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3 pages, 193 KiB

Open AccessEditorial

Lung Cell Toxicity of Metal-Containing Nanoparticles

by Hanna L. Karlsson and Andrea Hartwig

Nanomaterials 2022, 12(17), 3044; https://doi.org/10.3390/nano12173044 - 2 Sep 2022

Cited by 1 | Viewed by 984

Abstract

Among the various nanomaterials present in society, many contain metals or metal compounds [...] Full article

(This article belongs to the Special Issue Lung Cell Toxicity of Metal-containing Nanoparticles)

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15 pages, 2015 KiB

Open AccessArticle

Impact of Endocytosis and Lysosomal Acidification on the Toxicity of Copper Oxide Nano- and Microsized Particles: Uptake and Gene Expression Related to Oxidative Stress and the DNA Damage Response

by Bettina Maria Strauch, Wera Hubele and Andrea Hartwig

Nanomaterials 2020, 10(4), 679; https://doi.org/10.3390/nano10040679 - 3 Apr 2020

Cited by 21 | Viewed by 3142

Abstract

The toxicity of the copper oxide nanoparticles (CuO NP) has been attributed to the so-called “Trojan horse”-type mechanism, relying on the particle uptake and extensive intracellular release of copper ions, due to acidic pH in the lysosomes. Nevertheless, a clear distinction between extra- [...] Read more.

The toxicity of the copper oxide nanoparticles (CuO NP) has been attributed to the so-called “Trojan horse”-type mechanism, relying on the particle uptake and extensive intracellular release of copper ions, due to acidic pH in the lysosomes. Nevertheless, a clear distinction between extra- and intracellular-mediated effects is still missing. Therefore, the impact of the endocytosis inhibitor hydroxy-dynasore (OH-dyn), as well as bafilomycin A1 (bafA1), inhibiting the vacuolar type H⁺-ATPase (V-ATPase), on the cellular toxicity of nano- and microsized CuO particles, was investigated in BEAS 2 B cells. Selected endpoints were cytotoxicity, copper uptake, glutathione (GSH) levels, and the transcriptional DNA damage and (oxidative) stress response using the high-throughput reverse transcription quantitative polymerase chain reaction (RT-qPCR). OH-dyn markedly reduced intracellular copper accumulation in the cases of CuO NP and CuO MP; the modulation of gene expression, induced by both particle types affecting especially HMOX1, HSPA1A, MT1X, SCL30A1, IL8 and GADD45A, were completely abolished. BafA1 lowered the intracellular copper concentration in case of CuO NP and strongly reduced transcriptional changes, while any CuO MP-mediated effects were not affected by bafA1. In conclusion, the toxicity of CuO NP depended almost exclusively upon dynamin-dependent endocytosis and the intracellular release of redox-active copper ions due to lysosomal acidification, while particle interactions with cellular membranes appeared to be not relevant. Full article

(This article belongs to the Special Issue Lung Cell Toxicity of Metal-containing Nanoparticles)

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14 pages, 6650 KiB

Open AccessArticle

Transcriptome Profiling and Toxicity Following Long-Term, Low Dose Exposure of Human Lung Cells to Ni and NiO Nanoparticles—Comparison with NiCl₂

by Anda R. Gliga, Sebastiano Di Bucchianico, Emma Åkerlund and Hanna L. Karlsson

Nanomaterials 2020, 10(4), 649; https://doi.org/10.3390/nano10040649 - 31 Mar 2020

Cited by 20 | Viewed by 3503

Abstract

Production of nickel (Ni) and nickel oxide (NiO) nanoparticles (NPs) leads to a risk of exposure and subsequent health effects. Understanding the toxicological effects and underlying mechanisms using relevant in vitro methods is, therefore, needed. The aim of this study is to explore [...] Read more.

