Mechanisms of Reproductive Neuroendocrine Toxicity

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DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to determine the principal causes of neuroendocrine disruption and targets of the major environmental contaminants of public health concern. In this continuation proposal the proximal cause of Aroclor 1254 (PCB)-induced impairment of tryptophan hydroxylase (TPH) activity and the reproductive neuroendocrine consequences will be investigated in a fish model, Atlantic croaker. The following overall hypothesis will be tested in croaker: PCB-induced impairment of the serotonin-gonadotropin releasing hormone-luteinizing hormone (5-HT-GnRH-LH) neuroendocrine pathway controlling reproduction involves a non-coplanar congener-induced decrease in TPH activity, which is the result of oxidative effects/damage. Initially, the effects of a range of PCB concentrations on TPH activity and hypothalamic levels of the TPH protein and its mRNA will be investigated followed by experiments to investigate associations between oxidative damage and neuroendocrine disruption. Subsequently, the effects of vitamin E (an antioxidant) treatment on serotonergic functions, and its efficacy in reversing the effects of the PCB on lipid peroxidation, malondialdehyde-protein adduct formation, TPH activity, and neuroendocrine function, will be investigated. Finally, the effects of a coplanar dioxin-like PCB congener (PCB 77) on TPH activity will be compared to those observed with two non-coplanar di-ortho-substituted PCB congeners (PCB 47 and PCB 153) to identify likely causative agents of the neurotoxic effects in the PCB mixture. The consequences of PCB congener-induced impairment of hypothalamic serotonergic function on the functional integrity of the 5-HT-GnRH-LH neuroendocrine system will also be investigated. The specific objectives are to: i) determine whether the PCB-induced decrease in the hypothalamic TPH activity is accompanied by alterations in TPH protein and mRNA levels; ii) determine whether the PCB-induced decreases in TPH activity and 5-HT-GnRH-LH function are associated with oxidative damage, and the efficacy of an antioxidant in reversing these effects; iii) determine whether the non-coplanar di-ortho-substituted PCB congener component of PCB mixtures could account for their toxic effects on TPH activity and 5-HT-GnRH-LH function. There is now compelling evidence that the environmental or occupational exposure to PCBs or consumption of PCB-contaminated fish in the Great Lakes is associated with reproductive and neuroendocrine dysfunction in humans and developmental deficits in their children. However, the mechanisms of PCB neurotoxicity remain poorly understood. The proposed study will investigate a novel mechanism of PCB neurotoxicity and neuroendocrine toxicity which may also have significance for other neural functions such as those associated with mental health.