Hydroxylated Polybrominated Biphenyl Ethers Exert Estrogenic Effects via Non-Genomic G Protein–Coupled Estrogen Receptor Mediated Pathways

Abstract

Background:Numerous studies have indicated the estrogenic effects of polybrominated diphenyl ethers (PBDEs) and hydroxylated PBDEs (OH-PBDEs). However, the previous mechanistic studies focused on their estrogenic effects through genomic transcriptional activation of estrogen receptors.Objective:The present study aimed to investigate the estrogenic effects of PBDEs and OH-PBDEs via nongenomic G protein–coupled estrogen receptor (GPER) pathways.Methods:The binding affinities of 12 PBDEs and 18 OH-PBDEs with GPER were determined by a fluorescence competitive binding assay in a human breast cancer cell line (SKBR3). Molecular docking was performed to simulate the interactions. Their activities on GPER pathways were investigated by detecting calcium mobilization and cyclic adenosine monophosphate (cAMP) accumulation in SKBR3 cells. The effects on SKBR3 cell migration were investigated using Boyden chamber and wound-healing assays.Results:Our results showed that 11 of the OH-PBDEs but none of the PBDEs bound to GPER directly. Relative binding affinities ranged from 1.3% to 20.0% compared to 17β-estradiol. Docking results suggested that the hydroxyl group played an essential role in the binding of OH-PBDEs to GPER by forming hydrogen bond interactions. Most of the OH-PBDEs activated subsequent GPER signaling pathways. Among them, 4ʹ-OH-BDE-049, 5ʹ-OH-BDE-099, and 3ʹ-OH-BDE-154 displayed the highest activity with lowest effective concentrations (LOECs) of 10–100 nM. These three OH-PBDEs also promoted SKBR3 cell migration via GPER pathways with LOECs of 0.1–1μM.Conclusion:OH-PBDEs could bind to GPER, activate the subsequent signaling pathways, and promote SKBR3 cell migration via GPER pathways. OH-PBDEs might exert estrogenic effects by a novel nongenomic mechanism involving the activation of GPER at nanomolar concentrations. https://doi.org/10.1289/EHP2387

G Protein-Coupled Estrogen Receptor, GPER1, Offers a Novel Target for the Treatment of Digestive Diseases

“…In addition to antiestrogens, various nonselective GPER1 agonists have been identified: these include natural products like hydroxytyrosol and oleuropein, as well as phytoestrogens, such as coumestrol, and the endocrine-disrupting compounds Bisphenol A (BPA) ( Figure 2) (20-22). Additional studies have identified synthetic polybrominated diphenyl ethers (PBDEs) and hydroxylated PBDEs as potential GPER1 ligands; however, these compounds likely exhibit no selective activity (23).…”

Plasma concentration of brominated flame retardants and postmenopausal breast cancer risk: a nested case-control study in the French E3N cohort

“…Nonetheless, the systematic comparison between models with lipid-adjusted and wet-basis biomarkers did not yield substantial modifications of risk estimates, thus ruling out more complex underlying associations. We used the parent forms of PBDEs as biomarkers of internal exposure, while little is known about the potential adverse health effects of their hydroxylated forms as products of biotransformation metabolism, which have shown exert estrogenic effects [37]. Thus, one hypothesis to be deeper investigated for explaining the observed reverse associations would be the potential protective effect of adipose tissue by sequestrating the parent compounds and more biologically active hydroxylated metabolites, preventing the release into circulation and thus the exposure of carcinogenic cells [38].…”

Exploring the Biological Activity and Mechanism of Xenoestrogens and Phytoestrogens in Cancers: Emerging Methods and Concepts

“…PBDEs are used as flame retardants, electrical equipment coating, construction materials, textiles, and furniture padding [39,40]. PBDEs encompass a large umbrella of compounds that have a relative binding affinity range of 1.3-20 to ERs [41].…”