Mechanism of liver fibrosis induced by life-long triclosan exposure in offspring rats: an adverse outcome pathway framework validated by in vivo and in vitro experiments

Triclosan (TCS), a broad-spectrum lipophilic antiseptic, is frequently found in household and healthcare supplies. Its increased use during the COVID-19 pandemic has led to significant accumulation in soil and aquatic environments. In humans, TCS predominantly accumulates in the liver, while little is known about the molecular processes promoting TCS-induced hepatic damage. Adverse outcome pathways (AOPs) offer a structured toxicological framework linking molecular initiating events to adverse health outcomes. To examine how TCS exposure relates to liver fibrosis, we developed an AOP framework and established an offspring rat model subjected to lifelong TCS exposure. Through the milk and placenta, the offspring rats were exposed to TCS. After weaning, they received 0, 10, and 50 mg/kg doses until day 60. Our findings indicate that lifelong TCS exposure increased hepatic transforming growth factor-β (TGF-β1) levels and then modulates the advanced glycation end products (AGEs) and their receptor (RAGE) pathway (AGEs-RAGE pathway) to promote Collagen production, causing extracellular matrix deposition and hepatic fibrosis. The reliability of the AOP framework was validated by the significant decrease in the markers linked to fibrosis-related expression following this two-part inhibition. This framework received a "high" rating based on the Organization for Economic Cooperation and Development (OECD User Manual) assessment guidelines, by integrating this framework with in vitro and in vivo experiments. These findings offer a basis for future risk assessment and therapeutic strategies targeting TCS-induced liver fibrosis.

AGEs-RAGE signaling pathway; Adverse outcome pathways; Liver fibrosis; TGF-β1; Toxicological mechanisms; Triclosan.