2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and the related polyaromatic compounds, Beta-naphthoflavone (BetaNF) and 3-methylcholanthrene (3MC), are potent embryotoxins in experimental animals. This laboratory has investigated whether the adverse effects of TCDD, BetaNF and 3CM on fetal growth and tissue differentiation are mediated by alterations in cytochrome P-450 dependent reactions in steroid hormone biosynthesis in pregnant rats. We propose to further investigate the potential role of placental hypofunction and adrenal hyperfunction in mediating the adverse effects of TCDD on the fetus. Two lines of investigation will be pursued in this regard. 1) Studies will evaluate progesterone, androstenedione and testosterone synthesis from endogenous precursors in explants of placental tissue. Progesterone and androgen content of placental tissue and the incubation media will be compared to evaluate whether TCDD adversely affects synthesis and/or secretory processes. 2) Experiments will evaluate the synthesis of progesterone, cortisol, corticosterone, androstenedione and testosterone from endogenous precursors in intact adrenal tissue. Steroidogenesis in vitro will be evaluated for both maternal and fetal adrenals to determine whether TCDD is associated with increased formation of 17Alpha-hydroxylated corticosteroids. The proposed shift in adrenocortical products from corticosterone to cortisol and androgens may underlie some of the adverse effects of TCDD on fetal growth and tissue differentiation. Serum steroid hormone concentrations in maternal and fetal blood will be correlated with adrenal steroid synthesis in vitro, as well as with fetal body weight. A totally new line of investigation is proposed to evaluate whether TCDD treatment results in adverse effects on the binding of insulin and epidermal growth factor (EGF) to placental membranes. The hypothesis under study is that TCDD exposure will inhibit the binding of important trophic hormones to plasma membrane receptors. Receptor number and affinity parameters for EGF and insulin will be determined in placental membranes from control and TCDD-treated animals. We anticipate that this approach will provide new information regarding mechanisms by which polyaromatic compounds alter placental function, as well as fetal growth and tissue differentiation.
