The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the biological effects of polycyclic aromatic hydrocarbons (PAHs), halogenated-dioxins ("dioxins"), - dibenzofurans, -biphenyls (PCBs), and -diphenylethers. Because of its central role in acute toxicity, teratogenesis and carcinogenesis of a large number of environmental contaminants, mechanistic information about AHR signaling is used by regulatory agencies to establish acceptable exposure levels for these pollutants. The overarching hypothesis of this proposal is that at least three distinct AHR signaling pathways exist that are of toxicological significance to human populations and vertebrate species in general. We propose that these three pathways can be distinguished by their unique impacts on transcriptional profiles within target cell populations and that these pathways can be further defined based upon their dependence on fractional activation of the AHR, by their cellular context, and their influence on gene expression through enhancer elements known as AHREs. The goal of this proposal is to identify biomarkers that reflect exposure to agonists and their induced toxic responses. We will accomplish this through the identification of low and high affinity AHREs in the hepatocyte and endothelial cell compartments of novel recombinant mouse models. To these ends, we propose the following specific aims:
Specific Aim 1 : Use gene targeting in ES cells to generate recombinant alleles derived from a ligand responsive version of Ahr.
Specific Aim 2 : Demonstrate the importance of the cellular expression and concentration of AHR.
Specific Aim 3 : Classify the high and low affinity AHRE batteries using genomic approaches.
Specific Aim 4 : Provide evidence that environmental AHR agonists can stimulate the endogenous AHR pathway. We propose that the results of this effort will provide new models that will inform the mechanism of dioxin toxicity in humans, characterize DNA signatures of toxicity, and test a novel hypothesis that developmental toxicity arises from interference with the endogenous AHR pathway. Collectively these studies will set the stage for more accurate and informative risk assessment in man.
This project aims to understand the mechanisms of AHR-mediated transcriptional activation which leads to the adaptive, toxic, and developmental consequences of dioxin exposure and to search for biomarkers that are predictive of these disparate outcomes. These experiments will allow more relevant assessments of AHR-mediated dioxin toxicity as well as generate biomarkers predictive for relevant endpoints of dioxin exposure.
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