Influence of methylenetetrahydrofolate 677C > T variant in murine models following valproic acid exposure

Abstract

The teratogenic effects of valproic acid (VPA) can lead to abnormal fetal development, which may be related to abnormal maternal one-carbon metabolism. Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme involved in one-carbon metabolism. Variations in MTHFR, particularly 677 C>T, are associated with susceptibility to teratogenicity. However, the current research is limited to clinical practice. Therefore, an Mthfr^677C>T mouse model was constructed to explore whether the 677 C > T polymorphism increases the teratogenic susceptibility to VPA. Pregnant wild type and Mthfr^677C>T mice were exposed to a single teratogenic dose of 400 mg/kg VPA or saline via intraperitoneal injection on day 7.5 of gestation (E7.5), and fetuses were harvested on E18.5. Resorbed fetuses, malformations, including neural tube defects (NTDs) increased in the VPA-treated group. Consistent with the clinical data, Mthfr^677C>T mice also showed lower liver MTHFR enzymatic activity and elevated serum homocysteine (Hcy) levels. No abnormalities were observed in the saline-treated groups. Therefore, intraperitoneal injected VPA significantly increased the malformation rate of CT and TT heterozygote and homozygote mice, respectively, compared to that of CC mice (P < 0.05). In this study, an association between the 677 C > T polymorphism of MTHFR and susceptibility to VPA-induced teratogenesis in mice, especially in TT mice, was found. This may be related to changes in Hcy metabolism. Collectively, these data have important implications for exploring the different responses of individuals to drug-induced teratogenesis, which may help guide the adjustment of drug selection during pregnancy.