The stated long-term objective of the research is to understand the molecular mechanism by which the widespread environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits its adaptive and adverse biological effects. In experimental animals, TCDD induces the activities of xenobiotic-metabolizing enzymes, an adaptive response to a change in the cell' chemical environment. TCDD also produces adverse effects such as cancer, reproductive abnormalities, and immunotoxicity in animals. In humans, TCDD produces adaptive and adverse effects (enzyme induction, chloracne); however, the risk that TCDD poses to public health is a matter of current debate. Mechanistic knowledge of TCDD action should permit better understanding of its potential adverse health effects and provide a biological basis for models use to assess its risk. The experiments described here utilize biochemical, genetic, and molecular biological techniques to analyze the mechanism of TCDD action in mouse hepatoma cells in culture. The project involves (i) analysis o a domain of the aromatic hydrocarbon receptor (AhR) that inhibits its trans-activation capability, (ii) studies of a cytoplasmic AhR-interacting protein, and (iii) analysis of the mechanism by which TCDD induces ecto-ATPase gene expression. The experiments address issues related to non-genotoxic environmental contaminants, molecular toxicology, dioxin biology, the regulation of mammalian gene expression, AhR and related transcription factors adaptive responses to xenobiotics, and the maintenance of cellular homeostasis in the face of environmental changes.
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