Antimicrobial Triclocarban Exhibits Higher Agonistic Activity on Estrogen-Related Receptor γ than Triclosan at Human Exposure Levels: A Novel Estrogenic Disruption Mechanism

Abstract

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 γ (ERRγ) at human exposure levels. The fluorescence competitive binding assay showed that TCC had approximately 9-fold higher binding affinity with ERRγ than TCS. TCS and TCC demonstrated higher binding potency with ERRγ than a synthetic ERRγ 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 ERRγ, with the lowest observed effective concentration of 100 and 10 nM, respectively. Molecular docking showed that TCS and TCC tended to present an ERRγ 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.