Superfund Research Program
Molecular and Microbial Mechanisms Leading to Triclosan Induced Liver Fibrosis
Project Leader: Robert H. Tukey
Grant Number: P42ES010337
Funding Period: 2017-2022
Project Summary (2017-2022)
Triclosan (TCS) is a synthetic antimicrobial agent that has been widely used in the U.S. and globally for more than 40 years. First invented in the early 1970s to be employed as an antiseptic and disinfectant in healthcare environments, TCS now comes into direct contact with humans in household settings through a large number of consumer products ranging from personal care products to food packaging materials. Consequently, its rising environmental release causes serious contamination in the environment, and it is now known as an Emerging Contaminant (EC) - a detectable but currently unregulated and frequently untreated environmental contaminant.
While there have been numerous health concerns associated with TCS, this project's recent findings provide compelling evidence that long-term TCS exposure promotes liver carcinogenesis in mice. Using a carcinogen-induced animal model, the project researchers demonstrate that TCS causes toxicant-associated steatohepatitis (TASH) manifested by hepatic steatosis, inflammatory cell infiltration, and liver fibrosis, resulting in enhanced hepatocellular carcinoma (HCC). Similar to TCS, obesity and metabolic syndrome are also major etiologic factors causing steatohepatitis, termed nonalcoholic steatohepatitis (NASH).
The rising prevalence of TASH and NASH – mirroring the increase in environmental toxicant exposure and obesity – is tightly linked to a growing epidemic of advanced liver disease. Recent animal studies have revealed that the disrupted gut microbiota (dysbiosis) plays a causative role in the pathogenesis of TASH and NASH, and patients with several types of chronic liver diseases show impairment of the gut microflora and intestinal barrier, highlighting a primary etiologic role of intestinal dysbiosis in liver disease.
To explore the pathogenic mechanism underlying TCS-induced TASH, project researchers hypothesize that "persistent TCS exposure causes a structurally disrupted intestinal microbiota that is a driving force of TASH development, and chronic overnutrition by a high-fat diet (HFD) is synergistic with TCS-induced TASH, leading to end-stage liver disease and HCC." The researchers propose to examine the following aims:
- They will identify the gut microbiota composition following long-term TCS exposure using 16S rRNA sequencing and metatranscriptomics. They will also employ germ-free (GF) and humanized NASH mice to determine the role of gut flora in TCS-induced liver disease.
- The researchers will investigate regulatory roles of toll-like receptor (TLR) signaling in intestinal permeability and tight junctions responding to TCS treatment. They have rationalized that, reacting to TCS toxic insult, gut microbes releasing bacterial products and metabolites activate TLR signaling and initiate innate immune responses, stimulating profibrogenic and proinflammatory events in the liver. These experiments will use Myd88 liver conditional knockout mice to compare TCS and CCl4-induced liver toxicity.
- The researchers will evaluate whether TCS combined with a HFD confers greater susceptibility to the progression of TASH into tumorigenesis by using a diabetes animal model that displays signs of NASH following a HFD feeding. They postulate that autophagy status and IL-17A signaling underlines enhanced induction of HCC by TCS together with HFD.