Nrf2 Signaling Elicits a Neuroprotective Role Against PFOS-mediated Oxidative Damage and Apoptosis
Nrf2 Signaling Elicits a Neuroprotective Role Against PFOS-mediated Oxidative Damage and Apoptosis
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Nrf2 信号传导可针对 PFOS 介导的氧化损伤和细胞凋亡发挥神经保护作用。
DOI：
10.1007/s11064-018-2672-y
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发表时间：
2018
影响因子：
4.4
通讯作者：
Jiang Shengyang
中科院分区：
文献类型：
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作者：
Sun Pingping;Nie Xiaoke;Chen Xiaoxu;Yin Lifeng;Luo Jiashan;Sun Lingli;Wan Chunhua;Jiang Shengyang
全氟辛烷磺酸可通过引发氧化应激而导致神经毒性。在本研究中，我们研究了抗氧化核因子红细胞2相关因子2（Nrf 2）通路在全氟辛烷磺酸诱导的神经毒性中的作用。我们发现，人类神经母细胞瘤SH-SY 5 Y细胞表现出显着的凋亡细胞死亡后PFOS暴露，这一过程伴随着明显的活性氧化物质（ROS）的积累。此外，我们发现PFOS暴露会导致Nrf 2途径显着激活以及Nrf 2转录靶点血红素加氧酶-1的表达。我们进一步发现，用ROS清除剂N-乙酰基-L-半胱氨酸（NAC）预处理显著改善了PFOS诱导的ROS产生和Nrf 2信号转导。与这些发现一致，蛋白质印迹和Cell Counter Kit-8分析显示，与NAC预孵育抑制了全氟辛烷磺酸诱导的促凋亡蛋白表达和神经元活力受损。此外，Nrf 2抑制剂brusatol拮抗Nrf 2通路导致ROS产生增加，并增强PFOS诱导的凋亡相关蛋白的表达。最后，我们发现全氟辛烷磺酸暴露改变了SH-SY 5 Y细胞的线粒体跨膜电位，破坏了正常的线粒体形态。而NAC治疗改善了全氟辛烷磺酸诱导的线粒体疾病，与布鲁沙醇共孵育增加了全氟辛烷磺酸诱导的线粒体缺陷，从而导致神经元凋亡。这些结果表明，Nrf 2通路在PFOS诱导的神经毒性中起保护作用，为PFOS相关毒性的防治提供了新的思路。
Perfluorooctanesulfonate (PFOS) may cause neurotoxicity through the initiation of oxidative stress. In the current study, we investigated the role of anti-oxidant nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in PFOS-induced neurotoxicity. We found that human neuroblastoma SH-SY5Y cells exhibited significant apoptotic cell death following PFOS exposure, and this process was accompanied with apparent accumulation of reactive oxidative species (ROS). In addition, we revealed that PFOS exposure caused marked activation of Nrf2 pathway and the expression of Nrf2 transcription target heme oxygenase-1. We further found that pre-treatment with ROS scavengerN-acetyl-l-cysteine (NAC) dramatically ameliorated PFOS-induced ROS production and Nrf2 signaling. In keeping with these findings, western blot and Cell Counter Kit-8 analyses revealed that pre-incubation with NAC suppressed PFOS-induced expression of pro-apoptotic proteins and impairment of neuronal viability. Moreover, antagonizing Nrf2 pathway with Nrf2 inhibitor brusatol resulted in increased ROS production and enhanced PFOS-induced expression of apoptosis related proteins. Finally, we showed that PFOS exposure altered mitochondrial transmembrane potential and disrupted normal mitochondrial morphology in SH-SY5Y cells. Whereas treatment with NAC ameliorated PFOS-induced mitochondrial disorders, co-incubation with brusatol augmented PFOS-induced mitochondrial deficits, consequently contributing to neuronal apoptosis. These results manifest that Nrf2 pathway plays a protective role in PFOS-induced neurotoxicity, providing new insights into the prevention and treatment of PFOS-related toxicities.