Up-regulation of Gadd45α after exposure to metal nanoparticles: The role of hypoxia inducible factor 1α

Authors

  • Lingfang Feng,

    1. Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang, People's Republic of China
    2. Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, Kentucky, USA
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    • These authors contributed equally to this work.

  • Yue Zhang,

    1. Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, Kentucky, USA
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    • These authors contributed equally to this work.

  • Mizu Jiang,

    1. Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, Kentucky, USA
    2. Department of Gastroenterology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
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  • Yiqun Mo,

    1. Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, Kentucky, USA
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  • Rong Wan,

    1. Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, Kentucky, USA
    2. Department of Pathology, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
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  • Zhenyu Jia,

    1. Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang, People's Republic of China
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  • David J. Tollerud,

    1. Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, Kentucky, USA
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  • Xing Zhang,

    1. Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang, People's Republic of China
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  • Qunwei Zhang

    Corresponding author
    1. Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, Kentucky, USA
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ABSTRACT

The increased development and use of nanoparticles in various fields may lead to increased exposure, directly affecting human health. Our current knowledge of the health effects of metal nanoparticles such as cobalt and titanium dioxide (Nano-Co and Nano-TiO2) is limited but suggests that some metal nanoparticles may cause genotoxic effects including cell cycle arrest, DNA damage, and apoptosis. The growth arrest and DNA damage-inducible 45α protein (Gadd45α) has been characterized as one of the key players in the cellular responses to a variety of DNA damaging agents. The aim of this study was to investigate the alteration of Gadd45α expression in mouse embryo fibroblasts (PW) exposed to metal nanoparticles and the possible mechanisms. Non-toxic doses of Nano-Co and Nano-TiO2 were selected to treat cells. Our results showed that Nano-Co caused a dose- and time-dependent increase in Gadd45α expression, but Nano-TiO2 did not. To investigate the potential pathways involved in Nano-Co-induced Gadd45α up-regulation, we measured the expression of hypoxia inducible factor 1α (HIF-1α) in PW cells exposed to Nano-Co and Nano-TiO2. Our results showed that exposure to Nano-Co caused HIF-1α accumulation in the nucleus. In addition, hypoxia inducible factor 1α knock-out cells [HIF-1α (−/−)] and its wild-type cells [HIF-1α (+/+)] were used. Our results demonstrated that Nano-Co caused a dose- and time-dependent increase in Gadd45α expression in wild-type HIF-1α (+/+) cells, but only a slight increase in HIF-1α (−/−) cells. Pre-treatment of PW cells with heat shock protein 90 inhibitor, 17-(Allylamino)−17-demethoxygeldanamycin (17-AAG), prior to exposure to Nano-Co significantly abolished Nano-Co-induced Gadd45α expression. These results suggest that HIF-1α accumulation may be partially involved in the increased Gadd45α expression in cells exposed to Nano-Co. These findings may have important implications for understanding the potential health effects of metal nanoparticle exposure. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 490–499, 2015.

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