Epidermal Growth Factor Receptor Signaling Disruption by Endocrine and Metabolic Disrupting Chemicals

• Published in: Toxicological sciences 2018-04, Vol.162 (2), p.622-634
• Main Authors: Hardesty, Josiah E, Al-Eryani, Laila, Wahlang, Banrida, Falkner, K Cameron, Shi, Hongxue, Jin, Jian, Vivace, Brad J, Ceresa, Brian P, Prough, Russell A, Cave, Matthew C
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Chemical Disruption of Egfr Signaling; Constitutive Androstane Receptor; Endocrine Disruptors - toxicity; Endocytosis - drug effects; Epidermal Growth Factor - metabolism; ErbB Receptors - agonists; ErbB Receptors - metabolism; Hep G2 Cells; Humans; Metabolic Networks and Pathways - drug effects; Mice; Molecular Docking Simulation; Phosphorylation; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Signal Transduction - drug effects; Transfection
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfy004

Abstract The purpose of this study is to identify an environmentally relevant shared receptor target for endocrine and metabolism disrupting chemical pollutants. A feature of the tested chemicals was that they induced Cyp2b10 in vivo implicating activation of the constitutive androstane receptor (CAR). Recent studies suggest that these compounds could be indirect CAR activators via epidermal growth factor receptor (EGFR) inhibition. Assays included a CAR activity reporter assay, EGF endocytosis assay, and EGFR phosphorylation assay. Docking simulations were used to identify putative binding sites for environmental chemicals on the EGFR. Whole-weight and lipid-adjusted serum mean pollutant exposures were determined using data from the National Health and Examination Survey (NHANES) and compared with the IC50 values determined in vitro. Chlordane, trans-nonachlor, PCB-126, PCB-153, and atrazine were the most potent EGFR inhibitors tested. PCB-126, PCB-153, and trans-nonachlor appeared to be competitive EGFR antagonists as they displaced bound EGF from EGFR. However, atrazine acted through a different mechanism and could be an EGFR tyrosine kinase inhibitor. EGFR inhibition relative effect potencies were determined for these compounds. In NHANES, serum concentrations of trans-nonachlor, PCB-126, and PCB-153 greatly exceeded their calculated IC50 values. A common mechanism of action through EGFR inhibition for three diverse classes of metabolic disrupting chemicals was characterized by measuring inhibition of EGFR phosphorylation and EGF-EGFR endocytosis. Based on NHANES data, EGFR inhibition may be an environmentally relevant mode of action for some PCBs, pesticides, and herbicides.