Sex difference in monocrotaline-induced developmental toxicity and fetal hepatotoxicity in rats

Pyrrolizidine alkaloids (PM) are a class of hepatic toxins widely existing in plants. Cytochromes P450 (CYP) mediates PA bioactivation and toxicities in mammals. It has been reported that PAs can induce developmental toxicity, but systematic research is lacking. In this study, we investigated developmental toxicity of monocrotaline (MCT) in rats. Pregnant rats were administered with MCT (20 mg/kg) intragastrically from gestation day 9 to 20, followed by determination of changes in fetal growth, hepatic morphology, serum biochemical indices, and indicators of hepatocytes apoptosis. MCT was found to induce developmental toxicity and fetal hepatotoxicity, particularly in female fetuses. Metabolic activation was also studied by examination of bioactivation efficiency of MCT in fetal liver microsomes, serum MCT, pyrrole-protein adduction derived from MCT, and hepatic CYP3 A expression of fetuses in vivo. Male fetuses showed greater basal MCT bioactivation than that of female fetuses, but continuous exposure to MCT caused a selective CYP3 A induction in female fetuses, which may contribute to the sex difference in MCT-induced developmental toxicity.