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

Area of Science:

• Environmental Toxicology
• Molecular Toxicology
• Endocrinology

Background:

• Endocrine and metabolism disrupting chemical pollutants pose risks to human health.
• Some pollutants activate the constitutive androstane receptor (CAR), potentially via epidermal growth factor receptor (EGFR) inhibition.
• Identifying shared receptor targets is crucial for understanding pollutant mechanisms.

Purpose of the Study:

• To identify an environmentally relevant shared receptor target for endocrine and metabolism disrupting chemical pollutants.
• To investigate the role of EGFR inhibition as a common mechanism of action for diverse chemical pollutants.
• To compare in vitro EGFR inhibition potencies with human exposure data.

Main Methods:

• In vitro assays including CAR activity reporter assay, EGF endocytosis assay, and EGFR phosphorylation assay.
• In silico molecular docking simulations to identify pollutant binding sites on EGFR.
• Analysis of National Health and Examination Survey (NHANES) data for human pollutant exposure levels.

Main Results:

• Chlordane, trans-nonachlor, PCB-126, PCB-153, and atrazine were identified as potent EGFR inhibitors.
• PCB-126, PCB-153, and trans-nonachlor acted as competitive EGFR antagonists.
• Atrazine exhibited EGFR tyrosine kinase inhibition, indicating a different mechanism.
• Human serum concentrations of trans-nonachlor, PCB-126, and PCB-153 exceeded their calculated EGFR inhibition IC50 values.

Conclusions:

• EGFR inhibition represents a common mechanism of action for various metabolic disrupting chemicals, including PCBs, pesticides, and herbicides.
• EGFR inhibition is an environmentally relevant mode of action for certain pollutants.
• The findings highlight EGFR as a critical target for assessing the risks of chemical pollutants.