Wan Chong, Han Rui, Liu Limin, Zhang Fang, Li Fang, Xiang Mingdeng, Ding Wenjun
Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
Toxicol Appl Pharmacol. 2016 Mar 15;295:85-93. doi: 10.1016/j.taap.2016.01.023. Epub 2016 Feb 1.
Studies demonstrated that perfluorooctane sulfonate (PFOS) tends to accumulate in the liver and is capable to cause hepatomegaly. In the present study, we investigated the roles of miR-155 in PFOS-induced hepatotoxicity in SD rats and HepG2 cells. Male SD rats were orally administrated with PFOS at 1 or 10mg/kg/day for 28 days while HepG2 cells were treated with 0-50 μM of PFOS for 24h or 50 μM of PFOS for 1, 3, 6, 12 or 24h, respectively. We found that PFOS significantly increased the liver weight and serum alanine transaminase (ALT) and aspartate amino transferase (AST) levels in rats. Morphologically, PFOS caused actin filament remodeling and endothelial permeability changes in the liver. Moreover, PFOS triggered reactive oxygen species (ROS) generation and induced apoptosis in both in vivo and in vitro assays. Immunoblotting data showed that NF-E2-related factor-2 (Nrf2) expression and activation and its target genes were all suppressed by PFOS in the liver and HepG2 cells. However, PFOS significantly increased miR-155 expression. Further studies showed that pretreatment of HepG2 cells with catalase significantly decreased miR-155 expression and substantially increased Nrf2 expression and activation, resulting in reduction of PFOS-induced cytotoxicity and oxidative stress. Taken together, these results indicated that miR-155 plays an important role in the PFOS-induced hepatotoxicity by disrupting Nrf2/ARE signaling pathway.
研究表明，全氟辛烷磺酸（PFOS）易于在肝脏中蓄积，并能够导致肝肿大。在本研究中，我们调查了miR-155在PFOS诱导的SD大鼠和HepG2细胞肝毒性中的作用。雄性SD大鼠每天经口给予1或10mg/kg的PFOS，持续28天，而HepG2细胞分别用0-50μM的PFOS处理24小时或用50μM的PFOS处理1、3、6、12或24小时。我们发现，PFOS显著增加了大鼠的肝脏重量以及血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平。在形态学上，PFOS导致肝脏中肌动蛋白丝重塑和内皮通透性改变。此外，在体内和体外试验中，PFOS均引发活性氧（ROS）生成并诱导细胞凋亡。免疫印迹数据显示，PFOS在肝脏和HepG2细胞中均抑制了核因子E2相关因子2（Nrf2）的表达和激活及其靶基因。然而，PFOS显著增加了miR-155的表达。进一步研究表明，用过氧化氢酶预处理HepG2细胞可显著降低miR-155的表达，并大幅增加Nrf2的表达和激活，从而降低PFOS诱导的细胞毒性和氧化应激。综上所述，这些结果表明，miR-155通过破坏Nrf2/ARE信号通路在PFOS诱导的肝毒性中发挥重要作用。
