Human keratinocytes adapt to ZnO nanoparticles induced toxicity via complex paracrine crosstalk and Nrf2-proteasomal signal transduction

Nanotoxicology. 2018 Dec;12(10):1215-1229. doi: 10.1080/17435390.2018.1537409. Epub 2018 Nov 15.


Zinc oxide nanoparticles (Nano-ZnO) is currently one of the most extensively used inorganic particles in a wide range of skin care and consumable products. Therefore, examining the biological effects of Nano-ZnO, especially in the non-cytotoxic levels, thus holds important contemporary practical implications. Herein, our study demonstrates that long-term conditioning of human keratinocytes (HaCaTs) to non-cytoxic dose of Nano-ZnO (∼100 nm) can induce an adaptive response, leading to an enhancement of the cells tolerance against cytotoxic level of Nano-ZnO. It was found that the Nano-ZnO induced adaptive alteration is mediated by a strong synergism between the generation of reactive oxygen species (ROS) flares by a sub-population of cells that are loaded with Nano-ZnO and upregulation of several pro-inflammatory transcripts. Further studies revealed activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) stress response pathway and the associated downstream sustained augmented level of chymotrypsin-like 20 s proteasome activity to be the major mechanism underpinning this phenomenon. Interestingly, these cytoprotective responses can further aid the Nano-ZnO conditioned HaCaT cells to cross-adapt to harmful effects of ultraviolet-A (UVA) by reducing radiation-induced DNA damage. Our findings have unveiled a range of previously undocumented potent and exploitable bioeffects of Nano-ZnO induced ROS mediated signaling within the framework of nano-adaptation.

Keywords: Nrf-2 stress response; Zinc oxide nanoparticles; cellular adaptation; proteasome; reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Dose-Response Relationship, Drug
  • Humans
  • Keratinocytes / drug effects*
  • Keratinocytes / metabolism
  • Metal Nanoparticles / toxicity*
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress / drug effects
  • Paracrine Communication / drug effects*
  • Proteasome Endopeptidase Complex / metabolism*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Zinc Oxide / toxicity*


  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Reactive Oxygen Species
  • Proteasome Endopeptidase Complex
  • Zinc Oxide