TCDD (2,3, 7, 8-tetrachlorodibenzo-p-dioxin) is a representative from the class of environmental polyhalogenated aromatic hydrocarbons (PHAHs) that increase cancer risk, as well as causing disorders in reproduction, development, and immunological disorder. PHAHs are poorly metabolized and extremely hydrophobic, and remain in mammalian tissues for extended periods of time. Their effects are mediated by a cytosoloic ligand-activated transcription factor, the aromatic hydrocarbon receptor (AHR). Although generally considered to be nongenotoxic, based on negative results in prokaryotic short-term assays, many PHAHs produce an oxidative stress response leading to mutations and cellular transformation in mammalian cells. In Hepa-1 cells TCDD increases intracellular calcium and generates reactive oxygen, while in mice TCDD produces oxidation of DNA bases and hepatic thiols, mitochondrial production of reactive oxygen, and partial mitochondrial uncoupling. Based on these observations, the applicant proposed the hypothesis that acute exposure to TCDD triggers a chronic oxidative stress response mediated by mitochondria. The applicant will examine this hypothesis with three specific aims: 1. To determine the mechanism for the TCDD-mediate oxidative stress response in cultured cells. 2. To determine the mechanism for the TCDD-mediated oxidative stress response in mice, using Ahr, Cyp1a1 and cyp1a2 knockout mice. 3. To determine the involvement of the Ahr, cyp1a1 and cyp1a2 in TCDD-mediated mutagenesis in vivo, using Big Blue lacI transgenic/Ahr, Cyp1a1, and cyp1a2 knockout mice. These studies will improve our understanding of how PHAHs such as TCDD generate oxidative stress and mutagenesis, leading to better models for risk assessment and novel strategies for intervention in PHAH-mediated toxicity.
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