Zinc oxide nanoparticles effectively regulate autophagic cell death by activating autophagosome formation and interfering with their maturation

Zixuan Liu,Erqun Song,Xuting Liu,Lei Xu,Xiangyu Zhu,Yang Song,Xuying Lv

doi:10.1186/s12989-020-00379-7

Abstract

BackgroundWith the development of zinc oxide nanoparticles (ZnO NPs) in the field of nanotechnology, their toxicological effects are attracting increasing attention, and the mechanisms for ZnO NPs neurotoxicity remain obscure. In an attempt to address concerns regarding neurotoxicity of ZnO NPs, we explored the relationship between free zinc ions, reactive oxygen species (ROS) and neurotoxic mechanisms in ZnO NPs-exposed PC12 cells.ResultThis study demonstrated the requirement of free zinc ions shed by ZnO NPs to over generation of intracellular ROS. Next, we identified autophagic cell death was the major mode of cell death induced by ZnO NPs, and autophagosome accumulation resulted from not only induction of autophagy, but also blockade of autophagy flux. We concluded that autophagic cell death, resulting from zinc ions-ROS-c-Jun N-terminal kinase (JNK)-autophagy positive feedback loop and blockade of autophagosomal-lysosomal fusion, played a major role in the neurotoxicity of ZnO NPs.ConclusionOur study contributes to a better understanding of the neurotoxicity of ZnO NPs and might be useful for designing and developing new biosafety nanoparticles in the future.

Highlights

With the development of zinc oxide nanoparticles (ZnO NPs) in the field of nanotechnology, their toxicological effects are attracting increasing attention, and the mechanisms for ZnO NPs neurotoxicity remain obscure
Our study contributes to a better understanding of the neurotoxicity of ZnO NPs and might be useful for designing and developing new biosafety nanoparticles in the future
Propidium iodide (PI) and Hoechst 33258 were supplied by Solarbio (Beijing, China). 2′, 7′dichlorodihydrofluorescein diacetate (DCFH-DA), N-Acetyl cysteine (NAC), N,N,N′,N′-Tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), monodansylcadaverine (MDC), Ferrostatin-1 (Fer-1), Liproxstatin-1 (Lip-1) and antibody to light chain 3B (LC3B) were obtained from Sigma-Aldrich (Missouri, USA)

Summary

Introduction

With the development of zinc oxide nanoparticles (ZnO NPs) in the field of nanotechnology, their toxicological effects are attracting increasing attention, and the mechanisms for ZnO NPs neurotoxicity remain obscure. Nanoparticles (NPs) have been widely used in recent years, and the global market for nanotechnology products was estimated to reach 64.2 billion in 2019. The toxicities of ZnO NPs in mammalian organs, e.g. stomach, kidney, liver, spleen, and pancreas, have been widely studied [6], their potential hazardous effects on the central nervous system (CNS) are still limited. ZnO NPs may transfer to the CNS through blood brain barrier (BBB) [7], placental barrier [8], olfactory bulb or taste nerve pathways [9], leading to various neurotoxic effects. There are three inducers engaged in toxicity activities of ZnO NPs: the release of zinc ions

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