Lifelong Triclosan Exposure and Fatty Liver Disease

摘要：三氯生终身暴露与脂肪肝。 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上升 （NASH）-从脂肪变性进展的病理状况，其特征在于炎性细胞浸润， 纤维化、肝硬化和癌症的潜在进展-与晚期肝病的流行相关 反映了环境毒物暴露和肥胖的增加。三氯生（TCS），最初发明于 20世纪70年代被用作医疗保健行业的防腐剂和消毒剂，已广泛用于 美国在全球超过40年。TCS现在在家庭环境中与人类直接接触 通过从个人护理产品到食品包装材料的许多消费品。 因此，其不断增加的环境释放导致环境中的严重污染， 被称为一种新出现的污染物，与许多健康问题有关。虽然我们已经 先前的研究表明，TCS可增强氧化应激、代偿性肝细胞增殖和肝脏 肝纤维化和促进小鼠肝肿瘤发生，这些事件如何有助于肝脏发病机制， TCS发挥其毒性的调节机制，特别是在肝脏疾病的早期阶段，仍然是 大部分未开发。因为TCS已经在孕妇、母乳、年轻人和老年人中被检测到 在成年人中，人们越来越担心TCS可以作为终身毒物存在于人类中， 在幼儿中出现毒性。我们在初步研究结果中证明，当TCS在 正常饲料喂养雌性和雄性交配小鼠时，TCS在乳汁中蓄积，并可通过泌乳转移 护理新生儿。出生后14至21天，有早期迹象表明，加速脂质积累， 肝细胞，表明TCS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，然后高脂饮食（STZ-HFD模型），我们 进一步证明TCS促进加速脂肪性肝炎的发展。初步结果显示 TCS激活ATF 4和Nrf 2，两者都是内质网（ER）应激诱导的转录因子 由ER激酶PERK共同调节。根据我们的初步结果，确认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的模型中，将导致终身（新生儿-成人）TCS暴露。在年轻的成人 在小鼠中，我们将检查a）TCS激活PERK信号传导的能力，所述PERK信号传导能够抑制小鼠的整体免疫应答。 翻译和优先促进转录物子集的翻译，包括ATF 4，通过多聚体， 总RNA和多聚体RNA的谱分析和RNA-seq分析，和B）ATF 4和Nrf 2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Atf 4和Nrf 2条件性敲除来影响TCS诱导的TASH疾病状态 小鼠

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.