Humans are constantly exposed to a wide variety of ligands of the aromatic hydrocarbon receptor (AHR). In rodent studies, persistent AHR ligands such as by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) have been shown to induce a wide variety of biological and pathological effects including alterations in expression of specific AHR-regulated genes, altered cell growth, endocrine disruption and cancer. Alterations in expression of specific regulated genes occur via a mechanism that involves binding with the AHR, a basic helix-loop-helix protein that functions as a ligand-activated transcription factor. The primary goals of this research are to determine fundamental molecular mechanisms of action and toxicity of ligands of the AHR in both human and rodents cell systems and the application of this mechanistic information to address specific needs in the assessment of human health risk posed by exposure to these compounds. Our research this year indicates that the female specific induction of liver tumors in rats by TCDD likely involves a mechanism of indirect genotoxicity via a chronic induction of oxidative stress as a result of AHR receptor-mediated induction of cytochrome P450 isozymes and subsequent production of redox active estrogen metabolites, coupled with a disruption in cell growth with chronic exposure . This conclusion is supported by our observations that in the rat liver, the potency of induction of preneoplastic lesions by TCDD in females is greater than that in male rats. In addition the induction oxidative DNA damage and cell proliferation are female-specific, estrogen dependent, and requires persistent chronic exposure. 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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