linoleic-acid and 3-4-3--4--tetrachlorobiphenyl

Exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCBs) can cause endothelial cell (EC) activation by inducing pro-inflammatory signaling pathways. Our previous studies indicated that linoleic acid (LA, 18:2), a major omega-6 unsaturated fatty acid in the American diet, can potentiate PCB77-mediated inflammatory responses in EC. In addition, omega-3 fatty acids (such as alpha-linolenic acid, ALA and 18:3) are known for their anti-inflammatory properties. We tested the hypothesis that mechanisms of PCB-induced endothelial cell activation and inflammation can be modified by different ratios of omega-6 to omega-3 fatty acids. EC were pretreated with LA, ALA, or different ratios of these fatty acids, followed by exposure to PCB77. PCB77-induced oxidative stress and activation of the oxidative stress sensitive transcription factor nuclear factor kappaB (NF-kappaB) were markedly increased in the presence of LA and diminished by increasing the relative amount of ALA to LA. Similar protective effects by increasing ALA were observed by measuring NF-kappaB-responsive genes, such as vascular cell adhesion molecule-1 (VCAM-1) and cyclooxygenase-2 (COX-2). COX-2 catalyzes the rate limiting step of the biosynthesis of prostaglandin E(2) (PGE(2)). PCB77 exposure also increased PGE(2) levels, which were down-regulated with relative increasing amounts of ALA to LA. The present studies suggest that NF-kappaB is a critical player in the regulation of PCB-induced inflammatory markers as modulated by omega-6 and omega-3 fatty acids.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Cyclooxygenase 2; Dinoprostone; Endothelial Cells; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Gene Expression Regulation; Inflammation; Linoleic Acid; NF-kappa B; Polychlorinated Biphenyls; Pulmonary Artery; Swine; Vascular Cell Adhesion Molecule-1

Selected dietary lipids may increase the atherogenic effects of environmental chemicals, such as polychlorinated biphenyls (PCBs), by cross-amplifying mechanisms leading to dysfunction of the vascular endothelium. We have shown previously that the omega-6 parent fatty acid, linoleic acid, or 3,3',4,4'-tetrachlorobiphenyl (PCB 77), an aryl hydrocarbon (Ah) receptor agonist, independently can cause disruption of endothelial barrier function. Furthermore, cellular enrichment with linoleic acid can amplify PCB-induced endothelial cell dysfunction. We hypothesize that the amplified toxicity of linoleic acid and PCBs to endothelial cells could be mediated in part by cytotoxic epoxide metabolites of linoleic acid called leukotoxins (LTX) or their diol derivatives (LTXD). Exposure to LTXD resulted in a dose-dependent increase in albumin transfer across endothelial cell monolayers, whereas this disruption of endothelial barrier function was observed only at a high concentration of LTX. Pretreatment with the cytosolic epoxide hydrolase inhibitor 1-cyclohexyl-3-dodecyl urea partially protected against the observed LTX-induced endothelial dysfunction. Endothelial cell activation mediated by LTX and/or LTXD also enhanced nuclear translocation of the transcription factor NF-kappa B and gene expression of the inflammatory cytokine IL-6. Inhibiting cytosolic epoxide hydrolase decreased the LTX-mediated induction of both NF-kappa B and the IL-6 gene, whereas the antioxidant vitamin E did not block LTX-induced endothelial cell activation. Most importantly, inhibition of cytosolic epoxide hydrolase blocked both linoleic acid-induced cytotoxicity, as well as the additive toxicity of linoleic acid plus PCB 77 to endothelial cells. Interestingly, cellular uptake and accumulation of linoleic acid was markedly enhanced in the presence of PCB 77. These data suggest that cytotoxic epoxide metabolites of linoleic acid play a critical role in linoleic acid-induced endothelial cell dysfunction. Furthermore, the severe toxicity of PCBs in the presence of linoleic acid may be due in part to the generation of epoxide and diol metabolites. These findings have implications in understanding interactive mechanisms of how dietary fats can modulate dysfunction of the vascular endothelium mediated by certain environmental contaminants.

Topics: Alcohols; Animals; Aryl Hydrocarbon Hydroxylases; Cell Nucleus; Cells, Cultured; Cytochrome P-450 Enzyme System; Electrophoresis; Endothelium, Vascular; Enzyme Inhibitors; Epoxide Hydrolases; Epoxy Compounds; Fatty Acids; Interleukin-6; Linoleic Acid; Linoleic Acids; NF-kappa B; Polychlorinated Biphenyls; Reverse Transcriptase Polymerase Chain Reaction; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases; Swine