THE TERATOGENIC EFFECTS OF VALPROIC ACID IN HUMAN CHONDROGENESIS IN-VITRO

The anticonvulsant drug valproic acid (VPA) is a known teratogen in hu mans. In general, anticonvulsants effect major systems in the embryo c ausing craniofacial, cardiovascular, neurological, urogenital, and maj or and minor skeletal defects. The limb defects associated with in ute ro VPA exposure include digital hypoplasia, ectrodactyly, radial ray a plasia, and proximal phocomelia. Human studies are limited to case rep orts and to retrospective and/or prospective studies. Although animal studies have demonstrated a teratogenic effect of VPA on skeletogenesi s, these doses were well above the human therapeutic dose which makes extrapolation from these studies to humans difficult. The purpose of t his research was to evaluate the potential deleterious effects of VPA on chondrogenesis, a process that occurs in human limb formation. To a ccomplish this goal, human chondrocytes were cultured in a three dimen sional agarose gel and treated with VPA. The use of this model system was a novel approach to evaluate the teratogenic potential of VPA duri ng chondrogenesis. The influence of VPA on human chondrocytes was moni tored using histochemical, immunocytochemical, and morphological techn iques. There was a decrease in mitotic activity and the extracellular matrix was modified. At human therapeutic doses, immunofluorescence re vealed that type II collagen was reduced, while type I collagen increa sed. In addition, the alcian blue-staining matrices (i.e., sulfated pr oteoglycans) were reduced. Moreover, the Golgi apparatus had swelling in the trans-face cisternae suggesting that proteoglycan synthesis may be altered. (C) 1994 Wiley-Liss, inc