Year of Publication

2010

Degree Name

Doctor of Philosophy (PhD)

Document Type

Dissertation

College

Medicine

Department

Toxicology

First Advisor

Dr. Bernhard Hennig

Abstract

Cardiovascular diseases are the number one cause of death in Western societies. Endothelial dysfunction is an early event in the pathology of atherosclerosis, which is an underlying cause in the majority of cardiovascular events. Exposure to persistent environmental pollutants, such as polychlorinated biphenyls (PCBs), is a risk factor for the development of atherosclerosis.

First, we tested a hypothesis that coplanar PCBs, dioxin-like chemicals with affinity for aryl hydrocarbon receptor (AhR), can stimulate up-regulation of monocyte chemoattractant protein-1 (MCP-1), an endothelium-derived chemokine that attracts monocytes into sub-endothelial space in early stages of atherosclerosis. Coplanar PCBs 77 and 126 increased expression of MCP-1 in endothelial cells, and this effect was dependent on activation of AhR and increased levels of cytochrome P450 monoxygenases. Subsequent rise in the levels of reactive oxygen species (ROS) led to a downstream stimulation of redox-sensitive kinases and transcription factors. Lipid rafts, and particularly caveolae, are enriched in endothelial cells, and down-regulation of caveolin-1, a key structural protein of caveolae, decreases the progression of atherosclerosis. Studies using deletion of caveolin-1 in vitro and in vivo demonstrated that intact caveolae were required for up-regulation of MCP-1 and pro-inflammatory interleukin-6 (IL-6) by PCB77.

Nutrition can modulate adverse outcomes of human exposure to environmental chemicals. Fish oil-derived long-chain omega-3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA, 22:6ω-3), can alleviate inflammatory responses and the risk of cardiovascular disease. Cyclopentenone metabolites produced by oxidation of DHA contribute to these protective effects. Endothelial cells were pre-treated with oxidized DHA (oxDHA), prepared by incubation of the fatty acid with a free radical generator. Subsequent up-regulation of MCP-1 by coplanar PCB77 was markedly reduced. DHA-derived cyclopentenones increased nuclear translocation and DNA binding of a transcription factor NF-E2-related factor-2 (Nrf2), as well as expression levels of its target, antioxidant enzyme NAD(P)H:quinone oxidoreductase (NQO1). This stimulation of antioxidant responses prevented ROS production and inflammatory responses induced by PCB77. These data support the concept that nutrition prevents toxicity caused by environmental pollutants; thus, nutrition and can be a sensible approach to alleviate chronic pathologies associated with these chemicals.

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