Endoplasmic reticulum stress and oxidative stress are involved in ZnO nanoparticle-induced hepatotoxicity

•Administration orally with ZnO nanoparticles (Nano-ZnO) caused disruption of ER structure and function in hepatocytes, resulting in ER stress.•Nano-ZnO also caused ER stress-associated genes and proteins upregulation and hepatocyte apoptosis.•ER stress may be involved in Nano-ZnO-induced liver inju...

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Published in:	Toxicology letters Vol. 234; no. 1; pp. 40 - 49
Main Authors:	Yang, Xia, Shao, Huali, Liu, Weirong, Gu, Weizhong, Shu, Xiaoli, Mo, Yiqun, Chen, Xuejun, Zhang, Qunwei, Jiang, Mizu
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier Ireland Ltd 02-04-2015
Subjects:	Alanine Transaminase - blood Animals Apoptosis Aspartate Aminotransferases - blood Blotting, Western Chemical and Drug Induced Liver Injury - etiology Chemical and Drug Induced Liver Injury - metabolism DNA-Binding Proteins - analysis eIF-2 Kinase - analysis Endoplasmic reticulum stress Endoplasmic Reticulum Stress - drug effects Exposure Glutathione - analysis Heat-Shock Proteins - analysis Injuries Liver Liver injury Male Membrane Glycoproteins - analysis Mice Mice, Inbred C57BL Microscopy, Electron, Transmission Nano-ZnO Nanoparticles - toxicity Nanostructure Oxidative stress Phosphorylation Protein Disulfide-Isomerases - analysis Random Allocation Real-Time Polymerase Chain Reaction Regulatory Factor X Transcription Factors RNA - chemistry RNA - genetics Stresses Transaminases Transcription Factor CHOP - analysis Transcription Factors - analysis X-Box Binding Protein 1 Zinc Oxide - toxicity Oxidative stress pdi-3 gapdh JNK ALT MDA PERK Endoplasmic reticulum stress UPR bax CHOP GSH grp94 AST xbp-1 bcl-2 grp78 ER Liver injury eIF2α SEM bcl-1 Nano-ZnO TEM Apoptosis
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Summary:	•Administration orally with ZnO nanoparticles (Nano-ZnO) caused disruption of ER structure and function in hepatocytes, resulting in ER stress.•Nano-ZnO also caused ER stress-associated genes and proteins upregulation and hepatocyte apoptosis.•ER stress may be involved in Nano-ZnO-induced liver injury. 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 200mg/kg or 400mg/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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0378-4274 1879-3169
DOI:	10.1016/j.toxlet.2015.02.004