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

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Abstract
BACKGROUND: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS: 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. Birth Defects Research (Part A) 67:000–000, 2003.