The antimicrobial triclosan is a potent liver tumor promoter

描述（由申请人提供）：三氯生（TCS）是一种常见的抗菌剂，用于个人护理产品和许多消费品。公众暴露于TCS是由于其在众多日常护理产品、水道和环境样本中的流行。这一点可以通过以下事实得到证明：在人血浆、母乳和体液中检测到TCS，并且大量美国人口（74.6%）的尿液中可检测到TCS水平。虽然它在结构上类似于其他高度管制的环境化学品，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，没有基于机制的相关动物模型研究将TCS暴露与人类的负面健康影响直接联系起来。长期接触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。使用原致癌剂二乙基亚硝胺在小鼠中引发肿瘤发生，我们进一步证明TCS作为一种有效的肝肿瘤促进剂，加速肝细胞癌（HCC）的发展。与对照小鼠相比，TCS处理的小鼠表现出肿瘤多样性、大小和发病率的大幅增加。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是导致肝脏完整性和功能破坏的肝损伤的原因。TCS处理的肝脏的另一个突出特征是Toll样受体（TLR）2和4的显著诱导，Toll样受体（TLR）2和4是先天免疫系统中的关键分子。作为病原体的传感器，TLR作为抵抗入侵微生物的第一线防御检测保守的微生物组分。已知肠道细菌成分会导致肝脏疾病;新出现的证据也表明TLR 2和TLR 4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，通过破坏肠道植物群的稳态，将细菌成分释放到门静脉中，抗菌TCS激活TLR信号传导，通过TLR信号传导，肝脏通过经历纤维化、炎症和随后的肿瘤发生而慢性恶化。我们将研究生化和细胞事件以及肠道微生物菌群的组成，这些微生物菌群将TLR与Tlr 2-/Tlr 4-杂合或无效小鼠中TCS诱导的肝脏发病机制联系起来（目的1）。TCS诱导HCC生长的进展在很大程度上仍然未知。由于TCS治疗的小鼠表现出脂肪肝疾病（NAFLD）样特征，因此我们建议使用一种动物模型来检查TCS对NAFLD向脂肪变性和HCC进展的影响，在该动物模型中，仅在转基因小鼠中高脂肪饮食可导致HCC的发展。假设这些小鼠在患有TCS的动物中会更快地发展肝癌，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的肿瘤形成协同作用（目的2）。这些研究的结果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.