ARRA: Nutrition and Superfund Chemical Toxicity Summer Supplement Project 4

Atherosclerosis, a chronic inflammatory disease, is still the number one cause of death in the United States. Numerous risk factors for the development of atherosclerosis have been identified, including obesity, hypertriglyceridemia and exposure to Superfund chemicals such as persistent organic pollutants (e.g., PCBs). Plant-based bioactive food components are reported to have antioxidant and anti-inflammatory properties. Our preliminary data suggest that endothelial cell dysfunction and inflammatory events induced by exposure to coplanar PCBs can be markedly down-regulated by bioactive compounds such as flavonoids, events which also can be modified by the cellular lipid milieu. Little is known about mechanisms of nutritional modulation of environmental toxicity. Membrane lipid domains such as caveolae are particularly abundant in endothelial cells, where they are believed to playa major role in the regulation of endothelial vesicular trafficking. More recently, caveolae have also been implicated in the regulation of cell signal transductions. Thus, we hypothesize that caveolae are critical in the cellular responses to Superfund pollutants, lipids, and lipophilic bioactive compounds such as flavonoids. We also hypothesize that the anti-inflammatory properties offlavonoids against chemical insults may be enhanced by omega-3 fatty acids and antagonized or lessened by omega-6 fatty acids. These hypotheses will be tested in vitro as well as in vivo by studying the interactions of PCBs with dietary components such as fatty acids and flavonoids. Importantly, we will use cell and mouse models lacking the caveolin gene to determine the involvement of caveolae in inflammatory outcome. We propose to explore novel mechanisms of nutrient-mediated modulation of Superfund chemical toxicity, and the outcome of our proposed study will lead to novel nutritional recommendations and therapeutic interventions in populations exposed to Superfund chemicals. Superfund chemical exposure, specifically persistent organic pollutants like PCBs, has been linked to a heightened risk of cardiovascular disease to the public. Project 1 intends to investigate the mechanisms used by these chemicals resulting in disease, specifically signaling pathways controlled by the membrane domains, caveolae. Project 1 will focus on means of nutritional intervention by blocking these targets and thus proposing means of protecting the public from the harmful effects of Superfund chemical exposure.