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Article

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

, , , , &
Pages 1215-1229 | Received 05 Feb 2018, Accepted 13 Sep 2018, Published online: 15 Nov 2018
 

Abstract

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.

Acknowledgements

The authors would also like to acknowledge the Facility for Analysis, Characterization, Testing and Simulation (FACTS), Nanyang Technological University, Singapore, for use of their electron microscopy facilities.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors gratefully acknowledge support by the Ministry of Education (Singapore) MOE AcRF Tier 1 [R51/16] to C.Y.T.

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