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

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 alpha and gamma (ERR alpha and ERR gamma) pathways. By the competitive binding assay, we first found that BUVSs bond to ERR gamma ligand binding domain (ERR gamma-LBD) with K-d ranging from 0.66 to 19.27 mu M. According to the results of reporter gene assays, the transcriptional activities of ERR alpha and ERR gamma 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 mu M, most tested BUVSs showed higher agonistic activity toward ERR gamma than ERR alpha. The most effective two BUVSs promoted the MCF-7 proliferation dependent on ERR alpha and ERR gamma with a LOEC of 100 nM. The molecular dynamics simulation showed that most studied BUVSs had lower binding free energy with ERR gamma than with ERR alpha. 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 ERR gamma. Overall, our results provide novel insights into the estrogenic disruption effects of BUVSs.