Benzotriazole
Ultraviolet Stabilizers Promote Breast
Cancer Cell Proliferation via Activating Estrogen-Related Receptors
α and γ at Human-Relevant Levels
posted on 2022-01-31, 19:41authored bySen He, Han Xiao, Shuang Luo, Xin Li, Jia-Da Zhang, Xiao-Min Ren, Yuan Yang, Xian-De Xie, Yao-Yu Zhou, Yu-Long Yin, Lin Luo, Lin-Ying Cao
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.