Intranasal exposure to ZnO nanoparticles induces alterations in cholinergic neurotransmission in rat brain

Zhiling Guo, Peng Zhang*, Yali Luo, Heidi Qunhui Xie, Swaroop Chakraborty, Fazel Abdolahpur Monikh, Lijing Bu, Yiyun Liu, Yongchao Ma, Zhiyong Zhang, Eugenia Valsami-Jones, Bin Zhao*, Iseult Lynch

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
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Abstract

The neurotoxicity of inhaled ZnO nanoparticles (NPs) and the underlying mechanisms remain largely unknown. In this study, ZnO NPs (30 ± 6 nm) were intranasally instilled to rats via a single dose (13 mg Zn/kg BW), with ZnSO4 as the ionic control, and analysis 7-days post exposure. The hippocampus was found to be the main target for Zn accumulation for both ZnO NPs and ZnSO4. Synchrotron radiation based X-ray absorption fine structure (XAFS) analysis showed that no particulate ZnO was found, suggesting the occurrence of dissolution and transformation of ZnO NPs. Multi-omics analysis, including transcriptomics, proteomics and metabolomics, demonstrated that cholinergic neurotransmission was the main biological process affected following both treatments. The release of the key neurotransmitter acetylcholine (ACh) was increased by enhanced ACh synthesis, upregulation of vesicular ACh transporter, and suppression of the activity of ACh hydrolysis enzyme (AChE), either by direct Zn-AChE interaction or a transcriptional down-regulation mechanism. In addition, ZnO NPs and ZnSO4 induced similar molecular consequences and exhibited the same Zn chemical speciation (100 % of Zn complexes) in the hippocampal region evidenced by XAFS analysis, suggesting that the observed biological effects were mainly derived from Zn2+ released from the ZnO NPs. This study not only evidences a new pathway for the impact of ZnO NPs on the brain, but also identifies the origin of the impact as ionic Zn, which provides the basis for safe-by-design of ZnO NPs.

Original languageEnglish
Article number100977
Number of pages10
JournalNano Today
Volume35
Early online date17 Sept 2020
DOIs
Publication statusPublished - Dec 2020

Bibliographical note

Funding Information:
This work was supported by the National Natural Science Foundation of China (Grant Nos. 21836004, 91543204, and 21525730), the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB14030400 ), the National Key Research and Development Program of China (Grant No. 2018YFA0901103). Marie Skłodowska-Curie Individual Fellowships (NanoBBB Grant Agreement No. 798505 to Z. Guo; NanoLabels Grant Agreement No. 750455 to P. Zhang) under the European Union’s Horizon 2020 research program were acknowledged. Technical support from the Shanghai Applied Protein Technology facility (Shanghai, China) is gratefully acknowledged.

Publisher Copyright:
© 2020 The Author(s)

Keywords

  • Acetylcholine
  • Acetylcholinesterase
  • Brain
  • Cholinergic neurotransmission
  • Zinc oxide nanoparticles

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Materials Science(all)
  • Pharmaceutical Science

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