Dopant-Dependent Toxicity of CeO<sub>2</sub> Nanoparticles Is Associated with Dynamic Changes in H3K4me3 and H3K27me3 and Transcriptional Activation of NRF2 Gene in HaCaT Human Keratinocytes
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 (TM@CeO<sub>2</sub>; TM = Cr, Mn, Fe, Co, or Ni) nanop...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-03-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/6/3087 |
| _version_ | 1797540952175280128 |
|---|---|
| author | Jang Hyun Choi Haram Lee Hangil Lee Hansol Lee |
| author_facet | Jang Hyun Choi Haram Lee Hangil Lee Hansol Lee |
| author_sort | Jang Hyun Choi |
| collection | DOAJ |
| description | 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 (TM@CeO<sub>2</sub>; 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 CeO<sub>2</sub> 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 Cr@CeO<sub>2</sub> and Co@CeO<sub>2</sub> 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 Cr@CeO<sub>2</sub> NPs. Furthermore, exposure to relatively non-toxic Fe@CeO<sub>2</sub> NPs, but not the toxic Cr@CeO<sub>2</sub> 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 CeO<sub>2</sub> NPs and emphasize that careful evaluation of newly developed NPs should be preceded before industrial or biomedical applications. |
| first_indexed | 2024-03-10T13:08:23Z |
| format | Article |
| id | doaj.art-166eba7976454d38b576cf4db482fda9 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:08:23Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-166eba7976454d38b576cf4db482fda92023-11-21T10:55:08ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01226308710.3390/ijms22063087Dopant-Dependent Toxicity of CeO<sub>2</sub> Nanoparticles Is Associated with Dynamic Changes in H3K4me3 and H3K27me3 and Transcriptional Activation of NRF2 Gene in HaCaT Human KeratinocytesJang Hyun Choi0Haram Lee1Hangil Lee2Hansol Lee3Department of Biological Sciences, College of Natural Science, Inha University, 100 Inha-ro, Michuhol-gu, Incheon 22212, KoreaDepartment of Biological Sciences, College of Natural Science, Inha University, 100 Inha-ro, Michuhol-gu, Incheon 22212, KoreaDepartment of Chemistry, Sookmyung Women’s University, Seoul 04310, KoreaDepartment of Biological Sciences, College of Natural Science, Inha University, 100 Inha-ro, Michuhol-gu, Incheon 22212, KoreaDespite 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 (TM@CeO<sub>2</sub>; 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 CeO<sub>2</sub> 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 Cr@CeO<sub>2</sub> and Co@CeO<sub>2</sub> 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 Cr@CeO<sub>2</sub> NPs. Furthermore, exposure to relatively non-toxic Fe@CeO<sub>2</sub> NPs, but not the toxic Cr@CeO<sub>2</sub> 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 CeO<sub>2</sub> NPs and emphasize that careful evaluation of newly developed NPs should be preceded before industrial or biomedical applications.https://www.mdpi.com/1422-0067/22/6/3087cerium oxide nanoparticles (CeO<sub>2</sub> NPs)transition metal dopingreactive oxygen species (ROS)NRF2-KEAP1 pathwayhistone lysine methylation |
| spellingShingle | Jang Hyun Choi Haram Lee Hangil Lee Hansol Lee Dopant-Dependent Toxicity of CeO<sub>2</sub> 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 cerium oxide nanoparticles (CeO<sub>2</sub> NPs) transition metal doping reactive oxygen species (ROS) NRF2-KEAP1 pathway histone lysine methylation |
| title | Dopant-Dependent Toxicity of CeO<sub>2</sub> Nanoparticles Is Associated with Dynamic Changes in H3K4me3 and H3K27me3 and Transcriptional Activation of NRF2 Gene in HaCaT Human Keratinocytes |
| title_full | Dopant-Dependent Toxicity of CeO<sub>2</sub> Nanoparticles Is Associated with Dynamic Changes in H3K4me3 and H3K27me3 and Transcriptional Activation of NRF2 Gene in HaCaT Human Keratinocytes |
| title_fullStr | Dopant-Dependent Toxicity of CeO<sub>2</sub> Nanoparticles Is Associated with Dynamic Changes in H3K4me3 and H3K27me3 and Transcriptional Activation of NRF2 Gene in HaCaT Human Keratinocytes |
| title_full_unstemmed | Dopant-Dependent Toxicity of CeO<sub>2</sub> Nanoparticles Is Associated with Dynamic Changes in H3K4me3 and H3K27me3 and Transcriptional Activation of NRF2 Gene in HaCaT Human Keratinocytes |
| title_short | Dopant-Dependent Toxicity of CeO<sub>2</sub> Nanoparticles Is Associated with Dynamic Changes in H3K4me3 and H3K27me3 and Transcriptional Activation of NRF2 Gene in HaCaT Human Keratinocytes |
| title_sort | dopant dependent toxicity of ceo sub 2 sub nanoparticles is associated with dynamic changes in h3k4me3 and h3k27me3 and transcriptional activation of nrf2 gene in hacat human keratinocytes |
| topic | cerium oxide nanoparticles (CeO<sub>2</sub> NPs) transition metal doping reactive oxygen species (ROS) NRF2-KEAP1 pathway histone lysine methylation |
| url | https://www.mdpi.com/1422-0067/22/6/3087 |
| work_keys_str_mv | AT janghyunchoi dopantdependenttoxicityofceosub2subnanoparticlesisassociatedwithdynamicchangesinh3k4me3andh3k27me3andtranscriptionalactivationofnrf2geneinhacathumankeratinocytes AT haramlee dopantdependenttoxicityofceosub2subnanoparticlesisassociatedwithdynamicchangesinh3k4me3andh3k27me3andtranscriptionalactivationofnrf2geneinhacathumankeratinocytes AT hangillee dopantdependenttoxicityofceosub2subnanoparticlesisassociatedwithdynamicchangesinh3k4me3andh3k27me3andtranscriptionalactivationofnrf2geneinhacathumankeratinocytes AT hansollee dopantdependenttoxicityofceosub2subnanoparticlesisassociatedwithdynamicchangesinh3k4me3andh3k27me3andtranscriptionalactivationofnrf2geneinhacathumankeratinocytes |