Valproate-induced neural tube defects in folate-binding protein-2 (Folbp2) knockout mice

Folate is an important B vitamin that is transported into cells by way of folate-binding proteins and transporters. Folate-binding protein-2 nullizygous (Folbp2(-/-)) mice develop normally; however, we have found them to be more susceptible to the teratogenic effects of arsenate exposure than wild-type control mice.

In the current study, we wanted to extend our findings and test the hypothesis that Folbp2(-/-) mice are more susceptible to the teratogenic effects of valproic acid (VPA), a commonly used antiepileptic drug that is known to induce neural tube defects (NTDs) in both humans and laboratory animals.

Folbp2(-/-) mice had higher VPA-induced frequencies of embryonic lethality and exencephaly than did the wild-type control mice during folate supplementation and a control diet, respectively. All other differences in response between the two genotypes were short of reaching statistical significance. Folate supplementation of wild-type, but not Folbp2(-/-) dams reduced embryonic lethality of VPA-treated wild-type embryos compared to the folate-deficient diet.

Unlike our previous findings with arsenate, enhanced susceptibility of Folbp2(-/-) mice to in utero VPA exposure was demonstrated in some dietary folate regimens. Thus, our data indicate a relatively frail relationship between Folbp2 and VPA-induced NTDs.