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 ω-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-κB and gene expression of the inflammatory cytokine IL-6. Inhibiting cytosolic epoxide hydrolase decreased the LTX-mediated induction of both NF-κB 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.
|Number of pages||10|
|Journal||Toxicology and Applied Pharmacology|
|State||Published - Mar 15 2001|
Bibliographical noteFunding Information:
Supported in part by grants from NIEHS/EPA (1 P42 ES 07380 and 04699), NIEHS (RO1 ES02710 and P30 ES05707), NRICGP/USDA (97–35200-4231 and 00–35200-9101), DOD, and the Kentucky Agricultural Experimental Station. The content of this paper is solely the responsibility of authors and does not necessarily represent the official view of NIEHS, NIH, or EPA.
- Endothelial cells
- Fatty acids
- Polychlorinated biphenyls
ASJC Scopus subject areas