Polybrominated diphenyl ether flame retardants inhibit growth factor-induced activation of EGFR by binding to its extracellular domain

Abstract

For many years, polybrominated diphenyl ethers (PBDEs) were used as flame retardants in a large number of consumer products. Even though international law meanwhile prohibits the production and usage of PBDEs, these persistent and bioaccumulative chemicals still leak into the environment, and are frequently detected in wildlife and humans. Population-based studies reveal positive correlations between human PBDE exposure and various adverse health effects, emphasizing that a better understanding of the mode of action of these polybrominated chemicals is urgently needed. Therefore, we investigated the effect of two widespread PBDEs, namely BDE-47 and BDE-99, on epidermal growth factor receptor (EGFR) activity in human cells. Recent studies showed that the EGFR is not only orchestrating cellular functions, but also serves as a cell-surface receptor for dioxins, phenolic benzotriazoles and related organic pollutants. Results from in silico docking analyses, AlphaLISA-based receptor binding studies and SDS-PAGE/Western blot analyses revealed that BDE-47 and BDE-99 inhibit the growth factor-triggered activation of EGFR by binding to its extracellular domain. In keratinocytes, PBDEs also inhibit amphiregulin-induced and EGFR-mediated DNA synthesis as well as the EGFR-triggered trans-repression of the aryl hydrocarbon receptor signaling pathway. Our data identify EGFR as a cell-surface receptor for PBDEs and shed light on a novel mode of action of these ubiquitous and persistent chemicals. This finding may contribute to an improved hazard assessment of PBDEs and structurally related flame retardants.