Date Available

11-1-2013

Year of Publication

2013

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Nutritional Sciences

First Advisor

Dr. Bernhard Hennig

Abstract

Diseases, such as cardiovascular disease (CVD), are linked to chronic low levels of inflammation. This inflamed state is the product of risk factors including exposure to environmental pollutants, such as polychlorinated biphenyls (PCBs), which are correlated with increased risk for CVD and diabetes. In response to this health risk, our research addresses the mechanisms by which coplanar PCBs elicit an inflammatory response and the mitigation of PCB-induced inflammation through dietary intervention using docosahexaenoic acid (DHA), an omega-3 lipid. Investigators from the University of Kentucky Engineering Department are developing remediation technologies that detoxify PCBs through dechlorination. We studied the cellular toxicity of coplanar PCB 77 remediation products in primary vascular endothelial cells. The dechlorination products elicited different toxicological responses, which were less than the parent compound and contributed to the overall inflammatory response. The presence of PCB 77 at any concentration was sufficient to promote an inflammatory response, which was attenuated with complete dechlorination. PCB 77 is a good model for coplanar PCB-induced toxicity, but in environmental and human samples, coplanar PCB 126 is detected more frequently. Using different doses of PCB 126, we determined that acute exposure to 5 μmol PCB 126/kg mouse was sufficient to produce an inflammatory response without inducing a toxic wasting phenotype. PCB-induced inflammation was attenuated in vitro by DHA-derived neuroprostanes. Applying this information, we fed mice a DHA-enriched diet and exposed them to PCB 126. Liver and adipose lipid profiles confirm an increase in omega-3 fatty acid composition and DHA metabolites, and changes in gene expression indicate a heightened anti-oxidant response in the presence of PCB-induced inflammation. These data provide an overview of the in vivo response to a PCB-induced inflammation after DHA dietary feeding. We have demonstrated that PCB-induced endothelial dysfunction is propagated through lipid domains called caveolae. Caveolae are also signaling domains for toll-like receptor 4 (TLR4), and receptor for lipopolysaccharide (LPS). Similar to PCBs, TLR4 signaling is inhibited by DHA. We compared the caveolae-associated signaling response after exposure to coplanar PCB 126 or LPS. The domain localization of caveolae was altered by both PCB 126 and LPS. Our study determined that PCB 126-induced inflammation was not inhibited by a TLR4-specific inhibitor, but caveolae-based signaling was critical to both PCB 126- and LPS-induced inflammation. Environmental pollutants, such as coplanar PCBs, are risk factors in the development of chronic diseases. Here we investigate possible signaling pathways associated with environmental toxicity and apply potential dietary interventions with omega-3 lipids.

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