In vitro neuroteratogenicity of valproic acid and 4-en-VPA

Mouse embryos displaying 8 to 9 pairs of somites were cultured during 26 h in presence of 0.75 mM of VPA, or of 1 mM of 4-en-VPA. These concentrations induced approximately 50% of dysmorphogenic embryos. Irregular suture of caudal neural tube, abnormal head shape, cranial neural tube defects, and deformed optic vesicles were the most common defects observed with both compounds. The main differences in the types of dysmorphogeneses detected between the two compounds concerned the suture of the caudal neural tube and the telencephalic region. Other macroscopic effects induced by the two compounds were similar. Several of the observed abnormalities can be correlated with defects reported after in vivo exposure. The major alteration of the histological structure of the neural tube concerned a specific area in the hindbrain : VPA and 4-en-VPA induced an abnormal and irregular budding of the neuroepithelium at this level. Immunohistology with an antibody specific for radial glial fibers (RC-2) as well as SEM analysis showed a moderate effect on glial development, mainly after exposure to VPA.