Teratogenicity of valproic acid: In vivo and in vitro investigations

Abstract

The in vivo teratogenic potential of valproic acid was evaluated in the CD‐1 mouse. Dose selection was based on the estimated lethality curve and several doses were evaluated. Treatment during early organogenesis (Days 8–10) produced a dose related increase in congenital abnormalities which was accompanied by a decrease in fetal weight, Rib and vertebral abnormalities together with exencephaly were the most common defects. Greater embryo mortality was apparent following teatment during late organogenesis (Days 11–13), but the surviving fetuses were less sensitive to the dysmorphogenic effects and cleft palate was now the most common defect, Early neurula stage mouse (Day 9) and rat (Day 10) embryos were cultured in the presence of valproic acid (0.6–1.8 mM) for 48 hr. There was significant reduction in growth which was accompanied by a variety of dysmorphogenic effects. Irregular segmentation of somites together with incomplete and irregular fusion of brain folds were most evident. These were observed at concentrations of valproic acid where no adverse effects on the yolk sac circulatory system were apparent. These in vitro effects appear to be comparable to the in vivo observations and suggest a direct teratogenic action of valproic acid on the developing rodent embryo.