The antimicrobial triclosan is a potent liver tumor promoter

抗菌三氯生是一种有效的肝脏肿瘤促进剂

• 批准号: 8997081
• 负责人: Mei-Fei Yueh
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-21 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8997081
• 关键词: Accounting; Affect; Animal Model; Animals; Anti-Bacterial Agents; Antibiotics; Aromatic Hydrocarbons; Attention; Bacterial Translocation; Biochemical; Biological Assay; Body Fluids; Carcinogens; Caring; Characteristics; Chemicals; Cosmetics; Development; Diethylnitrosamine; Ecosystem; Endocrine disruption; Enteral; Environmental Health; Event; Exhibits; Exposure to; Fatty Liver; Fibrosis; Generations; Growth; Health; Hepatic; Hepatocarcinogenesis; Hepatocellular Damage; Hepatocyte; High Fat Diet; Homeostasis; Human; Human Milk; Immune system; Impairment; Incidence; Inflammation; Inflammatory; Inflammatory Response; Intestines; Invaded; Knockout Mice; Laboratories; Lead; Letters; Light; Link; Liver; Liver Fibrosis; Liver Regeneration; Liver diseases; Liver neoplasms; Malignant neoplasm of liver; Mediating; Molecular; Mus; Muscle Contraction; NADPH Oxidase; Natural Immunity; Nose; Nuclear Receptors; Obesity; Oncogenic; Oral cavity; Oxidative Stress; Pathogenesis; Pathway interactions; Pattern recognition receptor; Peroxisome Proliferation; Peroxisome Proliferator-Activated Receptors; Plasma; Population; Portal vein structure; Predisposition; Prevalence; Primary carcinoma of the liver cells; Probiotics; Protein Isoforms; Receptor Signaling; Regulation; Reporting; Risk; Role; Route; Sampling; Skin; Soaps; Stress; System; TLR2 gene; TLR4 gene; Toll-like receptors; Triclosan; Tumor Promoters; Urine; absorption; antimicrobial; antimicrobial drug; base; consumer product; cytokine; driving force; environmental chemical; feeding; fibrogenesis; gut microbiota; in vivo; lipid biosynthesis; liver cell proliferation; liver function; liver hyperplasia; liver injury; microbial; microorganism; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; pathogen; personal care products; receptor; response; screening; sensor; theories; tool; tumor; tumor growth; tumor progression; tumorigenesis

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.

描述（由申请人提供）：Triclosan（TCS）是个人护理产品和许多消费产品中使用的常见抗菌剂。公众因其在众多日常护理产品，水道和环境样本中的盛行而暴露于TCS。这一事实证明了这一事实是在人血浆，母乳和体液中检测到TCS，并且大量美国人群（74.6％）的尿液中可检测到的TCS水平。尽管它在结构上与其他高度调节的环境化学物质相似，但TC的调节不善，通常被认为是安全的。研究越来越多地将TC与一系列健康和环境影响联系起来。但是，没有针对相关动物模型的基于机制的研究，可以将TCS暴露于人类的负面健康影响。长期TC暴露后，小鼠表现出补偿性肝细胞增殖和纤维发生，并伴有氧化应激。使用procarcinegen二乙基硝基胺启动小鼠肿瘤发生，我们进一步证明，作为有效的肝肿瘤启动子TCS可以加速肝细胞癌（HCC）发育。与对照小鼠相比，经TCS治疗的小鼠的肿瘤多样性，大小和发射率大大增加。 TCS治疗后的ALT水平，组织学改变和深刻的炎症反应表明，TCS导致肝损伤导致肝脏完整性和功能破坏。 TCS处理的肝脏的另一个突出特征是对先天免疫系统中的关键分子的Toll样受体（TLRS）2和4的显着诱导。 TLR充当病原体的传感器，是针对入侵微生物的一线防御，检测保守的微生物成分。已知肠道细菌成分会引起肝病。新兴的证据还表明，TLR2和TLR4都与肠道菌群驱动的肝肿瘤发生密切相关。因此，我们假设通过破坏肠道菌群的稳态来释放细菌成分到门静脉静脉，抗菌TCS激活了TLR信号传导，肝脏通过纤维化，炎症，炎症和随后的肿瘤发生通过肝脏长期恶化。我们将检查将TLR与TCS诱导的肝脏发病机理联系起来的生化和细胞事件以及肠菌群的组成，即TLR2-/TLR4-杂合或无效小鼠（AIM 1）。 TCS诱导的HCC增长的进展仍然很大程度上是未知的。由于TCS治疗的小鼠表现出脂肪肝病（NAFLD）的特征，因此我们提议通过使用动物模型来检查TCS对NAFLD进展到脂肪变性和HCC的影响，在该动物模型中，该动物模型单独在转基因的小鼠中单独使用高脂饮食会导致HCC的发展。假设是，这些小鼠将在具有TC的动物中更快地发展肝癌，这表明脂肪生成与肥胖相关的变化与TCS介导的肝细胞损伤和纤维化之间的肿瘤形成协同作用（AIM 2）。源自这些研究的发现将提供一个新的机会，以说明TC可能引起的人类健康并发症。