Morphological alterations induced by sodium valproate on somites and spinal nerves in rat embryos

The antiepileptic drug valproic acid is a well-known teratogenic agent; its main target organ is the neural tube, though skeletal malformations have a lso been described. In our recent work, respecifications of vertebrae were described in rat fetuses after treatment with 400 mg/kg of sodium valproate at specific somitogenic stages. The observed malformations were stage-depe ndent. Morphological segmental respecification was observed at the level of segments in formation at the moment of exposure and at the level of more p osterior segments. Recently, specific alterations in the development of cra nial nerves and ganglia were described in mouse embryos after in vitro expo sure to VPA. The aim of the present work was to analyze dysmorphogenetic ef fects of VPA on embryonic metameric structures: somites, spinal and cranial nerves, and ganglia. Sodium valproate (400 mg/kg) was subcutaneously injec ted at specific gestational times corresponding to embryonic stages: presom itic or at about 2, 6, 10, 14, 18, or 22 somites. Females were sacrificed o n the day 12 post coitum, and embryos were examined. Morphological examinat ion of somites was performed by staining with acridine orange. Morphologica l examination of nerves and ganglia was performed by immunostaining, using monoclonal antibodies to the 160-kD neurofilament protein. No abnormalities were observed in the cranial nerves and ganglia. Specific and stage-depend ent alterations were observed both at the level of the somites and at the r evel of the spinal nerves. The following characteristic malformations were observed: fusions, duplications, and reductions of somites and correspondin g spinal nerves and ganglia. Our morphological data suggest a morphogenetic action of VPA at the level of the axial segments, with a possible respecif ication of the identity of the interested segments and their derivatives. T eratology 59:110-119, 1999. (C) 1999Wiley-Liss, Inc.