期刊
TOXICOLOGICAL SCIENCES
卷 124, 期 1, 页码 138-148出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfr206
关键词
nickel; nanoparticles; HIF-1 alpha; cytotoxicity; apoptosis; cancer
类别
资金
- National Institutes of Health Superfund Research Program [P42 ES013660, R01 ES016178]
- Environmental Protection Agency STAR [R833862]
- U.S. Environmental Protection Agency Region
- EPA [R833862, 150232] Funding Source: Federal RePORTER
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 NiCl(2), NiO nanoparticles induced stabilization and nuclear translocation of hypoxia-inducible factor 1 alpha (HIF-1 alpha) 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-1 alpha pathway that was stronger than that induced by soluble Ni (II). Soluble NiCl(2) 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-1 alpha pathway by metallic Ni nanoparticles could promote cell transformation and tumor progression.
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