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Lifelong Triclosan Exposure and Fatty Liver Disease

终生接触三氯生与脂肪肝

基本信息

批准号：
10192723
负责人：
Robert H Tukey
金额：
$ 19.74万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-16 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10192723
关键词：
Adult Age Animal Experiments Animal Model Anti-Bacterial Agents Antifungal Agents Antioxidants Benign Beta Cell Birth Blood Blood Glucose Cells Chemicals Child Cirrhosis Complex Development Diabetes Mellitus Discipline of Nursing Disease Disease Progression Disinfectants Dissociation Drug Metabolic Detoxication Dyslipidemias Endoplasmic Reticulum Environment Environmental Pollutants Environmental Pollution Epidemic Event Exhibits Exposure to Fatty Liver Fatty acid glycerol esters Female Fibrosis Food Packaging General Population Genes Genetic Transcription Health Healthcare Industry Hepatic Hepatocarcinogenesis Hepatocyte Hepatotoxicity High Fat Diet Homeostasis Household Human Human Milk Industrialization Infiltration Inflammation Inflammatory Insulin Resistance Knockout Mice Lactation Light Link Lipids Liver Liver Fibrosis Liver diseases Local Anti-Infective Agents Malignant Neoplasms Malignant neoplasm of liver Maternal Exposure Metabolic Metabolic syndrome Milk Modeling Molecular Mus Newborn Infant Nuclear Import Obesity Outcome Oxidative Stress Oxidative Stress Induction PERK kinase PF4 Gene Participant Partner in relationship Pathogenesis Pathologic Pathway interactions Pattern Phenols Phosphorylation Polyribosomes Pregnant Women Prevalence Primary carcinoma of the liver cells Process RNA Reactive Oxygen Species Regulation Rogaine Role Serum Severities Signal Transduction Steatohepatitis Streptozocin Stress Toxic Environmental Substances Toxic effect Toxicant exposure Transcript Transcriptional Regulation Translating Translation Initiation Translational Regulation Translations Triclosan Triglycerides Urine antimicrobial drug base biochemical tools biological adaptation to stress carcinogenesis conditional knockout consumer product early onset endoplasmic reticulum stress experimental study glucose metabolism islet lipid metabolism liver cell proliferation liver development male mature animal non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel nutrition packaging material pediatric non-alcoholic fatty liver disease personal care products polysome profiling programs protein folding response toxicant transcription factor transcriptome sequencing type I diabetic young adult

项目摘要

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 β 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.

摘要：终生接触三氯生与脂肪肝的关系。