title: Exposure to coplanar PCBs induces endothelial cell inflammation through epigenetic regulation of NF-κB subunit p65.
abstract: Epigenetic modifications of DNA and histones alter cellular phenotypes without changing genetic codes. Alterations of epigenetic marks can be induced by exposure to environmental pollutants and may contribute to associated disease risks. Here we test the hypothesis that endothelial cell dysfunction induced by exposure to polychlorinated biphenyls (PCBs) is mediated in part though histone modifications. In this study, human vascular endothelial cells were exposed to physiologically relevant concentrations of several PCBs congeners (e.g., PCBs 77, 118, 126 and 153) followed by quantification of inflammatory gene expression and changes of histone methylation. Only exposure to coplanar PCBs 77 and 126 induced the expression of histone H3K9 trimethyl demethylase jumonji domain-containing protein 2B (JMJD2B) and nuclear factor-kappa B (NF-κB) subunit p65, activated NF-κB signaling as evidenced by nuclear translocation of p65, and up-regulated p65 target inflammatory genes, such as interleukin (IL)-6, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and IL-1α/β. The increased accumulation of JMJD2B in the p65 promoter led to a depletion of H3K9me3 repression mark, which accounts for the observed up-regulation of p65 and associated inflammatory genes. JMJD2B gene knockdown confirmed a critical role for this histone demethylase in mediating PCB-induced inflammation of the vascular endothelium. Finally, it was determined, via chemical inhibition, that PCB-induced up-regulation of JMJD2B was estrogen receptor-alpha (ER-α) dependent. These data suggest that coplanar PCBs may exert endothelial cell toxicity through changes in histone modifications.
authors.affiliation: Superfund Research Center, University of Kentucky, Lexington, KY 40536, United States; Department of Animal and Food Sciences, College of Agriculture, Food and Environment, University of Kentucky, Lexington, KY 40536, United States.
authors.forename: Dandan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Superfund Research Center, University of Kentucky, Lexington, KY 40536, United States; Department of Animal and Food Sciences, College of Agriculture, Food and Environment, University of Kentucky, Lexington, KY 40536, United States.
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Perkins
authors.affiliation: Superfund Research Center, University of Kentucky, Lexington, KY 40536, United States; Graduate Center for Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, United States.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Petriello
authors.affiliation: Superfund Research Center, University of Kentucky, Lexington, KY 40536, United States; Department of Animal and Food Sciences, College of Agriculture, Food and Environment, University of Kentucky, Lexington, KY 40536, United States. Electronic address: bhennig@uky.edu.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hennig
mesh_terms: D002097:C-Reactive Protein / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects; D004785:Environmental Pollutants / Q000009:adverse effects*; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics; D006657:Histones / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008745:Methylation / Q000187:drug effects; D016328:NF-kappa B / Q000235:genetics*; D011078:Polychlorinated Biphenyls / Q000009:adverse effects*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics; D019892:eIF-2 Kinase / Q000235:genetics*
chemical_list: D004785:Environmental Pollutants; D006657:Histones; C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D002097:C-Reactive Protein; D011078:Polychlorinated Biphenyls; D019892:eIF-2 Kinase
keywords: ER-α; Epigenetics and vascular inflammation; H3K9me3; JMJD2B; PCBs; p65