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Open AccessArticle

Zinc Oxide Nanoparticles Induce Autophagy and Apoptosis via Oxidative Injury and Pro-Inflammatory Cytokines in Primary Astrocyte Cultures

1
Department of Veterinary Toxicology, College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 24341, Korea
2
Chuncheon Center, Korean Basic Science Institute, Chuncheon 24341, Korea
3
Department of Biochemistry, Kangwon National University, Chuncheon 24341, Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Nanomaterials 2019, 9(7), 1043; https://doi.org/10.3390/nano9071043
Received: 3 July 2019 / Revised: 13 July 2019 / Accepted: 18 July 2019 / Published: 21 July 2019
(This article belongs to the Special Issue Toxicity and Ecotoxicity of Nanomaterials)
The present study examined the potential toxic concentrations of zinc oxide nanoparticles (ZnO NPs) and associated autophagy and apoptosis-related injuries in primary neocortical astrocyte cultures. Concentrations of ZnO NPs ≥3 μg/mL induced significant toxicity in the astrocytes. At 24 h after exposure to the ZnO NPs, transmission electron microscopy revealed swelling of the endoplasmic reticulum (ER) and increased numbers of autophagolysosomes in the cultured astrocytes, and increased levels of LC3 (microtubule-associated protein 1 light chain 3)-mediated autophagy were identified by flow cytometry. Apoptosis induced by ZnO NP exposure was confirmed by the elevation of caspase-3/7 activity and 4′,6′-diamidino-2-phenylindole (DAPI) staining. Significant (p < 0.05) changes in the levels of glutathione peroxidase, superoxide dismutase, tumor necrosis factor (TNF-α), and interleukin-6 were observed by enzyme-linked immunoassay (ELISA) assay following the exposure of astrocyte cultures to ZnO NPs. Phosphatidylinositol 3-kinase (PI3K)/mitogen-activated protein kinase (MAPK) dual activation was induced by ZnO NPs in a dose-dependent manner. Additionally, the Akt (protein kinase B) inhibitor BML257 and the mTOR (mammalian target of rapamycin) inhibitor rapamycin contributed to the survival of astrocytes. Inhibitors of cyclooxygenase-2 and lipoxygenase attenuated ZnO NP-induced toxicity. Calcium-modulating compounds, antioxidants, and zinc/iron chelators also decreased ZnO NP-induced toxicity. Together, these results suggest that ZnO NP-induced autophagy and apoptosis may be associated with oxidative stress and the inflammatory process in primary astrocyte cultures. View Full-Text
Keywords: astrocyte cultures; autophagy; apoptosis; pro-inflammatory cytokines; zinc oxide nanoparticles astrocyte cultures; autophagy; apoptosis; pro-inflammatory cytokines; zinc oxide nanoparticles
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MDPI and ACS Style

Song, W.-J.; Jeong, M.-S.; Choi, D.-M.; Kim, K.-N.; Wie, M.-B. Zinc Oxide Nanoparticles Induce Autophagy and Apoptosis via Oxidative Injury and Pro-Inflammatory Cytokines in Primary Astrocyte Cultures. Nanomaterials 2019, 9, 1043.

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