Embryotoxicity of acrylonitrile in whole-embryo culture

Day 10 rat embryos were cultured in rat serum for 26 hr in the presence of acrylonitrile at concentrations ranging from 76 to 760 mum. Survival was not affected at any concentration tested. Normal development was observed at 76 mum. Acrylonitrile induced concentration-related decreases in growth parameters (yolk-sac diameter, crown-rump length, head length, number of somite pairs), which were statistically significant at concentrations of 304 mum or above. An acrylonitrile concentration of 152 mum induced a significant increase in the incidence of malformations, which rose by 100% at 304 mum. Malformations mainly consisted of a reduction of the brain and a shortened caudal extremity. The presence of 0.1-2.2 mm-reduced glutathione in the culture medium moderated the embryotoxic effects of 304 mum-acrylonitrile in a concentration-related manner. Growth retardation and severity of malformations induced by 304 mum-acrylonitrile were significantly increased by the addition of a hepatic microsomal preparation (S-9, microsomes) and cofactors for cytochrome P-450-dependent biotransformation (NADPH, glucose-6-phosphate) to the culture medium. Our results show that embryotoxicity of acrylonitrile does not require extra-embryonic biotransformation. However, the enhancement by exogenous cytochrome P-450-dependent monooxygenase systems supports a role for oxidative biotransformation in acrylonitrile embryotoxicity.