ABSTRACT: Lifelong Triclosan Exposure and Fatty Liver Disease.
The rising prevalence of toxicant-associated steatohepatitis (TASH) and Nonalcoholic steatohepatitis
(NASH) – pathological conditions advanced from steatosis and characterized by inflammatory cell infiltration with
the potential progression to fibrosis, cirrhosis, and cancer-associated with an epidemic of advanced liver disease
mirrors increases in environmental toxicant exposure and obesity. Triclosan (TCS), first invented in the early
1970s to be employed as an antiseptic and disinfectant in the healthcare industry, has been widely used in the
U.S. and globally for more than 40 years. TCS now comes into direct contact with humans in household settings
through many 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 that has been associated with numerous health concerns. While we have
previously demonstrated that TCS enhances oxidative stress, compensatory hepatocyte proliferation, and liver
fibrosis and promotes liver tumorigenesis in mice, how these events contribute to liver pathogenesis and the
regulatory mechanisms by which TCS exerts its toxicity, especially in the early stage of liver disease, are still
largely unexplored. Because TCS has been detected in pregnant women, in breast milk, and young and old
adults, there is a rising concern that TCS can exist as a lifelong toxicant in humans, potentially inducing the early
onset of toxicity in young children. We demonstrate in preliminary findings that when TCS is made available in
normal chow to female and male mating mice, TCS accumulates in milk and can be transferred through lactation
to nursing newborns. By 14 to 21 days after birth, there are early signs of accelerated lipid accumulation in
hepatocytes, indicating that TCS is inducing TASH. Using a type I diabetic adult animal model in which mice
receive streptozotocin (STZ), an agent damaging islet ß cells, followed by a high-fat diet (STZ-HFD model), we
further demonstrated that TCS promotes expediting the development of steatohepatitis. Preliminary results show
that TCS activates ATF4 and Nrf2, both being endoplasmic reticulum (ER) stress-inducible transcription factors
that are jointly regulated by ER kinase PERK. Based upon our preliminary results confirming 1) TCS exposure
to newborns and 2), TCS activation of ER stress in our adult STZ-HFD model, we are proposing to leverage
these findings into a single model that will result in lifelong (newborns – adult) TCS exposure. In young adult
mice, we will examine a) the ability of TCS to activate PERK signaling that is capable of inhibiting global
translation and preferentially promoting translation of a subset of transcripts, including ATF4, by polysomal
profiling and RNA-seq analysis of total RNA and polysomal RNA, and b) the precise role of ATF4 and Nrf2 in
controlling lipid metabolism, regulating their downstream target genes that provide antioxidant defense capacity,
and impacting the TCS induced TASH disease state by using liver-specific Atf4 and Nrf2 conditional knockout
mice.