Triclosan Induces Hepatotoxicity Through Disrupting Iron Metabolism And Bile Acid Metabolism

Triclonsan（TCS）is a broad-spectrum antimicrobial agent synthesized in the 1960s and is widely used in soaps,toothpastes,toys,cosmetics and mouthwashes because of its antiseptic and antibacterial properties.With the widespread use of personal care products,humans are inevitably exposed to TCS through oral intake and skin contact,etc.Because of its hydrophobic characteristic,TCS is not only difficult to remove in wastewater treatment processes,causing serious environmental pollution in water bodies,but also easily accumulates in the fatty tissues of living organisms.The presence of TCS has been reported to be detected in samples of human umbilical cord blood,breast milk,hair and urine.Liver is an important organ for metabolism and detoxification of the organism and is also the main target organ after TCS exposure.C urrent studies have shown that TCS exposure can trigger liver damage and even the development of fibrosis in different organisms,but the understanding of the mechanism of toxicity is still insufficient.Recent studies have shown that iron metabolism and ferroptosis play an important role in the fibrosis process of liver diseases.Firstly,in this paper,we intend to explore the relationship between TCS-induced fibrosis and iron metabolism from the perspective of iron content changes,so as to elucidate the toxic mechanism of TCS-induced fibrosis.Secondly,we intend to explore the toxic mechanism of TCS-induced liver injury from the perspective of bile acid metabolism from the effect of TCS-induced hepatotoxicity.From the perspective of environmental protection and health effects,this study will help people to broaden the theoretical mechanism of TCS-induced toxicity in organisms and promote the development of TCS pollution protection.In the first part of this study,we firstly found that liver tissue of mice gradually showed significant apoptosis,inflammatory effects,liver parenchymal injury,liver dysfunction and fibrosis after 4,8 and 12 weeks of continuous TCS exposure.Secondly,we also found that TCS-induced liver injury was positively correlated with hepatic iron content and was accompanied by increased intrahepatic malondialdehyde（MDA）content,as well as ferroptosis phenomena such as down-regulation of Gpx4 gene expression and up-regulation of Ptgs2 gene expression.Again,we found that TCS exposure in mice triggered iron deposition in the spleen and small intestine,and was accompanied by systemic iron disorders such as decreased serum iron levels.Furthermore,we found that TCS-exposed mice triggered an inflammatory response by studying the pathways involved in the regulation of systemic iron metabolism,which led to the upregulation of the inflammatory factor IL-6,resulting in the upregulation of Hepcidin expression and ultimately hepatic iron overload.Finally,an interventional study with the iron overload treated drug Ferriprox^?（DFP）revealed that DFP treatment significantly improved hepatic iron overload and its liver fibrosis symptoms in TCS-exposed mice.In the second part of the study,firstly,we observed different doses of TCS adminstration in mice triggered inflammatory response,and apoptosis and fibrosis in liver.Secondly,we found upregulation of serum ALP,DBIL and TBA content,and increasing of hepatic TBA level which points to intrahepatic cholestasis.Thildly,we discoverved that TCS adminstration mainly promoted the expression of Cyp7A1 which is rate-limiting enzyme for bile acid synthesis in the traditional pathway.We also observed that TCS adminstration enhanced the bile acids shifting into the liver and inhibited its exportation from the liver to the biliary tract and blood.Furthermore,we discovered that TCS adminstration in mice reduced the expression of Fxr,a regulator of bile acid synthesis and transportation.Finally,we found that TCS triggered the upregulation of IL-1β in the liver of mice,which prompted the activation of intrahepatic NF-κB signaling pathway.In summary,this study found that TCS admintration in mice caused hepatic iron accumulation and ferroptosis in liver through inflammatory-regulated hepcidin pathway and eventually led to hepatcotoxicity including liver fibrosis and abnormal liver function;On the other hand,it caused hepatotoxic phenomena such as intrahepatic cholestasis through the activation of intrahepatocellular NF-κB-Fxr signaling pathway regulating intrahepatic bile acid synthesis and transportation.This study will broaden the new ideas to understand hepatotoxic effects and the molecular mechanim induced by TCS.