The environment contains an increasing number of chemicals (flavones, hydrocarbons and their metabolites, and related compounds) that have been reported to adversely affect reproductive function in humans and in a variety of animal species. However, the molecular mechanisms underlying these effects remain largely unknown. It is proposed that these chemicals interact with the endocrine system (1) by binding to steroid hormone receptors and activating or blocking receptor-mediated events, (2) by interfering directly with endocrine mechanisms controlling cell function, and (3) by altering the ability of the gonads to respond to hormonal stimulation with appropriate steroid biosynthesis. These hypotheses will be tested in vitro by measurement of the kinetics of steroid hormone receptor interaction with representative environmental chemicals and by examination of the effects of these chemicals on hormone secretion by isolated gonadal cells. In vivo studies will include treatment of male and female rats with nonlethal doses of these environmental chemicals and evaluation of the effects of this treatment on serum hormone concentrations, on the activity of enzymes that synthesize steroid hormones and on gonadal cell function. Representative compounds tested will include naphthalene and phenanthrene (polycyclic aromatic hydrocarbons), 1-naphthol and 9-phenanthrol (hydroxylated polycyclic aromatic hydrocarbon metabolites), and morin and quinalizarin (flavones and quinones). The specific objective of the experiments described in this proposal is to determine the effects of environmental chemicals on steroid hormone receptor dynamics, gonadal steroid biosynthetic pathways, and endocrine mechanisms controlling gonadal cell function. The long-term objective of these studies is to increase our understanding of the molecular mechanisms of the interaction of environmental chemicals with the reproductive process. This may indicate methods for the treatment and prevention of ther adverse effects of environmental chemicals on reproduction.
