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Article

Dopant-Dependent Toxicity of CeO2 Nanoparticles Is Associated with Dynamic Changes in H3K4me3 and H3K27me3 and Transcriptional Activation of NRF2 Gene in HaCaT Human Keratinocytes

1
Department of Biological Sciences, College of Natural Science, Inha University, 100 Inha-ro, Michuhol-gu, Incheon 22212, Korea
2
Department of Chemistry, Sookmyung Women’s University, Seoul 04310, Korea
*
Authors to whom correspondence should be addressed.
Academic Editor: Lorenzo Corsi
Int. J. Mol. Sci. 2021, 22(6), 3087; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063087
Received: 10 March 2021 / Revised: 15 March 2021 / Accepted: 15 March 2021 / Published: 17 March 2021
(This article belongs to the Special Issue Toxicology of Metal Particles and OTC)
Despite advances in the preparation of metal oxide (MO) nanoparticles (NPs) as catalysts for various applications, concerns about the biosafety of these particles remain. In this study, we prepared transition metal-doped cerium oxide ([email protected]2; TM = Cr, Mn, Fe, Co, or Ni) nanoparticles and investigated the mechanism underlying dopant-dependent toxicity in HaCaT human keratinocytes. We show that doping with Cr or Co but not Fe, Mn, or Ni increased the toxicity of CeO2 NPs in dose- and time-dependent manners and led to apoptotic cell death. Interestingly, while both undoped and transition metal-doped NPs increased intracellular reactive oxygen species (ROS), toxic [email protected]2 and [email protected]2 NPs failed to induce the expression of NRF2 (nuclear factor erythroid 2-related factor 2) as well as its downstream target genes involved in the antioxidant defense system. Moreover, activation of NRF2 transcription was correlated with dynamic changes in H3K4me3 and H3K27me3 at the promoter of NRF2, which was not observed in cells exposed to [email protected]2 NPs. Furthermore, exposure to relatively non-toxic [email protected]2 NPs, but not the toxic [email protected]2 NPs, resulted in increased binding of MLL1 complex, a major histone lysine methylase mediating trimethylation of histone H3 lysine 4, at the NRF2 promoter. Taken together, our findings strongly suggest that failure of cells to respond to oxidative stress is critical for dopant-dependent toxicity of CeO2 NPs and emphasize that careful evaluation of newly developed NPs should be preceded before industrial or biomedical applications. View Full-Text
Keywords: cerium oxide nanoparticles (CeO2 NPs); transition metal doping; reactive oxygen species (ROS); NRF2-KEAP1 pathway; histone lysine methylation cerium oxide nanoparticles (CeO2 NPs); transition metal doping; reactive oxygen species (ROS); NRF2-KEAP1 pathway; histone lysine methylation
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MDPI and ACS Style

Choi, J.H.; Lee, H.; Lee, H.; Lee, H. Dopant-Dependent Toxicity of CeO2 Nanoparticles Is Associated with Dynamic Changes in H3K4me3 and H3K27me3 and Transcriptional Activation of NRF2 Gene in HaCaT Human Keratinocytes. Int. J. Mol. Sci. 2021, 22, 3087. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063087

AMA Style

Choi JH, Lee H, Lee H, Lee H. Dopant-Dependent Toxicity of CeO2 Nanoparticles Is Associated with Dynamic Changes in H3K4me3 and H3K27me3 and Transcriptional Activation of NRF2 Gene in HaCaT Human Keratinocytes. International Journal of Molecular Sciences. 2021; 22(6):3087. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063087

Chicago/Turabian Style

Choi, Jang H., Haram Lee, Hangil Lee, and Hansol Lee. 2021. "Dopant-Dependent Toxicity of CeO2 Nanoparticles Is Associated with Dynamic Changes in H3K4me3 and H3K27me3 and Transcriptional Activation of NRF2 Gene in HaCaT Human Keratinocytes" International Journal of Molecular Sciences 22, no. 6: 3087. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063087

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