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Toxicol Sci. 2018 Apr 1;162(2):622-634. doi: 10.1093/toxsci/kfy004.

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

Author information

1
Department of Biochemistry and Molecular Genetics.
2
Department of Pharmacology and Toxicology.
3
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40202.
4
The Robley Rex Veterans Affairs Medical Center, Louisville, Kentucky 40206.
5
The Jewish Hospital Liver Transplant Program, Louisville, Kentucky 40202.

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.

PMID:
29329451
PMCID:
PMC5888991
DOI:
10.1093/toxsci/kfy004
[Indexed for MEDLINE]
Free PMC Article

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