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.

Nickel-free stainless steel avoids neointima formation following coronary stent implantation

“…As described previously in rat pleural mesothelial cells [37] and human lung epithelial cells [38], Ni 2+ increased the level of HIF-1α (HIF1A) protein, which is important for SMC proliferation and vascular remodeling [39] under the normoxic conditions ( figure 3(b)). In addition, expression of downstream target genes of HIF-1α, including Vegfa, Adm1, Adm2 and Pdgfb [40,41], was markedly upregulated by Ni 2+ under normoxic conditions.…”

Nickel Nanoparticles Enhance Platelet-Derived Growth Factor–Induced Chemokine Expression by Mesothelial Cells via Prolonged Mitogen-Activated Protein Kinase Activation

“…Recent studies have also shown that nano-sized Ni particles can sustain HIF-1a activity in human cell lines (47,48). Therefore, we hypothesized that ROS mediated the induction of HIF-1a and chemokines that were induced by NiNPs or the combination of NiNPs and PDGF in NRM2 cells.…”

The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles

“…In vitro experiments showed higher cytotoxicity of well-dispersed mesoporous silica and amorphous silica, dolomite, ZnO, Ni, Ag, and polystyrene NPs compared to the respective microparticles. [6][7][8][9][10][11][12][13][14][15] When particles smaller than 100 nm are compared, still-smaller particles act more toxically than larger ones (quantum dots, 16 TiO 2 17 ). In contrast to these studies, no differences have been reported for 10-100 nm silica particles compared to 45 µm ones, 18 and for nickel ferrite NPs.…”