Chang Xuhong, Liu Fangfang, Tian Minmin, Zhao Hongjun, Han Aijie, Sun Yingbiao
Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, 730000, China.
Department of Chronic Noncommunicable Disease Control and Prevention, Gansu Provincial Centre for Disease Control and Prevention, Lanzhou, 730000, China.
Environ Toxicol. 2017 Dec;32(12):2492-2499. doi: 10.1002/tox.22492. Epub 2017 Sep 25.
Nickel oxide nanoparticles (nano NiO) could induce hepatocyte apoptosis, while its potential mechanisms are unclear. This study aimed to explore the role of endoplasmic reticulum (ER) stress pathways in hepatocyte apoptosis induced by nano NiO. Male Wistar rats were administrated with nano NiO (0.015, 0.06, and 0.24 mg/kg b.w.) and micro NiO (0.24 mg/kg b.w.) by intratracheal instillation twice a week for 6 weeks. We measured the hepatocyte apoptosis levels by TdT-mediated dUTP nick-end labeling (TUNEL) staining, ER stress related gene and protein expression levels in rat liver. The results showed that the TUNEL positive cells increased after exposure nano NiO, hinting hepatocyte apoptosis. The up-regulated gene and protein levels of 78 kD glucose regulated protein and CCAAT/enhancer binding protein homologous protein suggested that nano NiO triggered ER stress. Nano NiO exposure contributed to the increased protein contents of inositol-requiring enzyme 1 (IRE-1)α, p-IRE-1α, X box protein-1S, pancreatic ER kinase (PERK), p-PERK, eukaryotic initiation factor-2 alpha (eIF-2α), p-eIF-2α, caspase-12, -9, and -3, implicating that nano NiO can activate the pathways of ER stress-mediated apoptosis. These findings indicate that the ER stress pathways may play an important role in hepatocyte apoptosis induced by nano NiO.
氧化镍纳米颗粒（纳米NiO）可诱导肝细胞凋亡，但其潜在机制尚不清楚。本研究旨在探讨内质网（ER）应激途径在纳米NiO诱导的肝细胞凋亡中的作用。将雄性Wistar大鼠每周经气管内滴注纳米NiO（0.015、0.06和0.24mg/kg体重）和微米NiO（0.24mg/kg体重）两次，持续6周。我们通过TdT介导的dUTP缺口末端标记（TUNEL）染色、大鼠肝脏中ER应激相关基因和蛋白表达水平来检测肝细胞凋亡水平。结果显示，暴露于纳米NiO后TUNEL阳性细胞增加，提示肝细胞凋亡。78kD葡萄糖调节蛋白和CCAAT/增强子结合蛋白同源蛋白的基因和蛋白水平上调表明纳米NiO引发了ER应激。纳米NiO暴露导致肌醇需求酶1（IRE-1）α、p-IRE-1α、X盒结合蛋白1S、胰腺内质网激酶（PERK）、p-PERK、真核起始因子-2α（eIF-2α）、p-eIF-2α、半胱天冬酶-12、-9和-3的蛋白含量增加，这表明纳米NiO可激活ER应激介导的凋亡途径。这些发现表明，ER应激途径可能在纳米NiO诱导的肝细胞凋亡中起重要作用。
