Impaired methionine synthesis and hypomethylation in rats exposed to valproate during gestation

Background: The antiepileptic drug valproic acid (VPA) may be teratogenic. The mechanism of teratogenicity remains unclear, but it has been hypothesized that VPA interferes with folate metabolism. Objective: To study the effect of VPA on the methionine cycle and transmethylation reactions in pregnant rats. Methods: Wistar rats were treated with VPA (300 mg/kg/day) on gestation days 8, 9, and 10, alone or in combination with folinic acid (FOL, 4 mg/kg/day) on gestation days 8, 9, and 10 or S-adenosylmethionine (SAM, 10 mg/kg/day) throughout gestation days 1 to 10. Results: VPA induced a reduction in maternal methionine serum concentration (p < 0.05) caused by a 24% reduction of methionine synthase activity in liver. This provoked hepatic DNA hypomethylation, although the methylation ratio (S-adenosylmethionine/S-adenosylhomocysteine) was not altered. Homocysteine, folate, and vitamin B-12 serum concentrations, as well as methionine adenosyltransferase and betaine homocysteine methyltransferase hepatic activities, did not change. In fetuses exposed to VPA, no effect was observed in hepatic methionine content, but the methylation ratio was reduced (p < 0.01), leading again to hepatic DNA hypomethylation. Coadministration of FOL prevented VPA-induced alterations in methionine synthesis and corrected fetal DNA hypomethylation. By contrast, SAM did not exert a protective effect on fetal DNA methylation. Conclusion: Impaired methionine synthesis and DNA hypomethylation may be involved in VPA-induced teratogenesis.