Benzotriazole Ultraviolet Stabilizers Promote Breast Cancer Cell Proliferation via Activating Estrogen-Related Receptors α and γ at Human-Relevant Levels

Abstract

Benzotriazole ultraviolet stabilizers (BUVSs) are ubiquitous emerging pollutants that have been reported to show estrogenic disruption effects through interaction with the classic estrogen receptors (ERs) in the fashion of low activity. The present study aims at revealing the potential disruption mechanism via estrogen-related receptors α and γ (ERRα and ERRγ) pathways. By the competitive binding assay, we first found that BUVSs bond to ERRγ ligand binding domain (ERRγ-LBD) with Kd ranging from 0.66 to 19.27 μM. According to the results of reporter gene assays, the transcriptional activities of ERRα and ERRγ were promoted by most tested BUVSs with the lowest observed effective concentrations (LOEC) from 10 to 100 nM, which are in the range of human exposure levels. At 1 μM, most tested BUVSs showed higher agonistic activity toward ERRγ than ERRα. The most effective two BUVSs promoted the MCF-7 proliferation dependent on ERRα and ERRγ with a LOEC of 100 nM. The molecular dynamics simulation showed that most studied BUVSs had lower binding free energy with ERRγ than with ERRα. The structure-activity relationship analysis revealed that molecular polarizability, electron-donating ability, ionization potential, and softness were the main structural factors impacting the binding of BUVSs with ERRγ. Overall, our results provide novel insights into the estrogenic disruption effects of BUVSs.