title: Up-regulation of Gadd45α after exposure to metal nanoparticles: the role of hypoxia inducible factor 1α.
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.
authors.affiliation: Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang, People's Republic of China; Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Lingfang
authors.initials: L
authors.lastname: Feng
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mizu
authors.initials: M
authors.lastname: Jiang
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Mo
authors.forename: Rong
authors.initials: R
authors.lastname: Wan
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Jia
authors.forename: David J
authors.initials: DJ
authors.lastname: Tollerud
authors.forename: Xing
authors.initials: X
authors.lastname: Zhang
authors.forename: Qunwei
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D002478:Cells, Cultured; D003035:Cobalt / Q000633:toxicity; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D053768:Metal Nanoparticles / Q000633:toxicity*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D003035:Cobalt; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins
keywords: DNA damage; Gadd45α; HIF-1α; metal nanoparticles; mouse embryo fibroblasts