Developmental consequences of in utero sodium arsenate exposure in mice with folate transport deficiencies

Ofer Spiegelstein, Amy Gould, Bogdan Wlodarczyk, Marlene Tsie, Xiufen Lu, Chris Le, Aron Troen, Jacob Selhub, Jorge A. Piedrahita, J. Michael Salbaum, Claudia Kappen, Stepan Melnyk, Jill James, Richard H. Finnell*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


Previous studies have demonstrated that mice lacking a functional folate binding protein 2 gene (Folbp2-/-) were significantly more sensitive to in utero arsenic exposure than were the wild-type mice similarly exposed. When these mice were fed a folate-deficient diet, the embryotoxic effect of arsenate was further exacerbated. Contrary to expectations, studies on 24-h urinary speciation of sodium arsenate did not demonstrate any significant difference in arsenic biotransformation between Folbp2-/- and Folbp2+/+ mice. To better understand the influence of folate pathway genes on arsenic embryotoxicity, the present investigation utilized transgenic mice with disrupted folate binding protein 1 (Folbp1) and reduced folate carrier (RFC) genes. Because complete inactivation of Folbp1 and RFC genes results in embryonic lethality, we used heterozygous animals. Overall, no RFC genotype-related differences in embryonic susceptibility to arsenic exposure were observed. Embryonic lethality and neural tube defect (NTD) frequency in Folbp1 mice was dose-dependent and differed from the RFC mice; however, no genotype-related differences were observed. The RFC heterozygotes tended to have higher plasma levels of S-adenosylhomocysteine (SAH) than did the wild-type controls, although this effect was not robust. It is concluded that genetic modifications at the Folbp1 and RFC loci confers no particular sensitivity to arsenic toxicity compared to wild-type controls, thus disproving the working hypothesis that decreased methylating capacity of the genetically modified mice would put them at increased risk for arsenic-induced reproductive toxicity.

Original languageAmerican English
Pages (from-to)18-26
Number of pages9
JournalToxicology and Applied Pharmacology
Issue number1
StatePublished - 15 Feb 2005
Externally publishedYes

Bibliographical note

Funding Information:
This project was supported in part by grants P42ES04917, P30ES09106, and ES11775 from the National Institute of Environmental Health. We also acknowledge the work done at the Mayo Clinic in the generation of the RFC knockout mouse. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NIH. The authors would like to thank Ms. Michelle Merriweather and Mr. Joe Wicker for their technical assistance with this study; Dr. Laura E. Mitchell from the Center for Environmental and Genetic Medicine at the Institute of Biosciences and Technology for assisting with the statistical analysis.


  • Arsenic
  • Biotransformation
  • Detoxification
  • Folbp1
  • Neural tube defects
  • RFC
  • Teratogenicity


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