全氟烷基化合物（PFASs）是一类广泛分布于人体及环境中的持久性有机污染物。近年来多篇人类流行病学调查和动物实验研究显示PFASs暴露与胰岛β细胞的胰岛素分泌功能异常具有相关性，但其作用机制目前尚不清楚。本项目以β细胞内关键的调控胰岛素分泌的脂肪酸膜受体GPR40信号通路为PFASs的潜在作用靶标，研究PFASs对β细胞胰岛素分泌功能的干扰效应并探讨其分子起始事件和毒性作用机制。我们通过整体动物实验和细胞水平实验，系统地研究PFASs对小鼠β细胞胰岛素分泌功能的干扰效应。之后通过对GPR40进行基因敲除，探讨GPR40信号通路对PFASs胰岛素分泌功能干扰效应的介导作用。通过考察PFASs与GPR40受体的直接结合作用，研究PFASs对GPR40信号通路的影响，并计算模拟PFASs与GPR40受体的结合作用方式，揭示PFASs通过GPR40信号通路干扰β细胞胰岛素分泌功能的作用机制。

Perfluoroalkyl substances (PFASs), as a new class of persistent organic pollutants, have been wildly detected in the environment and human populations. Recently, several epidemiologic studies and animal experiments have found that increased serum PFASs concentrations were significantly associated with disruption of the β-cell insulin secretion function. However, the molecular mechanism is still unknown. In the present project, we will investigate the disruption activity of PFASs on insulin secretion function of the β-cell and further study the toxicity mechanism based on the fatty acid receptor GPR40 signaling pathway. This project will help to understand the molecular initiative event and toxicity mechanism of PFASs’ disruption effect on the β-cell insulin secretion function. We will study the disruption effect of PFASs on the insulin secretion function of mice β-cell by using the in vivo animal experiments, in vitro cell experiments. By using the GPR40 knockout mice, we will clarify the role of GPR40 signaling pathway in the insulin secretion disruption effect of PFASs. We will detect the direct binding of PFASs to GPR40 receptor, investigate the effect of PFASs on GPR40 signaling pathway, and further simulate the interactions of PFASs with GPR40 receptor. By combining the above results, we will reveal the toxicity mechanism of PFASs’ disruption effect on the β-cell insulin secretion function based on the GPR40 signaling pathway.