title: Zinc oxide nanoparticles-induced epigenetic change and G2/M arrest are associated with apoptosis in human epidermal keratinocytes.
abstract: As an engineered nanomaterial, zinc oxide nanoparticles (ZnO NPs) are used frequently in biological applications and can make contact with human skin. Here, we systematically investigated the effects of ZnO NPs on non-tumorigenic human epidermal keratinocytes, which were used as a test model for this in vitro study, at the epigenetic and molecular levels. Our results showed that ZnO NPs induced cell cycle arrest at the G2/M checkpoint before the viability of human epidermal keratinocytes was reduced, which was associated with the chromatin changes at the epigenetic level, including increased methylation of histone H3K9 and decreased acetylation of histone H4K5 accompanied by chromatin condensation at 24 hours. The mRNA expression of the methyltransferase genes G9a and GLP was also increased upon treatment with ZnO NPs, and the acetyltransferase genes GCN5, P300, and CBP were downregulated. Reactive oxygen species were found to be more abundant after treatment with ZnO NPs for 6 hours, and DNA damage was observed at 24 hours. Transmission electron microscopy and flow cytometry confirmed that ZnO NPs were absorbed into the cell when they were added to the medium. Apoptotic human epidermal keratinocytes were detected, and the expression of the proapoptotic genes Bax, Noxa, and Puma increased significantly, while the expression of the antiapoptotic gene Bcl-xl decreased 24 hours after exposure to ZnO NPs. These findings suggest that the ZnO NPs induced cell cycle arrest at G2/M, which was associated with epigenetic changes and accompanied by p53-Bax mitochondrial pathway-mediated apoptosis.
authors: State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
authors: Fei
authors: F
authors: Gao
authors: State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
authors: Ningjie
authors: N
authors: Ma
authors: State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
authors: Hong
authors: H
authors: Zhou
authors: State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
authors: Qing
authors: Q
authors: Wang
authors: State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
authors: Hao
authors: H
authors: Zhang
authors: State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
authors: Pu
authors: P
authors: Wang
authors: State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
authors: Haoli
authors: H
authors: Hou
authors: State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
authors: Huan
authors: H
authors: Wen
authors: State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
authors: Lijia
authors: L
authors: Li
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D000078404:Epidermal Cells; D044127:Epigenesis, Genetic / Q000187:drug effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects; D008239:Lysine / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D008745:Methylation / Q000187:drug effects; D008954:Models, Biological; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D015034:Zinc Oxide / Q000494:pharmacology*
chemical_list: D002843:Chromatin; C468783:H2AX protein, human; D006657:Histones; D017382:Reactive Oxygen Species; D008239:Lysine; D015034:Zinc Oxide
keywords: ZnO nanoparticle; cell cycle G2/M arrest; histone modification; p53-Bax mitochondrial apoptosis pathway; reactive oxygen species