MECHANISMS OF REPRODUCTIVE NEUROENDOCRINE TOXICITY

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The actions of representatives of two classes or reproductive toxicants, a heavy metal (lead), and a polychlorinated biphenyl mixture (Aroclor 1254), on the serotonin (5-HT)-gonadotropin releasing hormone (GnRH)-gonadotropin (GtH) neuroendocrine pathway controlling GtH secretion will be investigated in an extensive teleost model of reproductive endocrine function and endocrine toxicology, the Atlantic croaker (Micropogonias undulatus). Currently, the sites and mechanisms of xenobiotic interference with the reproductive neuroendocrine pathway are poorly understood. Therefore, the following overall hypothesis will be tested: that lead and Aroclor 1254 alter GtH secretion by disrupting different components of the 5-HT-GnRH-GtH stimulatory neuroendocrine pathway controlling reproduction. Preliminary results in croaker and other vertebrate species suggest that Aroclor 1254 acts primarily on the 5- HT component, whereas lead may act on the GnRH and GtH (pituitary) components of the neuroendocrine system. Therefore all three components of the system will be investigated using multiple indices of neuroendocrine function after exposure to the model compounds. Parallel studies will be conducted with several neuropharmacological agents which either mimic the xenobiotic-induced disturbances or reverse them. Parallel disturbances of GtH secretion will be interpreted as evidence that the model compound has the same primary site of action as the neuropharmacological agent. Specific objectives are to: 1. Compare the actions of Aroclor 1254 and the neuropharmacological agents on separate components of the 5-HT-GnRH-GtH pathway and GtH secretion; correlate PCB accumulation with the degree of neuroendocrine disruption. 2. Compare the actions of lead and the neuropharmacological agents on separate components of the 5-HT-GnRH-GtH pathway and GtH secretion; correlate lead accumulation with the degree of neuroendocrine disruption. The proposed research on the effects of the model compounds on components of a major neuroendocrine system controlling reproduction, the 5-HT-GnRH-GtH pathway, should provide valuable new information on the mechanisms and targets of reproductive neuroendocrine disruption by xenobiotics in vertebrates. The further evaluation of this non- mammalian model of reproductive neuroendocrine toxicology will facilitate comparisons of the mechanisms of endocrine disruption by chemicals among a broader range of vertebrates and thus provide a more accurate prediction of their long term reproductive hazards to humans. In addition this teleost model should be valuable as a sentinel of pollution damage to aquatic ecosystems and the potential reproductive hazards of environmental contamination to human populations.