Maternal Mthfr 677C>T genotype modifies folate responses to oxcarbazepine and is associated with developmental vulnerability in mice

Abstract Background Genetic variation in folate-dependent one-carbon metabolism may contribute to interindividual differences in developmental responses to antiseizure medications. We investigated whether maternal Mthfr 677C > T genotype modifies metabolic and developmental responses to gestational oxcarbazepine (OXC) exposure. Methods Pregnant Mthfr 677C > T knock-in mice (CC, CT, and TT; n = 67) received vehicle, 65 mg/kg OXC, or 130 mg/kg OXC at embryonic day 7.5. Maternal hepatic MTHFR activity, serum homocysteine (Hcy) and folate, and embryonic developmental outcomes were assessed. Results Hepatic MTHFR activity progressively decreased from CC to CT to TT dams. OXC increased Hcy and decreased folate. For Hcy, genotype and OXC showed significant main effects, but their interaction was not significant (P = 0.481). In contrast, folate showed a significant genotype × OXC interaction (F = 44.774, P < 0.0001), with the greatest reduction in TT dams. Compared with CC dams, TT dams had lower odds of fetal survival (OR = 0.202, 95% CI 0.041–0.991) and higher odds of resorption (OR = 4.945, 95% CI 1.009–24.245). Maternal genotype also affected mean fetal body weight per litter (P = 0.041), whereas OXC and genotype × OXC interactions were not significant for these developmental outcomes. Foot and dorsal congestion occurred only at 130 mg/kg OXC, without significant genotype-group differences. Conclusion Maternal Mthfr 677C > T genotype modifies the folate response to OXC and is associated with baseline developmental vulnerability, whereas genotype-dependent OXC developmental toxicity was not statistically established.