Yang Xia, Shao Huali, Liu Weirong, Gu Weizhong, Shu Xiaoli, Mo Yiqun, Chen Xuejun, Zhang Qunwei, Jiang Mizu
Department of Gastroenterology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY, USA.
Toxicol Lett. 2015 Apr 2;234(1):40-9. doi: 10.1016/j.toxlet.2015.02.004. Epub 2015 Feb 10.
Zinc oxide nanoparticles (Nano-ZnO) are widely used in sunscreens, clothes, medicine and electronic devices. However, the potential risks of human exposure and the potential for adverse health impacts are not well understood. Previous studies have demonstrated that exposure to Nano-ZnO caused liver damage and hepatocyte apoptosis through oxidative stress, but the molecular mechanisms that are involved in Nano-ZnO-induced hepatotoxicity are still unclear. Endoplasmic reticulum (ER) is sensitive to oxidative stress, and also plays a crucial role in oxidative stress-induced damage. Previous studies showed that ER stress was involved in many chemical-induced liver injuries. We hypothesized that exposure to Nano-ZnO caused oxidative stress and ER stress that were involved in Nano-ZnO-induced liver injury. To test our hypothesis, mice were gavaged with 200 mg/kg or 400 mg/kg of Nano-ZnO once a day for a period of 90 days, and blood and liver tissues were obtained for study. Our results showed that exposure to Nano-ZnO caused liver injury that was reflected by focal hepatocellular necrosis, congestive dilation of central veins, and significantly increased alanine transaminase (ALT) and aspartate transaminase (AST) levels. Exposure to Nano-ZnO also caused depletion of glutathione (GSH) in the liver tissues. In addition, our electron microscope results showed that ER swelling and ribosomal degranulation were observed in the liver tissues from mice treated with Nano-ZnO. The mRNA expression levels of ER stress-associated genes (grp78, grp94, pdi-3, xbp-1) were also up-regulated in Nano-ZnO-treated mice. Nano-ZnO caused increased phosphorylation of RNA-dependent protein kinase-like ER kinase (PERK) and eukaryotic initiation factor 2α (eIF2α). Finally, we found that exposure to Nano-ZnO caused increased ER stress-associated apoptotic protein levels, such as caspase-3, caspase-9, caspase-12, phosphorylation of JNK, and CHOP/GADD153, and up-regulation of pro-apoptotic genes (chop and bax). These results suggest that oxidative stress and ER stress-induced apoptosis are involved in Nano-ZnO-induced hepatotoxicity in mice.
氧化锌纳米颗粒（纳米氧化锌）广泛应用于防晒霜、衣物、药品和电子设备中。然而，人们对人体接触纳米氧化锌的潜在风险以及对健康的潜在不利影响了解不足。先前的研究表明，接触纳米氧化锌会通过氧化应激导致肝损伤和肝细胞凋亡，但纳米氧化锌诱导肝毒性的分子机制仍不清楚。内质网（ER）对氧化应激敏感，并且在氧化应激诱导的损伤中也起着关键作用。先前的研究表明，内质网应激参与了许多化学物质诱导的肝损伤。我们推测，接触纳米氧化锌会导致氧化应激和内质网应激，进而参与纳米氧化锌诱导的肝损伤。为了验证我们的假设，每天给小鼠灌胃200毫克/千克或400毫克/千克的纳米氧化锌，持续90天，然后采集血液和肝脏组织进行研究。我们的结果表明，接触纳米氧化锌会导致肝损伤，表现为局灶性肝细胞坏死、中央静脉充血扩张，以及丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平显著升高。接触纳米氧化锌还会导致肝脏组织中谷胱甘肽（GSH）耗竭。此外，我们的电子显微镜结果显示，在用纳米氧化锌处理的小鼠肝脏组织中观察到内质网肿胀和核糖体脱粒。内质网应激相关基因（grp78、grp94、pdi - 3、xbp - 1）的mRNA表达水平在纳米氧化锌处理的小鼠中也上调。纳米氧化锌导致RNA依赖性蛋白激酶样内质网激酶（PERK）和真核起始因子2α（eIF2α）的磷酸化增加。最后，我们发现接触纳米氧化锌会导致内质网应激相关凋亡蛋白水平升高，如半胱天冬酶 - 3、半胱天冬酶 - 9、半胱天冬酶 - 12、JNK磷酸化以及CHOP/GADD153，并且促凋亡基因（chop和bax）上调。这些结果表明，氧化应激和内质网应激诱导的凋亡参与了纳米氧化锌诱导的小鼠肝毒性。
