Exposure to environmental toxicants can profoundly affect neurological and reproductive development, function and behavior, particularly when the exposure occurs during the susceptible prenatal period. The overall goal of this research proposal is to study the molecular targets at which environmental toxicants act to disrupt reproductive neuroendocrine function in adulthood. It is our working hypothesis that in utero exposure to endocrine disrupting chemicals (EDCs) has long-term consequences on reproductive outcomes, manifested as alterations in reproductive behavior and function, diminished fertility and fecundity, and a hastening of reproductive aging. These changes are mediated at least in part by effects of EDCs on neuroendocrine regions of the brain responsible for the regulation of reproduction, namely the hypothalamus and preoptic area. Our goal is to establish a model for investigating how one class of EDCs, polychlorinated biphenyls (PCBs) causes these long-term consequences, and to identify the molecular and cellular targets of the EDCs, using female Sprague-Dawley rats as a model.
In Specific Aim 1, we will establish dose-response models to test effects of prenatal PCBs on reproductive neuroendocrine function in adulthood (fertility, fecundity, behavior, premature reproductive aging).
In Specific Aim 2, we will identify target genes acted upon by prenatal PCBs in the hypothalamus using novel gene technologies (differential display PCR and microarrays). Finally, in Specific Aim 3, we will examine the neuroanatomical expression and regulation of the target molecules on which PCBs act in neuroendocrine brain regions. These studies should provide novel information on the possible mechanisms by which prenatal exposure to PCBs interferes with reproductive neuroendocrine function of adult female mammals. The results should have important implications for understanding consequences of, and developing therapies for, exposures of wildlife and humans to EDCs such as PCBs. ? ?
