Superfund Research Program
The Effects of Nutrition on Polychlorinated Biphenyl-Mediated Endothelial Cell Activation - Implications in Atherosclerosis
The lining of blood vessels is protected by the endothelium, which is primarily composed of a layer of metabolically active cells known as endothelial cells. The vascular endothelium plays an active role in physiological processes such as regulation of vessel tone, blood coagulation and vascular permeability. In addition, the endothelium protects underlying tissues against various harmful blood-borne agents like plaque-forming materials, lipids or cellular debris. Maintenance of endothelial integrity is critical not only for protection against adverse metabolic activities that may be damaging to blood vessels, but also for performance of the normal barrier function of endothelial cells, which limit the entry of plasma components, such as cholesterol-rich lipoproteins, into the vessel wall.
Evidence is accumulating that suggests damage to the endothelium may predispose a vessel to further injury including the formation of atherosclerotic plaques or fatty deposits inside the vessel wall, and clinical symptoms of atherosclerosis, a disease which involves a thickening of the larger arteries in the body. In fact, some of the factors implicated in the development of atherosclerosis include chronic and cumulative metabolic alterations of the endothelium induced by inflammatory cytokines, specific dietary lipids that can produce oxidative injury, and even certain environmental contaminants found on Superfund sites.
Studies by a team of researchers at the University of Kentucky show that polychlorinated biphenyls (PCBs) can disrupt the normal metabolic activities and barrier function of vascular endothelial cells, events considered early steps in the development of atherosclerosis. These findings raise concern because, after exposure, PCBs have a long half-life in the body and may remain in the blood circulation for extended time periods. Moreover, the constant, intimate contact of vascular endothelial cells with blood components makes them highly vulnerable to chemical insult.
Three types of PCBs -- 3,3',4,4'-tetrachlorobiphenyl (PCB 77), 2,3,4,4',5-pentachlorobiphenyl (PCB 114) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) -- were investigated, representing examples of PCBs with documented acute and chronic health effects. Another reason these particular congeners were chosen for study is because they differ in their induction of cytochrome P450. PCB 77 induces cytochrome P450 1A, PCB 153 induces cytochrome P450 2B1, while PCB 114 can induce both types of enzymes.
Cultured vascular endothelial cells were exposed to each congener separately for up to 24 hours. PCB 77 and PCB 114 contributed markedly to cellular oxidative stress as measured by 2,7-dichlorofluorescin (DCF) fluorescence and lipid hydroperoxides. Enhanced oxidative stress in PCB 77- and PCB114-treated cells was accompanied by an increase in the activity and content of cytochrome P450 1A and a decrease in vitamin E, an antioxidant, in the culture medium. These PCBs also disrupted endothelial barrier function by allowing an increase in albumin transfer across endothelial monolayers. However, exposure of endothelial cells to PCB 153 had no effect on cellular oxidation or endothelial barrier function.
In addition to finding that vascular endothelial cells are vulnerable to oxidative damage and barrier dysfunction when exposed to certain PCBs, the University of Kentucky researchers provide evidence that dietary lipids may enhance these effects. The researchers have shown previously that certain diet-derived omega-6 unsaturated fatty acids by themselves may be atherogenic. In recent studies, cultured endothelial cells were treated with linoleic acid, a component of corn oil and other types of oils, followed by either one of two PCBs, PCB 77 or PCB 153.
What these experiments demonstrated is that enrichment with linoleic acid before treatment with PCB 77 diminished endothelial barrier function by almost 50% as compared to cells treated only with the PCB. This phenomenon appeared to be mediated by increased oxidative stress and a decrease in vitamin E content in the culture media. Similar to the endothelial permeability data, pre-enrichment of cells with linoleic acid increased the PCB 77-mediated induction of cytochrome P450 1A by 55%. However, linoleic acid plus PCB 153 had little to no effect on endothelial barrier function.
Altogether, the results from the above studies suggest that certain unsaturated fatty acids can potentiate PCB-mediated endothelial cell dysfunction and that the mechanism(s) by which PCBs alter endothelial cell function may involve oxidative stress and activation of the cytochrome P450 1A subfamily.
Of great interest are studies suggesting that antioxidant nutrients can downregulate the vascular disease-promoting effects of PCBs. Experiments with vitamin E (alpha-tocopherol) showed that it can completely block PCB 77-mediated endothelial barrier dysfunction in cultured cells. This protective effect was associated with a decrease in both oxidative stress (as measured by DCF fluorescence) and activation of a transcription factor that is sensitive to oxidative stress. Furthermore, vitamin E decreased PCB 77-mediated production of the inflammatory cytokine interleukin-6.
In addition to increasing our knowledge of how PCBs alter endothelial cell metabolism and function, these findings are significant for showing the atherogenic properties of PCBs can be influenced by common components of the diet. While these studies suggest diets rich in certain unsaturated fatty acids may amplify the adverse vascular effects of PCBs, they also give insight into the potential uses of vitamin E and related antioxidants to limit PCB-mediated endothelial cell injury. This valuable information could be used to develop dietary recommendations and nutritional interventions for populations at high risk for exposure to PCBs, including communities living near Superfund sites and those exposed via occupation or diet.
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To learn more about this research, please refer to the following sources:
- Twaroski TP, Arif JM, Gupta RC, Robertson LW. 1999. Antioxidant enzyme levels and oxidative damage in rats exposed to selected Polychlorinated Biphenyls (PCBs) after maximal cytochrome P450 induction. In: Proceedings of the Ninetieth Annual Meeting of the (AACR) American Association of Cancer Research, 1999. pp.4269.
- Slim RM, Toborek M, Robertson LW, Hennig B. 1998. Linoleic acid amplifies PCB-mediated dysfunction of endothelial cells. FASEB J 12(5):A1008.
- Toborek M, Barger SW, Mattson MP, Espandiari P, Robertson LW, Hennig B. 1995. Exposure to polychlorinated biphenyls causes endothelial cell dysfunction. J Biochem Toxicol 10(4):219-226. doi:10.1002/jbt.2570100406 PMID:8568836
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