PFOS诱导肝脏毒性的代谢紊乱机制

PFOS is an emerging persistent organic pollutant that have been detected almost ubiquitously in various environmental media, and human populations. Liver has been demonstrated to be the main target organ of PFOS. However, the underlying toxicological mechanisms of PFOS on liver has not been fully elucidated. Previous research have showed that PFOS can disturb genes and proteins that related to endogenous metabolic processes in the liver. However, whether downstream metabolites have been perturbed, which pathways have been dysregulated, and whether those perturbations are closely related to liver injury, remains unclear. In this project, a comprehensive LC/MS-based metabolomics approach will be conducted for the first time to explore the metabolic responses in mouse model exposed to PFOS. By analyzing the changes of endogenous metabolites in the liver and serum after PFOS exposure, mode of action for PFOS in the liver will be established. Furthermore, MALDI-TOF Imaging analysis will be conducted to visualize the in situ distribution of biomarkers in the liver tissue. The ion image of the biomarkers will be further overlaid with the histological image to identify metabolic signatures that closely related to live injury. The successful complete of this project will provide new clues on metabolic disturbances in liver induced by PFOS exposure, shed new light on the underlying hepatoxicity mechanisms of PFOS, and form the scientific foundation for future studies to identify interception strategies.

全氟辛烷磺酸（PFOS）是一种新型持久性有机污染物，广泛存在于环境介质和普通人群中。肝脏是PFOS作用的主要靶器官之一，但是其毒性机制仍然不是十分明确。以往的研究显示，PFOS在肝脏中可引起代谢相关的蛋白和基因水平的改变，但是下游的小分子代谢物是否发生了紊乱，哪些通路发生了改变，其变化是否与肝损伤密切相关，仍然缺乏代谢组学角度的确证。本项目拟采用基于LC/MS的代谢组学方法，以小鼠为模型，考察PFOS暴露后对小鼠肝脏和血清整体代谢谱的影响，筛选血清中可预警PFOS引起肝毒性的代谢标志物，揭示PFOS在肝脏中引起的代谢通路变化；并进一步采用质谱成像法揭示毒性标志物在肝脏中的空间分布特征，结合组织病理信息，筛选与肝组织损伤密切相关的代谢紊乱特征。该项目从小分子代谢物的角度更直观地阐明PFOS在肝脏中的代谢紊乱，为其肝毒性作用机制提供新的机理，为今后PFOS的疾病防治和解毒提供重要的参考依据。

全氟辛烷磺酸（PFOS）是一种新型持久性有机污染物，广泛存在于环境介质和普通人群中。肝脏是PFOS的主要毒性靶器官之一，但是其肝毒性机制仍然不是十分明确。本项目基于代谢组学技术，并联合其它多组学方法，以小鼠为模型，从代谢紊乱的角度探讨了PFOS致小鼠肝毒性的潜在机制。本项目的主要研究内容和结果如下：1，建立了PFOS致肝损伤的小鼠模型，结果显示PFOS能引起雌雄小鼠肝脏剂量依赖性的肿胀，炎症细胞浸润以及剂量依赖性的脂肪变性。2，建立并开展了基于LC/MS的代谢组学分析，发现PFOS可引起小鼠肝脏中整体代谢谱的紊乱，大部分受干扰的代谢物富集在氨基酸代谢通路，且这些氨基酸的变化与肝毒性显著相关。并进一步开展了蛋白质组学分析，验证了PFOS暴露后小鼠肝脏中与氨基酸代谢相关的蛋白发生了显著改变。3，基于上述结果和文献调研，我们推测肠道菌群极有可能参与了PFOS介导的肝毒性。因此开展了基于16s rRNA的肠道微生物组和粪便代谢组学分析，发现PFOS可干扰小鼠肠道菌群的组成及其代谢功能，且受干扰的菌群与肝毒性指标显著相关，预示着肠道菌群在PFOS肝毒性中扮演了重要角色，未来拟进一步深入探讨肠道菌群介导的PFOS肝毒性机制。