三氯生及其代谢物诱发肝病的质谱代谢组学研究

Triclosan (TCS) is a widely-used antibacterial chemical and it may be associated with the incidence of many diseases. TCS may transform to some degradation products or metabolites that may have more toxicity. Recent studies have shown that TCS substantially accelerates hepatocellular carcinoma (HCC) development, acting as a liver tumor promoter. However, the molecular mechanisms involved in the TCS and its metabolites elicited toxicity are still not well elucidated. In this study, mass spectrometry (MS)-based metabolomics as well as biological and molecular biology techniques will be established and applied for the study on liver disease induced by TCS and its metabolites by selecting models of cell line and animal model of live diseases. The methodologies of mass spectrometry, chemometrics, and epigenetics will be applied in the toxicological mechanism study. The metabolic network, pathways, and the global DNA methylation will be clarified at metabolism and nucleic acid levels. The synergism effect of TCS and its metabolites will also be investigated. It is expected that the obtained results may provide insight for investigating the correlation between TCS exposure and the development of liver diseases, interpreting the biological effect and toxicological mechanism, and clarifying the relationship between TCS as well as its toxic metabolites and liver diseases.

三氯生是一种应用广泛的抗菌剂，但可引起一定的健康风险，且三氯生有可能转化成毒性更强的代谢产物。最近有研究表明三氯生可能引起与肝脏相关的疾病并加速肝细胞癌的发展，但有关毒理作用机制尚不明确。本项目拟选择三氯生及其常见代谢产物为研究对象，采用肝癌相关的细胞和动物模型，运用复合暴露三氯生及其代谢产物的方法，研究三氯生及其代谢产物对肝脏系统的毒理效应，并建立其与肝病相关研究的质谱代谢组学研究平台，开展基于质谱方法学、化学计量学和表观遗传学的毒理作用机制研究，从内源代谢物水平和核酸水平阐明其对代谢网络、DNA甲基化变化等过程的影响。本项目研究将为揭示三氯生及其代谢产物的复合暴露与肝脏疾病发生的相关性提供直接证据，探讨三氯生及其代谢产物与肝病的联系和可能的作用机制。

三氯生是一种应用广泛的抗菌剂，但可引起一定的健康风险，且三氯生有可能转化成毒性更强的代谢产物。越来越多的证据表明三氯生对人体健康和生态毒性的影响，该化合物三氯生的毒理研究也引起人们的广泛关注。据报道三氯生暴露可能导致许多负面后果，如基因毒性、甲状腺功能受损、内分泌干扰、发育障碍、.氧化应激、肝癌发生和肌肉力量的障碍、肝纤维化和致癌等毒性等。最近有研究表明三氯生可能引起与肝脏相关的疾病并加速肝细胞癌的发展，但有关毒理作用机制尚不明确。本项目选择三氯生为研究对象，采用孕妇不同妊娠时期的尿液样本，珠三角地区北江流域的沉泥研究了中国人群的三氯生暴露水平以及环境污染情况；研究了三种常见的淡水藻类在水体中对三氯生的去除及生物降解过程，系统阐明了三氯生的代谢转化途径。采用肝癌相关的细胞和动物模型，研究三氯生及其代谢产物对肝脏系统的毒理效应，并建立其与肝病相关研究的质谱代谢组学研究平台，开展基于质谱方法学、化学计量学和表观遗传学的毒理作用机制研究，从内源代谢物水平和脂质水平阐明其对代谢网络的影响，为探索三氯生与肝脏以及皮肤相关的疾病发生的相关性和致病风险评价提供实验依据。