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


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.


Arsenic Metabolism Genetically diverse mice The Collaborative Cross 



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

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Supplementary material 1 (DOCX 3106 kb)


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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

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