2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent embryotoxin in laboratory animals and recently has been associated with miscarriages in women (Science 1979 203:1090). TCDD is also a potent inducer of microsomal monoxygenases and drug metabolism. Steroid hormones are endogenous substrates for the liver monoxygenase system and TCDD has been found to significantly alter cytochrome P-450 dependent steroid metabolism in rat liver (Gustafsson and Ingelman-Sundberg Biochem. Pharm.1979 28:497). In preliminary studies of TCDD toxicity in pregnant rats, we find that despite a 2-fold increase in microsomal cytochrome P-450 levels, ring A hydroxylation of estrogen in liver microsomes is only 20% of control levels. Thus a major pathway of hepatic estrogen metabolism is impaired with TCDD treatment. These data lead us to consider the possibility that the hormonal status of TCDD treated animals may not be adequate to maintain placental, fetal and neonatal growth. Cytochrome P-450 dependent enzymes in the ovary, placenta and adrenal are pivotal in steroid hormone biosynthesis. We propose to investigate whether TCDD-induced resorptions, malformations, and suppression of fetal and neonatal growth are mediated by the endocrine system, specifically by changes in cytochrome P-450 dependent reactions in steroid hormone biosynthesis. The proposed research will study the effects of TCDD during pregnancy on cytochrome P-450 catalyzed reactions involved in 1) estrogen biosynthesis in the ovary, 2) progesterone biosynthesis in the placenta, and 3) corticosterone synthesis in the maternal, fetal and neonatal adrenal glands. Ovarian, placental and adrenal function will be correlated with plasma levels of estradiol, progesterone and corticosterone. Each fetus and neonate will be studied as a distinct unit to correlate body weight and malformations with placental steroid synthesis and plasma corticosterone levels. In view of the hormonal requirements for placental function, organogenesis and fetal tissue differentiation, it is essential to determine the extent to which fetotoxic effects of environmental chemicals like TCDD are mediated by changes in the cytochrome P-450 dependent enzymes crucial to steroid hormone biosynthesis.