title: Bioavailability, intracellular mobilization of nickel, and HIF-1α activation in human lung epithelial cells exposed to metallic nickel and nickel oxide nanoparticles.
abstract: Micron-sized particles of poorly soluble nickel compounds, but not metallic nickel, are established human and rodent carcinogens. In contrast, little is known about the toxic effects of a growing number of Ni-containing materials in the nano-sized range. Here, we performed physicochemical characterization of NiO and metallic Ni nanoparticles and examined their metal ion bioavailability and toxicological properties in human lung epithelial cells. Cellular uptake of metallic Ni and NiO nanoparticles, but not metallic Ni microparticles, was associated with the release of Ni(II) ions after 24-48 h as determined by Newport Green fluorescence. Similar to soluble NiCl₂, NiO nanoparticles induced stabilization and nuclear translocation of hypoxia-inducible factor 1α (HIF-1α) transcription factor followed by upregulation of its target NRDG1 (Cap43). In contrast to no response to metallic Ni microparticles, nickel nanoparticles caused a rapid and prolonged activation of the HIF-1α pathway that was stronger than that induced by soluble Ni(II). Soluble NiCl₂ and NiO nanoparticles were equally toxic to H460 human lung epithelial cells and primary human bronchial epithelial cells; metallic Ni nanoparticles showed lower toxicity and Ni microparticles were nontoxic. Cytotoxicity induced by all forms of Ni occurred concomitant with activation of an apoptotic response, as determined by dose- and time-dependent cleavage of caspases and poly (ADP-ribose) polymerase. Our results show that metallic Ni nanoparticles, in contrast to micron-sized Ni particles, activate a toxicity pathway characteristic of carcinogenic Ni compounds. Moderate cytotoxicity and sustained activation of the HIF-1α pathway by metallic Ni nanoparticles could promote cell transformation and tumor progression.
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912, USA.
authors.forename: Jodie R
authors.initials: JR
authors.lastname: Pietruska
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Liu
authors.forename: Ashley
authors.initials: A
authors.lastname: Smith
authors.forename: Kevin
authors.initials: K
authors.lastname: McNeil
authors.forename: Paula
authors.initials: P
authors.lastname: Weston
authors.forename: Anatoly
authors.initials: A
authors.lastname: Zhitkovich
authors.forename: Robert
authors.initials: R
authors.lastname: Hurt
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Kane
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009532:Nickel / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D010316:Particle Size
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009532:Nickel; C028007:nickel monoxide