Antimicrobial Triclocarban Exhibits Higher Agonistic Activity on Estrogen-Related Receptor γ than Triclosan at Human Exposure Levels: A Novel Estrogenic Disruption Mechanism
Antimicrobial Triclocarban Exhibits Higher Agonistic Activity on Estrogen-Related Receptor γ than Triclosan at Human Exposure Levels: A Novel Estrogenic Disruption Mechanism
复制标题
在人体暴露水平下，抗菌剂三氯卡班对雌激素相关受体 γ 表现出比三氯生更高的激动活性：一种新的雌激素干扰机制
DOI：
10.1021/acs.estlett.0c00338
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发表时间：
2020-06-09
影响因子：
10.9
通讯作者：
Luo, Lin
中科院分区：
文献类型：
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作者：
Cao, Lin-Ying;Xu, Yun-Hao;Luo, Lin
三氯生(TCS)和三氯卡班(TCC)是两种广泛使用的抗菌剂，已被报道为雌激素干扰物。以往的研究表明，TCC和TCS对经典雌激素受体表现出微弱的或没有激动性的活性。在目前的研究中，我们首先证明了TCS和TCC通过雌激素相关受体伽马(ERR伽马)在人类暴露水平上扰乱雌激素系统。荧光竞争结合分析表明，TCC与ERR-γ的结合亲和力比TCS高约9倍。与ERRγ激动剂GSK4716相比，TCS和TCC与ERRY的结合能力更强，解离常数分别为886+/-141和96+/-10 nM。通过报告基因实验，我们发现TCS和TCC对ERR-γ具有激活活性，最低观察到的有效浓度分别为100和10 nM。分子对接表明，TCS和TCC倾向于呈现Err-Gamma激动型结合模式，TCC表现出比TCS更低的结合能，为我们的实验观察提供了良好的理论解释。我们的结果揭示了TCS和TCC类雌激素破坏的新机制，表明TCC具有更高的活性，值得在未来的研究中给予更多的关注。
Triclosan (TCS) and triclocarban (TCC) are two widely used antimicrobial agents that have been reported to be estrogenic disruptors. Previous researches have shown that TCC and TCS exhibit weak or no agonistic activity on classical estrogen receptors. We demonstrate first in the present study that TCS and TCC disrupt the estrogen system via the estrogen-related receptor gamma (ERR gamma) at human exposure levels. The fluorescence competitive binding assay showed that TCC had approximately 9-fold higher binding affinity with ERR gamma than TCS. TCS and TCC demonstrated higher binding potency with ERRy than a synthetic ERR gamma agonist GSK4716, with a dissociation constant of 886 +/- 141 and 96 +/- 10 nM, respectively. By using the reporter gene assay, we found that TCS and TCC exerted agonistic activity toward ERR gamma, with the lowest observed effective concentration of 100 and 10 nM, respectively. Molecular docking showed that TCS and TCC tended to present an ERR gamma agonistic binding mode, and TCC exhibited lower binding energy than TCS, which provided a good theoretical explanation for our experimental observations. Our results revealed a novel mechanism for the estrogenic disruption of TCS and TCC, demonstrating that TCC deserves more attention in future research due to its higher activity.