Lifelong Triclosan Exposure and Fatty Liver Disease

终生接触三氯生与脂肪肝

• 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
• 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

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。 毒物相关性脂肪性肝炎 (TASH) 和非酒精性脂肪性肝炎的患病率不断上升 (NASH) – 由脂肪变性发展而来的病理状况，其特征是炎症细胞浸润 与晚期肝病流行相关的潜在进展为纤维化、肝硬化和癌症 反映了环境毒物暴露和肥胖的增加。三氯生（TCS），早年首次发明 20世纪70年代被用作医疗保健行业的防腐剂和消毒剂，已广泛应用于 在美国和全球已有 40 多年的历史。 TCS 现在可以在家庭环境中与人类直接接触 涵盖从个人护理产品到食品包装材料等多种消费品。 因此，其不断增加的环境排放量对环境造成严重污染，目前已 被称为一种新兴污染物，与许多健康问题有关。虽然我们有 先前证明TCS可增强氧化应激、代偿性肝细胞增殖和肝脏功能 纤维化并促进小鼠肝脏肿瘤发生，这些事件如何促进肝脏发病机制以及 TCS发挥毒性作用的调节机制，特别是在肝病早期阶段，仍不清楚 很大程度上尚未探索。因为 TCS 已在孕妇、母乳以及年轻人和老年人中检测到 对于成年人来说，人们越来越担心 TCS 可能作为人类的终生毒物存在，可能会导致早期 幼儿出现毒性反应。我们在初步调查结果中证明，当 TCS 可用时 雌性和雄性交配小鼠的正常饮食中，TCS 会积聚在乳汁中，并可通过哺乳期转移 给哺乳新生儿。出生后14至21天，体内脂质加速积累的早期迹象 肝细胞，表明 TCS 正在诱导 TASH。使用 I 型糖尿病成年动物模型，其中小鼠 接受链脲佐菌素 (STZ)（一种破坏胰岛 β 细胞的药物），然后接受高脂肪饮食（STZ-HFD 模型），我们 进一步证明TCS促进脂肪性肝炎的加速发展。初步结果显示 TCS 激活 ATF4 和 Nrf2，两者都是内质网 (ER) 应激诱导转录因子 均受 ER 激酶 PERK 共同调控。根据我们确认的初步结果 1) TCS 暴露 2) 在我们的成人 STZ-HFD 模型中，TCS 激活 ER 应激，我们建议利用 将这些发现整合到一个单一模型中，该模型将导致终生（新生儿 - 成人）接触 TCS。在年轻成人中 小鼠，我们将检查 a) TCS 激活 PERK 信号传导的能力，该信号传导能够抑制全局 翻译并优先促进转录子子集的翻译，包括 ATF4，通过多聚体 总 RNA 和多核糖体 RNA 的分析和 RNA-seq 分析，以及 b) ATF4 和 Nrf2 在 控制脂质代谢，调节提供抗氧化防御能力的下游靶基因， 并通过使用肝脏特异性 Atf4 和 Nrf2 条件敲除来影响 TCS 诱导的 TASH 疾病状态 老鼠。