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 ? 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.