Superfund Research Program
Superfund Chemicals, Nutrition, and Multi-Organ Cardiovascular Risk
Final Progress Reports
Evidence from epidemiological studies suggests that exposure to environmental chemicals or pollutants can contribute to compromised health and the pathology of cardiovascular diseases. By utilizing vascular endothelial cell cultures and mice that mimic human pathology of atherosclerosis, recent research out of the University of Kentucky SBRP demonstrated, for the first time, that exposure to PCBs, and in particular co-planar PCBs, can contribute to vascular inflammation and atherosclerotic lesion formation. Complications from cardiovascular diseases are the major cause of death in the United States and in most countries world-wide. Unfortunately, there is no easy "fix" to protect or intervene against diseases associated with exposure to environmental pollutants. Studies derived from epidemiological and basic research and clinical data are evolving, which suggest that diet or nutrition, as well as life-style changes, can modify pathologies of chronic diseases as well as diseases associated with environmental toxic insults. For example, exposure to persistent organic pollutants, such as PCBs, can contribute to the development of inflammatory diseases ,such as atherosclerosis. Activation, chronic inflammation, and dysfunction of the vascular endothelium are critical events in the initiation and acceleration of atherosclerotic lesion formation.
Dr. Bernhard Hennigs studies indicate that an increase in cellular oxidative stress, and an imbalance in antioxidant status, are critical events in PCB-mediated induction of inflammatory genes and endothelial cell dysfunction. Hennig found that specific dietary fats rich in omega-6 fatty acids can further compromise endothelial dysfunction induced by selected PCBs. In contrast, Hennig also has preliminary data suggesting that PCB-induced endothelial dysfunction and inflammatory events can be markedly down-regulated by increasing omega-3 relative to omega-6 fatty acids. Most of all, recent data suggest that membrane lipid rafts, such as caveolae, which are critical cell-surface plasma membrane invaginations, may play a major role in the regulation of PCB-induced inflammatory signaling in endothelial cells. Results suggest that PCBs can disrupt endothelial functions in part by modification of caveolae structure. Coplanar PCBs 77 and 126 increased expression of the caveolae marker and major structural protein, caveolin-1, as well as the caveolae-associated pro-inflammatory enzyme cyclooxygenase-2. Up-regulation of caveolin seems to be dependent on activation of the aryl hydrocarbon receptor (AhR). Data suggests that intact caveolae are critical for activation of the endothelium by PCB 77. Caveolin-1 knockout mice lacked the induction of the pro-inflammatory cytokines interleukin-1beta, interleukin-6 and monocyte chemoattractant protein-1 in aortic tissue upon PCB 77 treatment compared to wild-type controls.
Currently, University of Kentucky researchers are exploring the hypothesis that atherosclerotic risk factors associated with exposure to Superfund pollutants, or the modulation of toxicity by dietary nutrients, are regulated, in part, through caveolae signaling within the vascular endothelium. Hennig's findings that caveolae-deficient mice are protected from coplanar PCB toxicity could be important for nutritional recommendations in PCB-exposed populations, and the ongoing studies are designed to demonstrate that caveolae-associated signaling can be suppressed by diets enriched in omega-3 polyunsaturated fatty acids or dietary bioactive compounds such as flavonoids. Even though the concept that nutrition may modify or ameliorate the toxicity of environmental chemicals is provocative and warrants further study, the implications for human health could be significant. More research is needed to understand observed interactions of PCB toxicity with nutritional interventions.