基于宿主代谢和肠道菌群变化研究四氯二苯并呋喃诱导肥胖发生的分子机理

2, 3, 7, 8-tetrachlorodibenzofuran (TCDF), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and many structurally related halogenated aromatic hydrocarbons (HAHs) and polynuclear aromatic hydrocarbons (PAHs) are environmentally persistent and toxic compounds commonly generated as byproducts of municipal waste combustion. Exposure to such compounds can lead to a broad range of species-specific biochemical and toxic effects including xenobiotic enzyme induction, wasting syndrome, tumor promotion, immunotoxicity, hepatotoxicity, and endocrine system modulation and hence poses a health risk for human populations..There is increasing evidence that chronic exposure to environmental chemicals through the diet, especially persistent organic pollutants (POPs), may promote the development of obesity and type 2 diabetes in humans. Of particular interest is the role of the aryl hydrocarbon receptor (AHR) in promoting obesity at low doses. Further, more recent evidence suggests that the gut microbiota and host metabolism may play a pivotal role in POPs-induced obesity. TCDF here is used instead of TCDD given its considerably shorter half-life in rodents, yet was provided at doses higher than that typically found in the diet. Increasing evidences showed that it is much more harmful for human with low doses and long-term exposure of POPs than their high doses. Alteration of the gut microbiota and host metabolism through diet manipulation and environmental contaminants may disturb physiological homeostasis leading to various diseases such as obesity, diabetes and inflammatory bowel disease (IBD). Recent studies further suggest that interactions between the gut microbiota and environmental toxicants may contribute in part to the development of obesity and diabetes. . In this project, a combination of 16S rRNA metagenomics, metabolite profiling (ultraperformance liquid chromatography coupled with triplequadrupole mass spectrometry), and metabolomics will be used to investigate the alteration of the gut microbiota and host metabolome in mice treated with TCDF through the diet with low dose and long term, which promotes development of obesity. In addition, the correlation between the gut microbiota composition and signaling pathways such as AHR and FXR under TCDF-treated conditions will be investigated with the goal to identify a specific host-microbiota signaling axis. These findings will provide new evidence that exposure to persistent environmental contaminants which impacts the gut microbiota and host metabolome in mice treated with TCDF through the diet with low dose and long term, which will induce obesity. These findings will provide new evidence that exposure to persistent environmental contaminants which impacts the gut microbiota and host metabolism inducing development of obesity.

环境污染物长期暴露是当今肥胖等代谢性疾病的重要诱因之一。2,3,7,8-四氯二苯并呋喃（TCDF）是环境中常见的一种持久性有机污染物，广泛存在于大气、土壤、水体沉积物等环境介质中。它能够通过各种途径暴露于人群等生物体，对人类和环境健康具有严重危害性。目前的研究主要集中在TCDF的含量检测、毒性、致癌致畸作用及其环境行为等方面。但是，TCDF暴露引起宿主代谢紊乱和肠道菌群变化进而诱导肥胖发生的分子机制尚不清楚。本项目拟采用基于NMR和LC/GC-MS检测的代谢组学方法结合宏基因组高通量测序等生物学技术，在细胞、组织和分子水平上着重探讨TCDF对小鼠长期暴露后其动物体液、肝脏-小肠轴等宿主代谢平衡，体内慢性炎症，肠道菌群结构和组成等方面的作用, 进而深入解析TCDF长期暴露诱导肥胖发长期暴露诱导肥胖发生发展的分子机理。研究结果可为评估环境中持久性有机污染物的慢性毒性并诱导肥胖发生提供新的依据。

2,3,7,8-四氯二苯并呋喃（TCDF）是环境中常见的一种持久性有机污染物，能够通过各种途径暴露于人群等生物体，对人类和环境健康具有严重危害性。按照项目申报书和任务书，本项目首先建立了低剂量TCDF长期暴露诱导非酒精性脂肪肝和肥胖的小鼠模型，采用了基于NMR和LC/GC-MS检测的代谢组学方法结合宏基因组高通量测序等生物学技术，在细胞、组织和分子水平上详细研究了TCDF长期暴露诱导肥胖发生发展的分子机理。本项目开展取得了一系列重要研究成果：1、成功建立了TCDF诱发脂肪肝和肥胖模型，而且发现了与高脂联合暴露更容易产生肥胖；2、TCDF暴露导致动物肝脏-小肠轴等宿主代谢平衡紊乱和体内慢性炎症，尤其是脂质代谢紊乱；3、TCDF暴露引起了肠道菌群结构和组成的紊乱；4、TCDF体外暴露于不同细胞的分子机制不完全一样，主要体现在脂质代谢的差异；5、发现了一种重要的代谢调节分子-神经酰胺在TCDF暴露诱发脂肪肝和肥胖过程中的重要作用；6、神经酰胺在脂肪细胞和肝脏细胞中的生物学功能存在一定的差异，其机制尚需深入研究。. 传统的二噁英毒理学研究主要集中在环境含量检测、毒性、致癌致畸作用及其环境行为等方面。本项目创新性地研究了TCDF环境剂量长期暴露诱发代谢性疾病的分子机理，本项目实施取得了令人满意的成果，上述研究结果分别发表如Chemical Research in Toxicity，Environmental Pollution等8篇国际高水平SCI文章。研究结果可为评估环境中持久性有机污染物的慢性毒性并诱导肥胖发生提供新的依据，对污染物低剂量长期环境暴露的健康危害性研究具有重要的科学意义。