| 1. |
- Di Bucchianico, Sebastiano, et al.
(author)
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Calcium-dependent cyto- and genotoxicity of nickel metal and nickel oxide nanoparticles in human lung cells
- 2018
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In: Particle and Fibre Toxicology. - : BMC. - 1743-8977. ; 15
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Journal article (peer-reviewed)abstract
- Background: Genotoxicity 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. Methods: BEAS-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 VFITC/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. Results: NPs 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. Conclusions: This 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.
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| 2. |
- Gliga, Anda R, et al.
(author)
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Prenatal arsenic exposure is associated with increased plasma IGFBP3 concentrations in 9-year-old children partly via changes in DNA methylation
- 2018
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In: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 92:8, s. 2487-2500
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Journal article (peer-reviewed)abstract
- Exposure to inorganic arsenic (As), a carcinogen and epigenetic toxicant, has been associated with lower circulating levels of insulin-like growth factor 1 (IGF1) and impaired growth in children of pre-school age. The aim of this study was to assess the potential impact of exposure to As on IGF1 and insulin-like growth factor-binding protein 3 (IGFBP3) as well as DNA methylation changes in 9-year-old children. To this end, we studied 9-year-old children from a longitudinal mother-child cohort in rural Bangladesh (n = 551). Prenatal and concurrent exposure to As was assessed via concentrations in maternal urine at gestational week 8 and in child urine at 9 years, measured by HPLC-HG-ICPMS. Plasma IGF1 and IGFBP3 concentrations were quantified with immunoassays. DNA methylation was measured in blood mononuclear cells at 9 years in a sub-sample (n = 113) using the Infinium HumanMethylation450K BeadChip. In multivariable-adjusted linear regression models, prenatal As (natural log-transformed), but not children's concurrent urinary As, was positively associated with IGFBP3 concentrations (β = 76, 95% CI 19, 133). As concentrations were not associated with IGF1. DNA methylation analysis revealed CpGs associated with both prenatal As and IGFBP3. Mediation analysis suggested that methylation of 12 CpG sites for all children was mediator of effect for the association between prenatal As and IGFBP3. We also found differentially methylated regions, generally hypermethylated, that were associated with both prenatal As and IGFBP3. In all, our study revealed that prenatal exposure to As was positively associated with IGFBP3 concentrations in children at 9 years, independent of IGF1, and this association may, at least in part, be epigenetically mediated.
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| 3. |
- Gliga, Anda R., et al.
(author)
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RNA-sequencing reveals long-term effects of silver nanoparticles on human lung cells
- 2018
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Journal article (peer-reviewed)abstract
- Despite a considerable focus on the adverse effects of silver nanoparticles (AgNPs) in recent years, studies on the potential long-term effects of AgNPs are scarce. The aim of this study was to explore the effects of AgNPs following repeated low-dose, long-term exposure of human bronchial epithelial cells. To this end, the human BEAS-2B cell line was exposed to 1 mu g/mL AgNPs (10 nm) for 6 weeks followed by RNA-sequencing (RNA-Seq) as well as genome-wide DNA methylation analysis. The transcriptomics analysis showed that a substantial number of genes (1717) were differentially expressed following AgNP exposure whereas only marginal effects on DNA methylation were observed. Downstream analysis of the transcriptomics data identified several affected pathways including the 'fibrosis' and 'epithelial-mesenchymal transition' (EMT) pathway. Subsequently, functional validation studies were performed using AgNPs of two different sizes (10 nm and 75 nm). Both NPs increased collagen deposition, indicative of fibrosis, and induced EMT, as evidenced by an increased invasion index, anchorage independent cell growth, as well as cadherin switching. In conclusion, using a combination of RNA-Seq and functional assays, our study revealed that repeated low-dose, long-term exposure of human BEAS-2B cells to AgNPs is pro-fibrotic, induces EMT and cell transformation.
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| 4. |
- Mukherjee, Sourav P., et al.
(author)
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Graphene oxide is degraded by neutrophils and the degradation products are non-genotoxic
- 2018
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In: Nanoscale. - : Royal Society of Chemistry (RSC). - 2040-3364 .- 2040-3372. ; 10:3, s. 1180-1188
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Journal article (peer-reviewed)abstract
- Neutrophils were previously shown to digest oxidized carbon nanotubes through a myeloperoxidase (MPO)-dependent mechanism, and graphene oxide (GO) was found to undergo degradation when incubated with purified MPO, but there are no studies to date showing degradation of GO by neutrophils. Here we produced endotoxin-free GO by a modified Hummers' method and asked whether primary human neutrophils stimulated to produce neutrophil extracellular traps or activated to undergo degranulation are capable of digesting GO. Biodegradation was assessed using a range of techniques including Raman spectroscopy, transmission electron microscopy, atomic force microscopy, and mass spectrometry. GO sheets of differing lateral dimensions were effectively degraded by neutrophils. As the degradation products could have toxicological implications, we also evaluated the impact of degraded GO on the bronchial epithelial cell line BEAS-2B. MPO-degraded GO was found to be non-cytotoxic and did not elicit any DNA damage. Taken together, these studies have shown that neutrophils can digest GO and that the biodegraded GO is non-toxic for human lung cells.
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