Ministry of Education Key Laboratory of Pollution Processes and Environmental Criteria, College of Environmental Science and Engineering, Nankai University, Tianjin, 300350, China.
Ministry of Education Key Laboratory of Pollution Processes and Environmental Criteria, College of Environmental Science and Engineering, Nankai University, Tianjin, 300350, China; School of Environmental Science and Safety Engineering, Tianjin University of Technology, Tianjin, 300384, China.
Environ Pollut. 2021 Jun 1;278:116840. doi: 10.1016/j.envpol.2021.116840. Epub 2021 Mar 1.
Per- and polyfluoroalkyl substances (PFASs) are environmentally and biologically persistent anthropogenic chemicals linked to adverse health outcomes. Epidemiological data have revealed association between exposure to specific PFAS and disruption of insulin level in bodies. However, the effect of PFASs on insulin secretion and the responsible molecular mechanism are poorly understood. In the present study, we used perfluorooctane sulfonate (PFOS) as a representative PFAS family member to investigate its effect on the insulin secretion in mouse pancreatic β cells (β-TC-6). Our results showed that exposure to PFOS inhibited silent information regulator 1 (SIRT1) activity, and molecular simulation showed PFOS could fit into the pocket overlapped with the nicotinamide adenine dinucleotide (NAD) binding cavity in SIRT1. PFOS exposure upregulated uncoupling protein 2 (UCP2) expression, and this upregulation was blunted in the presence of Ex-527, a SIRT1 specific inhibitor. The mitochondria membrane potential (ΔΨm), as well as the glucose-induced ATP production and Ca influx decreased under PFOS treatment. PFOS continual exposure (48 h) impaired glucose stimulated insulin secretion (GSIS), while the gene expression of insulin was not significantly altered. Importantly, the SIRT1 activator and UCP2 inhibitor could partly reverse the PFOS-induced impairment of GSIS. Taken together, the results suggested that PFOS continual exposure could inhibit SIRT1 activity, and the SIRT1-UCP2 pathway mediated, at least partially, the PFOS induced GSIS impairment.
全氟和多氟烷基物质（PFASs）是环境和生物持久性的人为化学物质，与不良健康结果有关。流行病学数据显示，暴露于特定的 PFAS 与体内胰岛素水平的紊乱有关。然而，PFASs 对胰岛素分泌的影响及其负责的分子机制尚不清楚。在本研究中，我们使用全氟辛烷磺酸（PFOS）作为 PFAS 家族的代表性成员，研究其对小鼠胰腺β细胞（β-TC-6）胰岛素分泌的影响。我们的结果表明，暴露于 PFOS 抑制沉默信息调节因子 1（SIRT1）的活性，分子模拟表明 PFOS 可以与 SIRT1 中与烟酰胺腺嘌呤二核苷酸（NAD）结合腔重叠的口袋结合。PFOS 暴露上调解偶联蛋白 2（UCP2）的表达，而在 SIRT1 特异性抑制剂 Ex-527 的存在下，这种上调作用减弱。在 PFOS 处理下，线粒体膜电位（ΔΨm）以及葡萄糖诱导的 ATP 产生和 Ca2+内流减少。PFOS 持续暴露（48 小时）损害了葡萄糖刺激的胰岛素分泌（GSIS），而胰岛素的基因表达没有明显改变。重要的是，SIRT1 激活剂和 UCP2 抑制剂可以部分逆转 PFOS 诱导的 GSIS 损伤。总之，这些结果表明，PFOS 持续暴露可抑制 SIRT1 活性，SIRT1-UCP2 途径至少部分介导了 PFOS 诱导的 GSIS 损伤。
