title: Endoplasmic reticulum stress and oxidative stress are involved in ZnO nanoparticle-induced hepatotoxicity.
abstract: 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.
authors: Department of Gastroenterology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
authors: Xia
authors: X
authors: Yang
authors: Department of Gastroenterology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
authors: Huali
authors: H
authors: Shao
authors: Department of Gastroenterology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
authors: Weirong
authors: W
authors: Liu
authors: Department of Gastroenterology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
authors: Weizhong
authors: W
authors: Gu
authors: Department of Gastroenterology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
authors: Xiaoli
authors: X
authors: Shu
authors: Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY, USA.
authors: Yiqun
authors: Y
authors: Mo
authors: Department of Gastroenterology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
authors: Xuejun
authors: X
authors: Chen
authors: Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY, USA. Electronic address: Qunwei.Zhang@louisville.edu.
authors: Qunwei
authors: Q
authors: Zhang
authors: Department of Gastroenterology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China. Electronic address: mizu@zju.edu.cn.
authors: Mizu
authors: M
authors: Jiang
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005978:Glutathione / Q000032:analysis; D006360:Heat-Shock Proteins / Q000032:analysis; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000633:toxicity*; D019704:Protein Disulfide-Isomerases / Q000032:analysis; D012313:RNA / Q000737:chemistry / Q000235:genetics; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D000071701:Regulatory Factor X Transcription Factors; D051742:Transcription Factor CHOP / Q000032:analysis; D014157:Transcription Factors / Q000032:analysis; D000071717:X-Box Binding Protein 1; D015034:Zinc Oxide / Q000633:toxicity*; D019892:eIF-2 Kinase / Q000032:analysis
chemical_list: D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D005978:Glutathione; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D019704:Protein Disulfide-Isomerases; D012313:RNA; D000071701:Regulatory Factor X Transcription Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D015034:Zinc Oxide; D019892:eIF-2 Kinase; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C053387:endoplasmin
keywords: Apoptosis; Endoplasmic reticulum stress; Liver injury; Nano-ZnO; Oxidative stress