A mouse model for valproate teratogenicity: parental effects, homeotic transformations, and altered HOX expression

Valproate (VPA) is one of several effective anti-epileptic and mood-stabili zing drugs, many of which are also potent teratogens in humans and several other mammalian species, Variable teratogenicity among inbred strains of la boratory mice suggests that genetic factors influence susceptibility, While studying the genetic basis for VPA teratogenicity in mice, we discovered t hat parental factors influence fetal susceptibility to induced malformation s, Detailed examination of these malformations revealed that many were home otic transformations. To test whether VPA, like retinoic acid (RA), alters HOX expression, pluripotent human embryonal carcinoma cells were treated wi th VPA or RA and Hox expression assessed, Altered expression of specific Ho x genes may thus account for the homeotic transformations and other malform ations found in VPA-treated fetuses.