2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and other agonists of the Ah receptor (AhR) are thought to elicit their effects by altering gene expression in susceptible cells. The goals of this research are to determine the biological activity, cell specificity and dose-response characteristics of growth regulatory members of the human Ah gene battery, and to identify proteins that may be used to monitor exposed people. The long term objective of this research is to elucidate the events that occur in humans exposed to AhR agonists, and to test the hypothesis that the species and tissue-specific effects of TCDD are caused by the altered expression of specific subsets of genes that are regulated by the AhR.
The specific aims of this proposal are: 1) To characterize two TCDD-responsive cDNA clones, designated clone 1 and clone 141, that represent previously unidentified human genes. The structure, complexity and function these clones and their protein products will be determined. 2) To determine the tissue specificity of certain members of the human Ah gene battery, including clone 1 and clone 141, and alpha-human chorionic gonadotropin, interleukin-1beta, ornithine decarboxylase, plasminogen activator inhibitor-2, and transforming growth factor-alpha. Constitutive expression in normal human tissues and inducibility in human epidermal keratinocytes will also be analyzed. 3) To determine if treatment with TCDD increases the rate of transcription of the genes identified in aim 2. 4) To determine if treatment with TCDD results in increased production of active IL-1beta and PAI-2. 5) To determine the dose-response, structure activity, and kinetics of induction of the growth regulatory members of the human Ah gene battery. This research will improve our knowledge of the toxic actions of Ah receptor agonists in a primary target tissue in man. The proposed measurements will improve our ability to extrapolate the human health risk of exposure to this class of compounds from known rodent bioassay results.
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