title: Polychlorinated biphenyls disrupt hepatic epidermal growth factor receptor signaling.
abstract: 1. Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that disrupt hepatic xenobiotic and intermediary metabolism, leading to metabolic syndrome and nonalcoholic steatohepatitis (NASH). 2. Since phenobarbital indirectly activates Constitutive Androstane Receptor (CAR) by antagonizing growth factor binding to the epidermal growth factor receptor (EGFR), we hypothesized that PCBs may also diminish EGFR signaling. 3. The effects of the PCB mixture Aroclor 1260 on the protein phosphorylation cascade triggered by EGFR activation were determined in murine (in vitro and in vivo) and human models (in vitro). EGFR tyrosine residue phosphorylation was decreased by PCBs in all models tested. 4. The IC50values for Aroclor 1260 concentrations that decreased Y1173 phosphorylation of EGFR were similar in murine AML-12 and human HepG2 cells (∼2-4 μg/mL). Both dioxin and non-dioxin-like PCB congeners decreased EGFR phosphorylation in cell culture. 5. PCB treatment reduced phosphorylation of downstream EGFR effectors including Akt and mTOR, as well as other phosphoprotein targets including STAT3 and c-RAF in vivo. 6. PCBs diminish EGFR signaling in human and murine hepatocyte models and may dysregulate critical phosphoprotein regulators of energy metabolism and nutrition, providing a new mechanism of action in environmental diseases.
authors.affiliation: a Department of Biochemistry and Molecular Genetics , University of Louisville School of Medicine , Louisville , KY , USA.
authors.forename: Josiah E
authors.initials: JE
authors.lastname: Hardesty
authors.affiliation: b University of Kentucky Superfund Research Center, University of Kentucky , Lexington , KY , USA.
authors.forename: Banrida
authors.initials: B
authors.lastname: Wahlang
authors.affiliation: c Department of Medicine , Division of Gastroenterology, Hepatology and Nutrition , and.
authors.forename: K Cameron
authors.initials: KC
authors.lastname: Falkner
authors.affiliation: a Department of Biochemistry and Molecular Genetics , University of Louisville School of Medicine , Louisville , KY , USA.
authors.forename: Heather B
authors.initials: HB
authors.lastname: Clair
authors.affiliation: a Department of Biochemistry and Molecular Genetics , University of Louisville School of Medicine , Louisville , KY , USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Clark
authors.affiliation: d Department of Pharmacology and Toxicology , University of Louisville School of Medicine , Louisville , KY , USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Ceresa
authors.affiliation: a Department of Biochemistry and Molecular Genetics , University of Louisville School of Medicine , Louisville , KY , USA.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Prough
authors.affiliation: a Department of Biochemistry and Molecular Genetics , University of Louisville School of Medicine , Louisville , KY , USA.|c Department of Medicine , Division of Gastroenterology, Hepatology and Nutrition , and.|d Department of Pharmacology and Toxicology , University of Louisville School of Medicine , Louisville , KY , USA.|e The Robley Rex Veterans Affairs Medical Center , Louisville , KY , USA , and.|f The Kentucky One Health Jewish Hospital Liver Transplant Program , Louisville , KY , USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cave
mesh_terms: D000818:Animals; D004785:Environmental Pollutants / Q000633:toxicity*; D066246:ErbB Receptors / Q000378:metabolism*; D051379:Mice; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects*; D015262:Xenobiotics / Q000633:toxicity
chemical_list: D004785:Environmental Pollutants; D015262:Xenobiotics; D011078:Polychlorinated Biphenyls; D066246:ErbB Receptors
keywords: Aroclor 1260; constitutive androstane receptor; epidermal growth factor receptor; nonalcoholic steatohepatitis; polychlorinated biphenyls; protein kinases