierce BL, Kibriya MG, Tong L, Jasmine F, Argos M, Roy S, Paul-Brutus R, Rahaman R, Rakibuz-Zaman M, Parvez F, Ahmed A, Quasem I, Hore SK, Alam S, Islam T, Slavkovich V, Gamble MV, Yunus M, Rahman M, Baron JA, Graziano JH, Ahsan H (2012) Genome-wide association study identifies chromosome 10q24.32 variants associated with arsenic metabolism and toxicity phenotypes in Bangladesh. PLoS Genet 8(2):e1002522Google Scholar
  45. Rahbar MH, Samms-Vaughan M, Ma J, Bressler J, Loveland KA, Ardjomand-Hessabi M, Dickerson AS, Grove ML, Shakespeare-Pellington S, Beecher C, McLaughlin W, Boerwinkle E (2014) Role of metabolic genes in blood arsenic concentrations of Jamaican children with and without autism spectrum disorder. Int J Environ Res Public Health 11(8):7874–7895Google Scholar
  46. Recio-Vega R, Gonzalez-Cortes T, Olivas-Calderon E, Clark Lantz R, Jay Gandolfi A, Michel-Ramirez G (2016) Association between polymorphisms in arsenic metabolism genes and urinary arsenic methylation profiles in girls and boys chronically exposed to arsenic. Environ Mol Mutagen 57(7):516–525Google Scholar
  47. Rodrigues EG, Kile M, Hoffman E, Quamruzzaman Q, Rahman M, Mahiuddin G, Hsueh Y, Christiani DC (2012) GSTO and AS3MT genetic polymorphisms and differences in urinary arsenic concentrations among residents in Bangladesh. Biomarkers 17(3):240–247Google Scholar
  48. Schlawicke Engstrom K, Nermell B, Concha G, Stromberg U, Vahter M, Broberg K (2009) Arsenic metabolism is influenced by polymorphisms in genes involved in one-carbon metabolism and reduction reactions. Mutat Res 667(1–2):4–14Google Scholar
  49. Spratlen MJ, Grau-Perez M, Best LG, Yracheta J, Lazo M, Vaidya D, Balakrishnan P, Gamble MV, Francesconi KA, Goessler W, Cole SA, Umans JG, Howard BV, Navas-Acien A (2018) The association of arsenic exposure and arsenic metabolism with the metabolic syndrome and its individual components: prospective evidence from the strong heart family study. Am J Epidemiol 187(8):1598–1612Google Scholar
  50. Stanton BA, Caldwell K, Congdon CB, Disney J, Donahue M, Ferguson E, Flemings E, Golden M, Guerinot ML, Highman J, James K, Kim C, Lantz RC, Marvinney RG, Mayer G, Miller D, Navas-Acien A, Nordstrom DK, Postema S, Rardin L, Rosen B, SenGupta A, Shaw J, Stanton E, Susca P (2015) MDI biological laboratory arsenic summit: approaches to limiting human exposure to arsenic. Curr Environ Health Rep 2(3):329–337Google Scholar
  51. Steinmaus C, Bates MN, Yuan Y, Kalman D, Atallah R, Rey OA, Biggs ML, Hopenhayn C, Moore LE, Hoang BK, Smith AH (2006) Arsenic methylation and bladder cancer risk in case–control studies in Argentina and the United States. J Occup Environ Med 48(5):478–488Google Scholar
  52. Steinmaus C, Moore LE, Shipp M, Kalman D, Rey OA, Biggs ML, Hopenhayn C, Bates MN, Zheng S, Wiencke JK, Smith AH (2007) Genetic polymorphisms in MTHFR 677 and 1298, GSTM1 and T1, and metabolism of arsenic. J Toxicol Environ Health A 70(2):159–170Google Scholar
  53. 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 232(1):3–13Google Scholar
  54. Tseng CH (2007) Arsenic methylation, urinary arsenic metabolites and human diseases: current perspective. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 25(1):1–22Google Scholar
  55. Vahter M (1999) Methylation of inorganic arsenic in different mammalian species and population groups. Sci Prog 82(Pt 1):69–88Google Scholar
  56. Vahter M (2000) Genetic polymorphism in the biotransformation of inorganic arsenic and its role in toxicity. Toxicol Lett 112–113:209–217Google Scholar
  57. Yang J, Yan L, Zhang M, Wang Y, Wang C, Xiang Q (2015) Associations between the polymorphisms of GSTT1, GSTM1 and methylation of arsenic in the residents exposed to low-level arsenic in drinking water in China. J Hum Genet 60(7):387–394Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Miroslav Stýblo
    • 1
    Email author
  • Christelle Douillet
    • 1
  • Jacqueline Bangma
    • 2
  • Lauren A. Eaves
    • 2
  • Fernando Pardo-Manuel de Villena
    • 3
  • Rebecca Fry
    • 2
    Email author
  1. 1.Department of Nutrition, CB# 7461, Gillings School of Global Public HealthUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.Department of Environmental Sciences and Engineering, CB#7431, Gillings School of Global Public HealthUniversity of North Carolina at Chapel HillChapel HillUSA
  3. 3.Department of Genetics, Lineberger Comprehensive Cancer Center, School of MedicineUniversity of North CarolinaChapel HillUSA

Personalised recommendations