The Native American population of the Mohawk national who inhabit the Akwesasne in the St. Regis Indian Reservation is at high risk of polychlorinated biphenyl (PCB) exposures from the adjacent highly contaminated Massena, NY Superfund site. Studies have demonstrated that mixtures of PCBs (Aroclors) or specific PCB congeners exhibit estrogenic effects in non-human systems which, together with the known potential of estrogens to alter neurochemical function alteration of estrogens, provide a putative mechanism for PCB-potentiated changes in neurochemical function. We hypothesize that PCB mediated alterations are estrogenic and that this estrogenicity is dependent on the specific structure of the PCB and on its P450-catalyzed metabolism to a hydroxylated metabolite. The estrogenicity of PCBs has only been established in animal systems and then only in very limited detail. The establishment of mechanisms in support of proposed extensive epidemiologic studies to establish a role for environmental pollutants in neurochemical disfunction at the Superfund Site at Akwesasne will require further extensive evaluations of the estrogenic potential of PCBs and their metabolites in human derived systems.
The specific aims of the project are: 1. To evaluate the in vitro estrogenicity and antiestrogenicity of PCB congeners and their hydroxylated metabolites in a human breast cancer cell line, MCF-7, using the induction of estrogen dependent and points. This will develop structure-function relationships and establish whether metabolism of the PCBs is an essential prerequisite for their estrogenic action. 2. To investigate the metabolism in human systems of selected PCB congeners using human P450s in microsomes from induced or control MCF-7 cells, human hepatocytes, and human P450s expressed in mammalian cells. 3. To characterize the PCB metabolism potentiated in microsomes prepared from tissue (liver, brain, kidney, and uterus) from PCB exposed rats generated by the neurotoxicity studies. 4. To determine the estrogenic and/or antiestrogenic activity associated with extracts of sediment samples from biodegradation studies.
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