Year of Publication

2015

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Toxicology and Cancer Biology

First Advisor

Dr. Bernhard Hennig

Abstract

Cardiovascular disease is the leading cause of mortality in Western societies and is linked to multiple modifiable risk factors including lifestyle choices. Emerging evidence implicates exposure to persistent environmental pollutants, such as polychlorinated biphenyls (PCBs), as a risk factor for the development or progression of cardiovascular disease. To reduce disease risks, it is critical to identify sensible means of biomedically reducing the toxicity of persistent organic pollutants and related environmental stressors.

First, we tested a hypothesis that endothelial cell inflammation and subsequent cardiovascular toxicity initiated by coplanar PCBs is modulated by the crosstalk between caveolae and Nuclear factor (erythroid-derived 2)-like 2(Nrf2) related proteins. Caveolae are lipid-enriched organelles found abundantly in endothelial cells and are important mediators of endocytosis and signal transduction. Caveolin-1 (Cav-1), the major structural protein of caveolae, is known to bind and concentrate multiple proteins related to cardiovascular disease and PCB toxicity. Downregulation of Cav-1 protects against PCB-induced vascular toxicity, but possible mechanisms of this defense remain elusive. Studies using endothelial cells isolated from mice deficient in Cav-1 as well as in vitro silencing assays demonstrated that loss of Cav-1 increases available antioxidant enzymes by upregulating the antioxidant master controller Nrf2.

Nutritional interventions focused on diets high in bioactive food components, such as polyphenols or certain fatty acids, may prove to be effective at decreasing environmental pollutant induced diseases. To test the hypothesis that dietary intervention can sensitize Nrf2 and/or caveolae signaling pathways, leading to a more effective anti-inflammatory defense against PCB insults, mice were fed a green tea polyphenol enriched diet and challenged with coplanar PCB 126. Mice fed an enriched diet and exposed to PCBs exhibited lower levels of oxidative stress and higher levels of multiple Nrf2 target antioxidant enzymes. Also, in separate in vitro studies, pretreatment of endothelial cells with the endogenously formed nutrient metabolite, nitro-linoleic acid, altered caveolae and Nrf2 related proteins, resulting in a modified response to PCB exposure. Together, these data support the paradigm that nutritional modulation may be a sensible means of reducing disease risks associated with exposure to environmental pollutants.

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