Effects of early life Triclosan exposure through lactation on the gut-liver axis and its implications in the development of steatotic liver disease in adults - Metabolic dysfunction-associated steatotic liver disease (MASLD), encompassing adult and pediatric steatohepatitis (MASH), represents a burgeoning public health challenge linked to nutritional imbalances. However, the escalating prevalence of MASLD cannot be attributed solely to diet and obesity. Our research has unveiled that specific environmental toxicants synergize with high-fat diets (HFD) to expedite MASH progression in mice, leading us to hypothesize that exposure to unidentified environmental pollutants during early life may predispose individuals to early-onset MASLD/MASH. One likely suspect is triclosan (TCS), a pervasive antiseptic and disinfectant that humans encounter through an array of consumer products and environmental sources. TCS has been detected in the plasma of adolescents, pregnant women, and breast milk. Exposing obese or diabetic adult mice to TCS concentrations mirroring human exposure triggers characteristic signs of MASLD-related toxicant-associated steatotic liver disease (TASLD) and steatohepatitis (TASH), including steatosis, hepatocyte damage, inflammatory infiltrates, and liver fibrosis. TCS enhances HFD-induced MASLD by suppressing the expression of fibroblast growth factor 21 (FGF21), thereby leading to abnormal expression of enzymes associated with amino acid and fatty acid synthesis. Given the evidence of TCS accumulation in breast milk, we conducted experiments involving mating mice exposed to dietary TCS, which resulted in efficient lactational TCS transmission to newborn pups. This induced rapid onset hepatosteatosis, endoplasmic reticulum (ER) stress, inflammation, and fibrosis, all mechanistically linked to elevated expression of transcription factors ATF4 and PPARα. Lactational TCS exposure also led to intestinal barrier disruption, akin to the pathology observed in mice fed high fructose (HF) diets. In conjunction with hepatic ER stress, this disruption led to MASH development. Notably, targeted activation of barrier-protective STAT3 and YAP signaling in enterocytes mitigated lactational TCS-induced liver pathologies. These findings bear clinical significance, because children and adolescents are primary consumers of fructose-enriched, energy-dense diets and are subject to both lactational and environmental TCS exposure. To explore the pathogenic potential of this combination, we will employ mouse models in this MPI application, combining Dr. Tukey’s expertise in TCS-driven MASLD/TASLD with Dr. Karin’s expertise in studying the impact of fructose and energy-dense diets on MASLD/MASH and barrier integrity. We aim to investigate the mechanisms by which lactational TCS heightens the risk and severity of HFHFD-induced liver disease, with a focus on the role of ER stress effectors PERK and ATF4, along with the identification of the cell types in which they operate. Additionally, we will examine the protective roles of FGF21 and the barrier- fortifying cytokine IL-22, primarily active in enterocytes, as well as the hypothesis that lactational TCS exposure establishes an epigenetic memory that accelerates TASLD progression to MASH in later life. This project will yield novel mechanistic insights into early-life toxicant exposure.
