Sodium valproate augments spontaneous neural tube defects and axial skeletal malformations in TO mouse fetuses...

The TO mouse exhibits a low incidence (3.65%) of spontaneous exencephaly 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 200, 400, or 600 mg/kg of VPA were administered on one of gestation days (GD) 7 to 10 and fetuses were collected on GD 18. Significant augmentation of the background incidence of exencephaly was observed in the GD 7 and 8 treatment groups. Absence of the skull vault, hemorrhage, and degeneration of the exposed brain, polyhydramnios, and a female excess 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 associated with exencephaly. Morphometric evaluation of the alizarin red-stained skeleton confirmed significant skeletal growth inhibition. Histologic sections of GD 10 embryos revealed early onset of treatment-related growth retardation. Arrest of closure appeared to affect intermittent segments of the neural tube. The closure defect sometimes only involved the surface ectoderm of the dorsal midline. The unclosed neural tube was at times covered by a continuous layer of surface ectoderm. Cell death per se was not pronounced in the neuroepithelium. The mesenchyme was generally sparse and edema was obvious in embryos with partial closure. Growth inhibition of the optic and otic primordia was marked by pronounced cell death in these structures as well as in the otic and trigeminal ganglia and in the pharyngeal arch mesenchyme. Evidence for neural crest cell migration was also recorded. These data indicate that VPA interacts with genetic susceptibility, augments the frequency of exencephaly, and also induces other malformations in the TO mouse. The widespread malformations of the cranifacial structures are suggestive of the preferential effect of VPA on the neural crest or its derivatives.