The long-range plan of this project is to evaluate the actions of receptors for halogenated aromatic chemicals in relation to the carcinogenic potency of these compounds. These studies focus on receptor mediated effects in short-term models, 1 vitro models, and in the two-stage model for promotion of hepatocarcinogenesis. One goal of this project is to evaluate the role of the Ah receptor in the action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on other receptor systems such as the glucocorticoid receptor, epidermal growth factor (EGF) receptor, and the estrogen receptor. These receptors are known to modulate cell proliferation pathways and ongoing studies are comparing the dose-response for the effects of TCDD on these receptors in livers of wild type (Ah+) and congenic strains of mice containing a defective Ah receptor (Ah-). If the effects of TCDD are mediated by the Ah receptor, a 10-fold difference in the dose response is predicted between Ah- and Ah+ mice. Studies will also examine effects on protein kinases and phosphorylation (signal transduction pathways) of the receptor proteins. TCDD has been shown to promote the number of enzyme-altered foci in DEN initiated intact female rats and to increase metabolic activation of estrogen in this model. Additional studies will compare the effects of TCDD on tumors, enzyme altered foci and receptor systems in intact and ovariectomized rats using this model to determine the possible role of estrogens and DNA adducts in this process. We will also attempt to develop in vitro models to obtain additional information on the mode of action of TCDD and obtain data on structure- activity relationships. These will include wild type and receptor defective hepa 1c1c7 cells. Additional in vitro systems used for dose-response analysis will include lymphocytes from humans as well as Ah- and Ah+ animals to determine whether humans more nearly resemble responsive or nonresponsive strains. Data generated from this project should provide information useful in the risk assessment of the ubiquitous halogenated aromatics.
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