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. 2005 Feb 15;203(1):18-26.
doi: 10.1016/j.taap.2004.07.006.

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

Ofer Spiegelstein  1 , 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
Affiliations

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

Ofer Spiegelstein et al. Toxicol Appl Pharmacol. .

Abstract

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.

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Figures

Fig. 1
Fig. 1
Targeted inactivation of the murine RFC gene. (A) Endogenous genomic loci. (B) Targeted RFC loci before Cre-mediated excision. Heavy line represents targeting construct; arrow head represents the location of loxP sites. (C) Targeted loci following Cre-mediated excision.
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