College of Eco-Environmental Engineering, Guizhou Minzu University, Guiyang 550025, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
College of Eco-Environmental Engineering, Guizhou Minzu University, Guiyang 550025, China.
Ecotoxicol Environ Saf. 2024 Oct 1;284:116989. doi: 10.1016/j.ecoenv.2024.116989. Epub 2024 Sep 10.
Triclosan (TCS) is an eminent antibacterial agent. However, extensive usage causes potential health risks like hepatotoxicity, intestinal damage, kidney injury, etc. Existing studies suggested that TCS would disrupt bile acid (BA) enterohepatic circulation, but its toxic mechanism remains unclear. Hence, the current study established an 8-week TCS exposure model to explore its potential toxic mechanism. The results discovered 8 weeks consecutive administration of TCS induced distinct programmed cell death, inflammatory cell activation and recruitment, and excessive BA accumulation in liver. Furthermore, the expression of BA synthesis and transport associated genes were significantly dysregulated upon TCS treatment. Additional mechanism exploration revealed that Fxr inhibition induced by TCS would be the leading cause for unusual BA biosynthesis and transport. Subsequent Fxr up-stream investigation uncovered TCS exposure caused pyroptosis and its associated IL-1β would be the reason for Fxr reduction mediated by NF-κB. NF-κB blocking by dimethylaminoparthenolide ameliorated TCS induced BA disorder which confirmed the contribution of NF-κB in Fxr repression. To sum up, our findings conclud TCS-caused BA disorder is attributed to Fxr inhibition, which is regulated by the IL-1β-NF-κB signaling pathway. Hence, we suggest Fxr would be a potential target for abnormal BA stimulated by TCS and its analogs.
三氯生（TCS）是一种卓越的抗菌剂。然而，广泛使用会导致潜在的健康风险，如肝毒性、肠道损伤、肾损伤等。现有研究表明，TCS 会破坏胆汁酸（BA）的肠肝循环，但其毒性机制尚不清楚。因此，本研究建立了 8 周 TCS 暴露模型，以探讨其潜在的毒性机制。结果发现，连续 8 周给予 TCS 会导致明显的细胞程序性死亡、炎症细胞激活和募集，以及肝脏中 BA 过度积累。此外，TCS 处理后，BA 合成和转运相关基因的表达明显失调。进一步的机制探索表明，TCS 诱导的 Fxr 抑制是异常 BA 合成和转运的主要原因。随后对 Fxr 上游的研究发现，TCS 暴露引起的细胞焦亡及其相关的 IL-1β 是 NF-κB 介导的 Fxr 减少的原因。二甲氨基丙烯酰胺抑制 NF-κB 可改善 TCS 诱导的 BA 紊乱，证实了 NF-κB 在 Fxr 抑制中的作用。总之，我们的研究结果表明，TCS 引起的 BA 紊乱归因于 Fxr 抑制，这是由 IL-1β-NF-κB 信号通路调节的。因此，我们建议 Fxr 可能是 TCS 及其类似物刺激异常 BA 的潜在靶点。
