The primary goals of this project are the use to determine fundamental molecular mechanisms of action and toxicity of ligands of the aryl hydrocarbon receptor (AHR) and the application of this mechanistic information to address specific needs in the assessment of human health risk posed by exposure to these compounds. There are a wide variety of AHR ligands including persistent lipophilic polyhalogenated aromatic hydrocarbons (e.g. 2,3,7 8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated-dibenzodioxins, -dibenzofurans and -biphenyls), non-persistent polycyclic aromatic hydrocarbons (e.g. 3-methylcholanthrene) and endogenous/dietary ligands (e.g. indole and tryptophan metabolites). The polyhalogenated aromatic hydrocarbons are persistent environmental pollutants, and their lipophilicity and subsequent bioaccumulation through the food chain results in chronic lifetime low-level human exposure. ? ? In rodent studies, these persistent AHR ligands have been shown to induce a wide variety of biological and pathological effects including alteration in expression of specific AHR-regulated gene subsets, altered cell growth, endocrine disruption and cancer. Alterations in expression of these specific regulated genes occur via a mechanism that involves a high affinity interaction of dioxins and related ligands with the AHR, a basic helix-loop-helix protein that functions as a ligand-activated transcription factor. While the relationship between exposure and observed health effects has been well established in rodent models, considerable scientific controversy exists in the assessment of human health risk posed by the persistent daily low-level exposure to these potent environmental contaminants. This is due to the fact that the mechanisms relating activation of the AHR by either persistent or non-persistent ligands to the subsequent development of adverse health effects have not been established.? ? Specifically our research is focussed in three areas ? (1) Identification of cell specific and species differences in the AHR-dependent transcriptional response network between humans and rodents. ? (2) Determination of key events in the mechanism of carcinogenicity of TCDD in rodents? (3) Assessment of the suitability of relative potency factors for the prediction of cancer risk posed by TCDD and structurally related persistent polyhalogenated aromatic hydrocarbons. ? ? To address the issue of concordance of human and rodent carcinogenicity, we are examining the interaction and cross-talk between the biological response pathways that are altered by exposure to AHR ligands. Using parallel gene expression profiling studies of multiple human cell types and rodent cells, we have shown that TCDD leads to an activation of a network of signal transduction pathways that predict a disruption of cell growth and differentiation and may be involved in TCDD-induced neoplasia .
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