SODIUM VALPROATE AUGMENTS SPONTANEOUS NEURAL-TUBE DEFECTS AND AXIAL SKELETAL MALFORMATIONS INTO MOUSE FETUSES

The TO mouse exhibits a low incidence (3.65%) of spontaneous exencepha ly at birth, The objectives of this study were to determine if sodium valproate (VPA) would augment this background frequency of exencephaly and to characterize its gross and histologic bases. Single doses of 2 00, 400, or 600 mg/kg of VPA were administered on one of gestation day s (GD) 7 to 10 and fetuses were collected on GD 18, Significant augmen tation of the background incidence of exencephaly was observed in the GD 7 and 8 treatment groups, Absence of the skull vault, hemorrhage, a nd degeneration of the exposed brain, polyhydramnios, and a female exc ess characterized the abnormality, Exencephalic embryos were markedly growth retarded, In addition to craniofacial and urogenital anomalies, severe axial skeletal malformations were found to be consistently ass ociated with exencephaly, Morphometric evaluation of the alizarin red- stained skeleton confirmed significant skeletal growth inhibition, His tologic sections of GD 10 embryos revealed early onset of treatment-re lated growth retardation, Arrest of closure appeared to affect intermi ttent segments of the neural tube, The closure defect sometimes only i nvolved the surface ectoderm of the dorsal midline. The unclosed neura l tube was at times covered by a continuous layer of surface ectoderm, Cell death per se was not pronounced in the neuroepithelium. The mese nchyme was generally sparse and edema was obvious in embryos with part ial closure. Growth inhibition of the optic and otic primordia was mar ked by pronounced fell death in these structures as well as in the oti c and trigeminal ganglia and in the pharyngeal arch mesenchyme, Eviden ce for neural crest cell migration was also recorded, These data indic ate that VPA interacts with genetic susceptibility, augments the frequ ency of exencephaly, and also induces other malformations in the TO mo use. The widespread malformations of the cranifacial structures are su ggestive of the preferential effect of VPA on the neural crest or its derivatives.