The studies that we propose in this application will help elucidate the role of environmental agents in ischemic heart disease and their mechanism of action. More than 35 different predisposing risk factors for the disease have been identified but little is known of the role of environmental agents due in part to lack of epidemiologic studies and it part to lack of adequate animal models. As described above, recent studies strongly indicate that exposure to B aboutaJP or TCDD is an important risk factor for ischemic heart disease. At the molecular level, B aboutaJP and TCDD act through the Ah receptor, which is also activated by many other atherogenic polycycic aromatic hydrocarbons. We do not propose that PAHs cause the initial injury responsible for the development of atherosclerosis: injury and repair are likely to be part of the normal vessel physiology. Rather, we propose that sustained exposure to these compounds is a risk factor that accelerates the development of the disease. We are confident that our findings will be relevant beyond the experimental design that we propose to issues of susceptibility factors for atherosclerosis, and of the role of gene-environment interactions in human health. Furthermore, we expect that this research will help uncover molecular markers of exposure that will suggest correlations between genotype and disease as a result of PAH and HAH exposure that may be invaluable in the eradication of the human disease.
