The antimicrobial triclosan is a potent liver tumor promoter

描述（由申请人提供）：三氯生（TCS）是一种常用的抗菌剂，用于个人护理产品和许多消费品。由于TCS在众多日常护理产品、水道和环境样本中普遍存在，公众暴露于TCS。事实证明，TCS已经在人类血浆、母乳和体液中被检测到，而且大量美国人口（74.6%）在他们的尿液中检测到TCS水平。虽然它在结构上与其他受到严格管制的环境化学品相似，但TCS监管不力，通常被认为是安全的。研究越来越多地将TCS与一系列健康和环境影响联系起来；然而，没有相关动物模型的基于机制的研究直接将TCS暴露与人类的负面健康影响联系起来。长期暴露于TCS后，小鼠表现出代偿性肝细胞增殖和纤维化，并伴有氧化应激。利用致癌物二乙基亚硝胺在小鼠中启动肿瘤发生，我们进一步证明了TCS作为一种有效的肝脏肿瘤促进剂，加速了肝细胞癌（HCC）的发展。与对照组小鼠相比，tcs治疗小鼠的肿瘤多样性、大小和发生率均有显著增加。TCS治疗后ALT水平升高、组织学改变和严重的炎症反应表明，TCS是导致肝损伤的原因，导致肝完整性和功能破坏。tcs处理肝脏的另一个突出特征是显著诱导toll样受体（TLRs） 2和4，这是先天免疫系统的关键分子。tlr作为病原体的传感器，作为抵御入侵微生物的第一道防线，检测保守的微生物成分。已知肠道细菌成分可引起肝脏疾病；越来越多的证据表明，TLR2和TLR4与肠道微生物群驱动的肝脏肿瘤发生密切相关。因此，我们假设，通过破坏肠道菌群的稳态，将细菌成分释放到门静脉，抗菌TCS激活TLR信号，肝脏通过纤维化、炎症和随后的肿瘤发生慢性恶化。我们将在Tlr2-/ tlr4杂合或无基因小鼠中研究将TLRs与tcs诱导的肝脏发病联系起来的生化和细胞事件以及肠道菌群的组成（目的1）。TCS诱导HCC生长的进展在很大程度上仍是未知的。由于TCS治疗的小鼠表现出脂肪性肝病（NAFLD）样特征，因此我们建议通过使用动物模型来研究TCS对NAFLD进展为脂肪变性和HCC的影响，在这种动物模型中，转基因小鼠单独的高脂肪饮食可导致HCC的发展。假设这些小鼠在TCS动物中会更快地发展为肝癌，这表明肥胖相关的脂肪生成变化与TCS介导的肝细胞损伤和纤维化之间存在肿瘤形成的协同作用（Aim 2）。来自这些研究的发现将提供一个新的机会来说明TCS可能引起的人类健康并发症。

DESCRIPTION (provided by applicant): Triclosan (TCS) is a common antibacterial agent used in personal care products and many consumer products. The public is exposed to TCS as a result of its prevalence in a multitude of daily care products, waterways, and environmental samples. This is evidenced by the fact that TCS has been detected in human plasma, breast milk, and body fluids, and a large U.S. population (74.6%) had detectable TCS levels in their urine. Although it is structurally similar to other highly-regulated environmental chemicals, TCS is poorly regulated and is generally accepted as safe. Studies have increasingly linked TCS to a range of health and environmental effects; however, there are no mechanism-based studies with relevant animal models that directly link TCS exposure to negative health effects in humans. Following long-term TCS exposure, mice exhibited compensatory hepatocyte proliferation and fibrogenesis, which are accompanied by oxidative stress. Using the procarcinogen diethylnitrosamine to initiate tumorigenesis in mice, we further demonstrated that TCS, as a potent liver tumor promoter, accelerates hepatocellular carcinoma (HCC) development. TCS-treated mice exhibited a large increase in tumor multiplicity, size, and incidence compared to control mice. Increased ALT levels, histological alterations, and profound inflammatory responses following TCS treatment suggest that TCS is responsible for liver injury that leads to disrupted liver integrity and function. Another prominent feature of the TCS-treated livers is significant induction of Toll-like receptors (TLRs) 2 and 4, key molecules in the innate immunity system. Acting as sensors for pathogens, TLRs as a first-line defense against invading microorganisms detect conserved microbial components. Intestinal bacterial components are known to cause liver diseases; an emerging body of evidence also indicates that both TLR2 and TLR4 are closely linked with gut microbiota-driven liver tumorigenesis. Thus, we hypothesize that by disrupting the homeostasis of gut flora that release bacterial components into the portal vein, antibacterial TCS activates the TLR signaling through which the liver chronically deteriorates by undergoing fibrosis, inflammation, and subsequent tumorigenesis. We will examine the biochemical and cellular events as well as the composition of enteric microflora that link TLRs to TCS-induced liver pathogenesis in mice that are Tlr2-/Tlr4-heterozygous or null mice (Aim 1). The progression of HCC growth induced by TCS is still largely unknown. Since TCS-treated mice exhibited fatty liver disease (NAFLD)-like features, we therefore propose examining the effect of TCS on NAFLD progression to steatosis and to HCC by using an animal model in which high-fat diet alone in genetically modified mice can lead to the development of HCC. The hypothesis is that these mice will develop liver cancer more rapidly in animals with TCS, pointing to a synergy in tumor formation between obesity-related changes in lipogenesis and TCS-mediated hepatocellular damage and fibrosis (Aim 2). The findings originating from these studies will provide a novel opportunity to illustrate the human health complications that TCS may elicit.