The Ah receptor (AhR) has been shown to be largely responsible for the toxic and tumor promotional properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), especially in rodents. In addition, the AhR is a key regulator of xenobiotic metabolism. The human population is exposed to low levels of TCDD and related compounds (e.g. planar PCBs), mostly through the diet. However, the actual long-term health effects of human exposure to TCDD remain to be fully elucidated. Little is known about the biochemical processes involved in the activation and regulation of this ligand-activated helix-loop-helix/basic region transcription factor. In this application the ability of the human and mouse AhR to regulate gene transcription through protein-protein interactions will be examined in three specific aims;1) Use transgenic mouse models to compare the ability of the human versus the mouse Ah receptor to activate gene expression and mediate liver tumor promotion, 2) Determine the ability of the AhR to modulate transcriptional activity other than through binding to dioxin response elements (DRE), and 3) Determine whether the AhR can alter gene regulation as a monomer. To achieve these goals, a combination of AhR-null cell lines and null-AhR mice with a mutant form of mAhR, WT-mAhR or human AhR """"""""knocked-in"""""""" will be used. An emphasis will be placed on determining the multiple mechanisms that lead to direct AhR-mediated changes in gene expression and the target genes that are affected, as well as examine liver toxicity upon exposure to TCDD. Significant preliminary data is provided to support each aim, including the production of the hAhR and mAhR-A78D transgenic mouse models. The combined results from these studies will establish how the AhR/ARNT heterocomplex mediates transcription through a DRE and a non-DRE driven mechanism, and whether differences in the structure of the human AhR results in altered modulation of gene transcription. Lay Relevance: Liver insufficiency can result from environmental and dietary chemical exposure and lead to death in humans. Results from these studies will determine the mechanisms used by the Ah receptor to alter gene regulation that can lead to liver toxicity or tumor formation.
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