Polycyclic aromatic hydrocarbons (PAH) are a class of environmental carcinogens known to occur at high concentrations in hazardous waste sites. A proximal event in PAH binding to a cytosolic protein, the aromatic hydrocarbon receptor (AhR). Ligated AhR complexes with an accessory molecule (ARNT), translocates to the nucleus, binds specific DNA recognition sequences and induces cytochrome P450IA1 (CyPIA1) mRNA transcription. The resulting induction of monooxygenase activity leads to production of carcinogenic PAH metabolites. Recently, it has been shown the PAH exposure compromises the immune system, the biologic system responsible for killing newly formed tumors. These observations exemplify the breadth of biologic and potentially pathologic responses to PAH. We and others have noted that PAH induce a variety of intracellular changes including Ca2+ flux, protein phosphorylation, proto-oncogene induction, and modulation of hormone and growth factor receptors in what appears to be P- 450-independent signal transduction pathways. A role for the AhR in many of these intracellular events has been implicated, but not formally proven. If a role for the AhR in these responses is confirmed, then it would be predicted that the level of AhR activity represents a critical an limiting factor in the induction of multiple pathways of hydrocarbon-induced cell activation. Herein we propose to test this hypothesis initially be manipulating AhR activity in well-defined animal systems and eventually be evaluating AhR activity in humans. The following specific aims have been proposed. 1) To produce somatic hybrid mice which bear lymphocytes expressing no AhR, high levels of AhR, or a mutant AhR capable of binding PAH but incapable of complexing with DNA recognition elements; 2) To evaluate AhR function in the PAH-responsiveness of lymphocytes from these somatic hybrid mice. Emphasis will be placed on the role of the AhR in inducing apoptosis in PAH treated lymphocytes and on other immunotoxicologic endpoints. Comparison of the responses of these lymphocytes to PAH will help dissect the putative alternative pathways of PAH bioactivation. 3) To extend results obtained in these animal systems by evaluating AhR polymorphism and expression in humans and projecting the likelihood that particular AhR phenotypes represent molecular biomarkers for PAH susceptibility in humans.
Showing the most recent 10 out of 398 publications
