Zinc Oxide Nanoparticles Exhibit Both Cyclooxygenase- and Lipoxygenase-Mediated Apoptosis in Human Bone Marrow-Derived Mesenchymal Stem Cells
Toxicological Research 2019;35:83−91
Published online January 15, 2019;  https://doi.org/10.5487/TR.2019.35.1.083
© 2019 Korean Society of Toxicology.

Dong-Yung Kim1, Jun-Hyung Kim1, Jae-Chul Lee2, Moo-Ho Won2, Se-Ran Yang3, Hyoung-Chun Kim4 and Myung-Bok Wie1

1Department of Veterinary Toxicology, College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Korea, 2Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Korea, 3Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University, Chuncheon, Korea, 4Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chuncheon, Korea
Myung-Bok Wie, Department of Veterinary Toxicology, College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 24341, Korea, E-mail: mbwie@kangwon.ac.kr
Received: July 16, 2018; Revised: August 16, 2018; Accepted: August 30, 2018
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Nanoparticles (NPs) have been recognized as both useful tools and potentially toxic materials in various industrial and medicinal fields. Previously, we found that zinc oxide (ZnO) NPs that are neurotoxic to human dopaminergic neuroblastoma SH-SY5Y cells are mediated by lipoxygenase (LOX), not cyclooxygenase-2 (COX-2). Here, we examined whether human bone marrow-derived mesenchymal stem cells (MSCs), which are different from neuroblastoma cells, might exhibit COX-2- and/or LOX-dependent cytotoxicity of ZnO NPs. Additionally, changes in annexin V expression, caspase-3/7 activity, and mitochondrial membrane potential (MMP) induced by ZnO NPs and ZnO were compared at 12 hr and 24 hr after exposure using flow cytometry. Cytotoxicity was measured based on lactate dehydrogenase activity and confirmed by trypan blue staining. Rescue studies were executed using zinc or iron chelators. ZnO NPs and ZnO showed similar dose-dependent and significant cytotoxic effects at concentrations ≥ 15 μg/mL, in accordance with annexin V expression, caspase-3/7 activity, and MMP results. Human MSCs exhibited both COX-2 and LOX-mediated cytotoxicity after exposure to ZnO NPs, which was different from human neuroblastoma cells. Zinc and iron chelators significantly attenuated ZnO NPs-induced toxicity. Conclusively, these results suggest that ZnO NPs exhibit both COX-2-and LOX-mediated apoptosis by the participation of mitochondrial dysfunction in human MSC cultures.
Keywords : Zinc oxide nanoparticles, Apoptosis, Lipoxygenase, Cyclooxygenase-2, Mitochondrial membrane potential


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