The overall objective of the proposed research is to determine the primary sites and mechanisms by which several different classes of reproductive toxins impair endocrine function in female vertebrates. The principal aim of this research is to identify common mechanisms of reproductive endocrine toxicity in vertebrates which will be of predictive value for future clinical and epidemiological studies on reproductive hazards of chemicals to humans. The actions of cadmium, lead, a polychlorinated biphenyl mixture (Aroclor 1254), an antiestrogen (clomiphene) and an estrogenic pesticide (chlordecone) will be investigated in a comprehensive teleost model of female reproductive endocrine function, the Atlantic croaker (Micropogonia undulatus). The following possible mechanisms of endocrine toxicity will be examined in detail: interference by heavy metals with second messenger systems; alterations of neuroendocrine function; enhanced metabolic clearance of steroid hormones; and interference with the molecular actions of steroid hormones. In particular, it is proposed to test the hypotheses that (1) cadmium and other heavy metals interfere with the calcium-dependent phosphoinositol system for gonadotropin secretion and the adenylate cyclase system for gonadal steroid secretion; (2) lead and Aroclor 1254 act primarily at the hypothalamus to disrupt reproduction. Moreover, it is proposed to compare the effects of Arochlor 1254 treatment on the production and metabolic clearance of steroids in vivo in order to determine the physiological significance of enhanced steroid metabolism. Finally, the mechanisms by which antiestrogens interfere with the molecular actions of estrogen will be examined in an in vitro assay of estrogen gene expression. The effects of the model compounds on reproductive endocrine function in croaker will be compared to previously published data on the effects of these chemicals in mammals to further examine the utility of this alternative animal model for predicting long-term reproductive hazards of chemical to humans. Potential advantages of using this model include: (1) greater predictive value for reproductive hazard assessment when used in combination with mammalian studies; (2) greater public acceptance as test organisms; (3) lower costs for animal care; (4) more precise investigations of gametogenesis and the molecular actions of steroid hormones; (5) applicability as an early-warning indicator of pollution damage to aquatic ecosystems and the potential reproductive hazards of environmental contamination to human populations.
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