The long-term objective is to understand the mechanisms by which cells adapt to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the mechanisms by which TCDD produces its biological effects. In animals, TCDD produces adverse teratogenic, reproductive, immunological, and neoplastic changes, as well as adaptive increases in xenobiotic-metabolizing enzymes. The risk that TCDD poses to human health is uncertain. Mechanistic analyses of TCDD action provide perspective on its adaptive and adverse health effects and impose constraints upon models used to assess its risk to public health. The induction of CYP1A1 gene transcription constitutes a useful response for analyzing the mechanism of TCDD action. The CYP1A1 gene encodes the microsomal cytochrome P4501A1 enzyme, which oxygenates certain lipophilic xenobiotics as the initial step in their metabolic processing to water-soluble derivatives. The experiments proposed in this application involve biochemical and genetic techniques in mouse hepatoma cells to analyze (1) the mechanism by which the aromatic hydrocarbon receptor mediates transactivation, enhancer-promoter communication, and alterations in chromatin structure for the CYP1A1 gene and (2) the mechanism by which TCDD down-regulates the transcription of the MHC Q1b gene. The studies address issues related to dioxin action, environmental toxicity, cellular homeostasis, and the regulation of mammalian gene transcription.
