Endoplasmic reticulum stress induced by zinc oxide nanoparticles is an earlier biomarker for nanotoxicological evaluation

Rui Chen, Lingling Huo, Xiaofei Shi, Ru Bai, Zhenjiang Zhang, Yuliang Zhao, Yanzhong Chang, Chunying Chen

Research output: Contribution to journalArticlepeer-review

221 Scopus citations


Zinc oxide nanoparticles (ZnO NPs) have been widely used in cosmetics and sunscreens, advanced textiles, self-charging and electronic devices; the potential for human exposure and the health impact at each stage of their manufacture and use are attracting great concerns. In addition to pulmonary damage, nanoparticle exposure is also strongly correlated with the increase in incidences of cardiovascular diseases; however, their toxic potential remains largely unclear. Herein, we investigated the cellular responses and endoplasmatic reticulum (ER) stress induced by ZnO NPs in human umbilical vein endothelial cells (HUVECs) in comparison with the Zn2+ ions and CeO2 NPs. We found that the dissolved zinc ion was the most significant factor for cytotoxicity in HUVECs. More importantly, ZnO NPs at noncytotoxic concentration, but not CeO2 NPs, can induce significant cellular ER stress response with higher expression of spliced xbp-1, chop, and caspase-12 at the mRNA level, and associated ER marker proteins including BiP, Chop, GADD34, p-PERK, p-eIF2α, and cleaved Caspase-12 at the protein levels. Moreover, ER stress was widely activated after treatment with ZnO NPs, while six of 84 marker genes significantly increased. ER stress response is a sensitive marker for checking the interruption of ER homeostasis by ZnO NPs. Furthermore, higher dosage of ZnO NPs (240 μM) quickly rendered ER stress response before inducing apoptosis. These results demonstrate that ZnO NPs activate ER stress-responsive pathway and the ER stress response might be used as an earlier and sensitive end point for nanotoxicological study.

Original languageEnglish (US)
Pages (from-to)2562-2574
Number of pages13
JournalACS Nano
Issue number3
StatePublished - Mar 25 2014


  • apoptosis
  • ceria
  • cytotoxicity
  • ER stress
  • nanoparticles
  • signaling pathways
  • ZnO

ASJC Scopus subject areas

  • Engineering(all)
  • Materials Science(all)
  • Physics and Astronomy(all)


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