Effects of polychlorinated biphenyls on vascular endothelial cell dysfunction: Modification by dietary lipids.

摘要

Mechanisms by which polychlorinated biphenyls (PCBs) cause vascular endothelial cell (EC) dysfunction and the influence of fatty acids (primarily linoleic acid) on modifying the activation of EC by PCBs were studied. Selected PCB congeners with varying binding avidity to the aryl hydrocarbon receptor (AhR) and differences in their induction pattern of cytochrome P450s were used in the presence or absence of linoleic acid. Coplanar PCBs such as PCB 77 (3,3 ',4,4'-tetrachlorobiphenyl) and PCB 169 (3,3',4,4',5,5'-hexachlorobiphenyl), but not PCB 153 (2,2',4,4',5,5 '-hexachlorobiphenyl) caused cell activation and endothelial barrier dysfunction. Linoleic acid potentiated PCB 77-mediated increase in cellular oxidative stress and activation of NF-kappaB. The enhanced oxidative stress was accompanied by increased activity of CYP 1A, accumulation of membrane linoleic acid and a decrease in the vitamin E content in the culture medium. Inhibition of cytosolic epoxide hydrolase blocked both linoleic acid-induced cytotoxicity, as well as the synergistic toxicity of linoleic acid plus PCB 77 to EC. These data suggest that cytotoxic epoxide metabolites of linoleic acid mediate linoleic acid and PCB-induced EC dysfunction.;Pre-treating endothelial cells with dl-alpha-tocopherol or an AhR antagonist, alpha-naphthoflavone, protected against PCB 77-mediated endothelial barrier dysfunction, increase in oxidative stress and interleukin 6 production. These results suggest that AhR and/or CYP 1A induction by coplanar PCBs is in part responsible for the observed increase in oxidative stress and disruption of endothelial barrier function.;In a separate study, PCB 77 and PCB 153 were shown to induce c-Jun amino-terminal/stress-activated protein kinases (JNK/SAPK) and caspase 3 activities, both of which are important parameters involved in apoptotic signaling pathway. The final execution of DNA fragmentation, however, was observed only after modulating the glutathione status in PCB 77 treated cells. These results suggest that certain PCBs, in the presence of a pro-oxidant, may trigger apoptotic signaling pathways in addition to inflammatory and necrotic (cytotoxic) events.;In summary, the present study provides evidence that cellular lipid, and in particular fatty acid composition can modulate PCB-mediated EC activation and dysfunction. This may have implication in understanding the role of nutrition and exposure to specific environmental contaminants in the etiology of atherosclerosis.