Common hierarchies of susceptibility to the induction of neural tube defects in mouse embryos by valproic acid and its 4‐propyl‐4‐pentenoic acid metabolite

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Abstract
The teratogenic effects of valproic acid and its 4‐propyl‐4‐pentenoic acid (4‐en) metabolite were investigated in three inbred mouse strains that were known to possess differing sensitivity to heat‐induced neural tube defects. In the heat‐resistant DBA/2J strain, administration of either valproic acid or the metabolite during the critical period of neural tube development failed to produce any abnormal offspring. Similar treatment in the moderately heat‐sensitive LM/Bc strain resulted in up to 19.8% exencephalic fetuses. The highly heat‐sensitive SWV strain was also very susceptible to the induction of neural tube defects by either valproic acid or its 4‐en metabolite. When administered on gestational day 8 plus 12 hours, the parent compound produced 35% exencephalic fetuses, while the metabolite had a response frequency of 32.4%. Thus, the hierarchy of susceptibility for the induction of neural tube defects in these inbred mouse strains was exactly the same whether the teratogen was a physical agent such as hyperthermia or a chemical compound such as valproic acid. If such diverse agents as these should interact to produce malformations, then it is possible that a wide variety of other agents might interact in a similar manner to produce neural tube defects.