Lifelong Triclosan Exposure and Fatty Liver Disease

摘要：三氯生终生暴露与脂肪肝 中毒物相关性脂肪性肝炎(TASH)和非酒精性脂肪性肝炎患病率上升 (NASH)-脂肪变性进展的病理条件，以炎性细胞浸润为特征 与晚期肝病流行相关的肝纤维化、肝硬变和癌症的潜在进展 反映了环境毒物暴露和肥胖的增加。三氯生(TCS)，最早发明于 20世纪70年代被用作医疗行业的防腐剂和消毒剂，已被广泛用于 在美国和全球都有40多年的历史。TCS现在可以在家庭环境中与人类直接接触 通过许多消费品，从个人护理产品到食品包装材料。 因此，其日益增长的环境排放导致了环境的严重污染，现在正在 被称为一种新出现的污染物，与许多健康问题有关。当我们有了 先前证明，天花粉蛋白可增强氧化应激、代偿性肝细胞增殖和肝脏 纤维化和促进小鼠肝肿瘤的发生，这些事件如何在肝脏发病机制和 TCS发挥毒性的调节机制，特别是在肝病的早期阶段，仍然是 很大程度上是未被开发的。因为在孕妇、母乳、年轻人和老年人中都检测到了TCS 对于成年人来说，人们越来越担心TCS可能会作为一种终生毒物存在于人类体内，可能会导致早期 在幼儿中出现中毒。我们在初步调查结果中证明，当TCS在 雌性和雄性交配小鼠的正常饮食，TCS在乳汁中积累并可通过哺乳转移 为哺乳新生儿干杯。到出生后14到21天，有早期迹象表明脂肪加速积累。 肝细胞，表明天花粉蛋白可诱导TASH。使用一种I型糖尿病成年动物模型，在该模型中 接受链脲佐菌素(一种破坏胰岛β细胞的试剂)，然后接受高脂饮食(STZ-HFD模型)，我们 进一步证明天花粉蛋白可促进脂肪性肝炎的发展。初步结果显示 TCS激活ATF4和NRF2，两者都是内质网(ER)应激诱导的转录因子 受ER激酶PERK共同调控。根据我们确认1)接触TCS的初步结果 对于新生儿和2)，在我们的成人STZ-HFD模型中，TCS激活内质网应激，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。在年轻人中 小鼠，我们将检测a)TCS激活PERK信号的能力，该信号能够抑制全局 翻译并优先促进转录子集的翻译，包括ATF4，由多聚体 总RNA和多体RNA的图谱和RNA-SEQ分析，以及b)ATF4和Nrf2在 控制脂肪代谢，调节其下游提供抗氧化防御能力的靶基因， 肝脏特异性ATF4和Nrf2条件性基因敲除对TCS诱导的Tash病状态的影响 老鼠。

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.