SUPERFUND CHEMICALS AND ENDOTHELIAL CELL DYSFUNCTION

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Polyhalogenated aromatic hydrocarbons (e.g. PCBs) and polycyclic aromatic hydrocarbons (e.g., BP) have been implicated in the atherosclerotic disease process. Even though mechanisms of the atherogenic potential of these environmental contaminants are not known, critical events of cell dysfunction may occur at the endothelial cell level. The vascular endothelium 'communicates' with blood-borne cells and abluminal tissues and acts as a barrier to the movement of plasma components (e.g., cholesterol-rich lipoproteins) from the blood to the arterial wall. Cell injury, or any event which disrupts endothelial integrity and thus endothelia permeability properties, may be involved in the early events leading to atherosclerotic lesion formation. We propose that aromatic hydrocarbons are atherogenic by causing cell dysfunction and a subsequent disruption of endothelial barrier function. We hypothesize that these events are mediated by 1) alteration in lipid profile and lipid metabolism, 2) cytochrome P-450 1A1 induction, 3) increased oxidative stress, 4) DNA adduct formation and oxidative DNA damage, and 5) alteration of calcium metabolism. Thus, the extent of the movement of atherogenic lipoprotein remnants across and into the arterial wall may be directly correlated to the severity of endothelial cell barrier function disruption. We also hypothesize that diet-derived fats, i.e., fatty acids differing in carbon length and degree of unsaturation, can greatly alter the cellular lipid and oxidant/antioxidant environment and thus influence the aromatic hydrocarbon-mediated cell dysfunction. Furthermore, this research will explore mechanisms by which certain nutrients or chemicals having antioxidant or membrane stabilizing properties, may protect the endothelium from aromatic hydrocarbon-induced cell injury. Porcine- and human-derived endothelial cells will be cultured and used in the proposed research. First, a series of studies will be conducted to determine mechanisms of aromatic hydrocarbon-mediated endothelial cell dysfunction. In the second phase, the interactive events of certain lipids and aromatic hydrocarbons on endothelial cell metabolism will be explored. During the third phase, a series of studies will be undertaken to determine the mechanisms by which selected nutritional interventions in culture may protect agonist cell injury under the conditions cited above. Results of the proposed studies should identify mechanisms of Superfund Chemical-mediated endothelial cell dysfunction and their implication in atherosclerosis.