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Abstract
BackgroundGenotoxicity is an important toxicological endpoint due to the link to diseases such as cancer. Therefore, an increased understanding regarding genotoxicity and underlying mechanisms is needed for assessing the risk with exposure to nanoparticles (NPs). The aim of this study was to perform an in-depth investigation regarding the genotoxicity of well-characterized Ni and NiO NPs in human bronchial epithelial BEAS-2B cells and to discern possible mechanisms. Comparisons were made with NiCl2 in order to elucidate effects of ionic Ni.MethodsBEAS-2B cells were exposed to Ni and NiO NPs, as well as NiCl2, and uptake and cellular dose were investigated by transmission electron microscopy (TEM) and inductively coupled plasma mass spectrometry (ICP-MS). The NPs were characterized in terms of surface composition (X-ray photoelectron spectroscopy), agglomeration (photon cross correlation spectroscopy) and nickel release in cell medium (ICP-MS). Cell death (necrosis/apoptosis) was investigated by Annexin V-FITC/PI staining and genotoxicity by cytokinesis-block micronucleus (cytome) assay (OECD 487), chromosomal aberration (OECD 473) and comet assay. The involvement of intracellular reactive oxygen species (ROS) and calcium was explored using the fluorescent probes, DCFH-DA and Fluo-4.ResultsNPs were efficiently taken up by the BEAS-2B cells. In contrast, no or minor uptake was observed for ionic Ni from NiCl2. Despite differences in uptake, all exposures (NiO, Ni NPs and NiCl2) caused chromosomal damage. Furthermore, NiO NPs were most potent in causing DNA strand breaks and generating intracellular ROS. An increase in intracellular calcium was observed and modulation of intracellular calcium by using inhibitors and chelators clearly prevented the chromosomal damage. Chelation of iron also protected against induced damage, particularly for NiO and NiCl2.ConclusionsThis study has revealed chromosomal damage by Ni and NiO NPs as well as Ni ionic species and provides novel evidence for a calcium-dependent mechanism of cyto- and genotoxicity.
Highlights
Genotoxicity is an important toxicological endpoint due to the link to diseases such as cancer
The transmission electron microscopy (TEM) analysis showed Ni NPs to be of varying sizes but predominantly less than 100 nm, and nickel oxide (NiO) NPs less than 50 nm (Fig. 1a)
The results showed NiO NPs to be highly reactive when the assay was performed without HRP whereas Ni and NiO showed rather similar effects in the presence of HRP
Summary
Genotoxicity is an important toxicological endpoint due to the link to diseases such as cancer. An increased understanding regarding genotoxicity and underlying mechanisms is needed for assessing the risk with exposure to nanoparticles (NPs). The International Agency for Research on Cancer has classified nickel compounds as carcinogenic to humans (Group 1) whereas Ni metal, on the other hand, is classified as Group 2B (possibly carcinogenic to humans) [3, 4]. This is due to a lack of associations observed in epidemiological studies and no clear association between respiratory tumors and micron-sized nickel metal powder in a chronic inhalation study on rats [5].
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