Spiegelstein Ofer, Merriweather Michelle Y, Wicker Ned J, Finnell Richard H
Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas, USA.
Birth Defects Res A Clin Mol Teratol. 2003 Dec;67(12):974-8. doi: 10.1002/bdra.10128.
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.
叶酸是一种重要的B族维生素，通过叶酸结合蛋白和转运蛋白进入细胞。叶酸结合蛋白2基因敲除（Folbp2(-/-)）小鼠发育正常；然而，我们发现它们比野生型对照小鼠更容易受到砷酸盐暴露致畸作用的影响。
在本研究中，我们想扩展我们的发现，并检验Folbp2(-/-)小鼠更容易受到丙戊酸（VPA）致畸作用影响的假设，丙戊酸是一种常用的抗癫痫药物，已知在人类和实验动物中都会诱发神经管缺陷（NTDs）。
在补充叶酸和对照饮食期间，Folbp2(-/-)小鼠的VPA诱导的胚胎致死率和无脑畸形发生率分别高于野生型对照小鼠。两种基因型之间的所有其他反应差异均未达到统计学意义。与叶酸缺乏饮食相比，补充叶酸的野生型母鼠（而非Folbp2(-/-)母鼠）降低了VPA处理的野生型胚胎的胚胎致死率。
与我们之前关于砷酸盐的研究结果不同，在某些饮食叶酸方案中，Folbp2(-/-)小鼠对子宫内VPA暴露的易感性增强。因此，我们的数据表明Folbp2与VPA诱导的NTDs之间的关系相对脆弱。