Production of nickel (Ni) and nickel oxide (NiO) nanoparticles (NPs) leads to a risk of exposure and subsequent health effects. Understanding the toxicological effects and underlying mechanisms using relevant in vitro methods is, therefore, needed. The aim of this study is to explore changes in gene expression using RNA sequencing following long term (six weeks) low dose (0.5 µg Ni/mL) exposure of human lung cells (BEAS-2B) to Ni and NiO NPs as well as soluble NiCl₂. Genotoxicity and cell transformation as well as cellular dose of Ni are also analyzed. Exposure to NiCl₂ resulted in the largest number of differentially expressed genes (197), despite limited uptake, suggesting a major role of extracellular receptors and downstream signaling. Gene expression changes for all Ni exposures included genes coding for calcium-binding proteins (S100A14 and S100A2) as well as TIMP3, CCND2, EPCAM, IL4R and DDIT4. Several top enriched pathways for NiCl₂ were defined by upregulation of, e.g., interleukin-1A and -1B, as well as Vascular Endothelial Growth Factor A (VEGFA). All Ni exposures caused DNA strand breaks (comet assay), whereas no induction of micronuclei was observed. Taken together, this study provides an insight into Ni-induced toxicity and mechanisms occurring at lower and more realistic exposure levels. Full article

(This article belongs to the Special Issue Lung Cell Toxicity of Metal-containing Nanoparticles)

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14 pages, 1590 KiB

Open AccessArticle

Dry Generation of CeO₂ Nanoparticles and Deposition onto a Co-Culture of A549 and THP-1 Cells in Air-Liquid Interface—Dosimetry Considerations and Comparison to Submerged Exposure

by Francesca Cappellini, Sebastiano Di Bucchianico, Venkatanaidu Karri, Siiri Latvala, Maria Malmlöf, Maria Kippler, Karine Elihn, Jonas Hedberg, Inger Odnevall Wallinder, Per Gerde and Hanna L. Karlsson

Nanomaterials 2020, 10(4), 618; https://doi.org/10.3390/nano10040618 - 27 Mar 2020

Cited by 27 | Viewed by 5024

Abstract

Relevant in vitro assays that can simulate exposure to nanoparticles (NPs) via inhalation are urgently needed. Presently, the most common method employed is to expose lung cells under submerged conditions, but the cellular responses to NPs under such conditions might differ from those [...] Read more.

Relevant in vitro assays that can simulate exposure to nanoparticles (NPs) via inhalation are urgently needed. Presently, the most common method employed is to expose lung cells under submerged conditions, but the cellular responses to NPs under such conditions might differ from those observed at the more physiological air-liquid interface (ALI). The aim of this study was to investigate the cytotoxic and inflammatory potential of CeO₂ NPs (NM-212) in a co-culture of A549 lung epithelial cells and differentiated THP-1 cells in both ALI and submerged conditions. Cellular dose was examined quantitatively using inductively coupled plasma mass spectrometry (ICP-MS). The role of serum and LPS-priming for IL-1β release was further tested in THP-1 cells in submerged exposure. An aerosol of CeO₂ NPs was generated by using the PreciseInhale^® system, and NPs were deposited on the co-culture using XposeALI^®. No or minor cytotoxicity and no increased release of inflammatory cytokines (IL-1β, IL-6, TNFα, MCP-1) were observed after exposure of the co-culture in ALI (max 5 µg/cm²) or submerged (max 22 µg/cm²) conditions. In contrast, CeO₂ NPs cause clear IL-1β release in monocultures of macrophage-like THP-1, independent of the presence of serum and LPS-priming. This study demonstrates a useful approach for comparing effects at various in-vitro conditions. Full article

(This article belongs to the Special Issue Lung Cell Toxicity of Metal-containing Nanoparticles)

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18 pages, 1669 KiB

Open AccessArticle

Gene Expression and Epigenetic Changes in Mice Following Inhalation of Copper(II) Oxide Nanoparticles

by Pavel Rossner, Jr., Kristyna Vrbova, Andrea Rossnerova, Tana Zavodna, Alena Milcova, Jiri Klema, Zbynek Vecera, Pavel Mikuska, Pavel Coufalik, Lukas Capka, Kamil Krumal, Bohumil Docekal, Vladimir Holan, Miroslav Machala and Jan Topinka

Nanomaterials 2020, 10(3), 550; https://doi.org/10.3390/nano10030550 - 18 Mar 2020

Cited by 23 | Viewed by 3188

Abstract

We investigated the transcriptomic response and epigenetic changes in the lungs of mice exposed to inhalation of copper(II) oxide nanoparticles (CuO NPs) (8 × 10⁵ NPs/m³) for periods of 3 days, 2 weeks, 6 weeks, and 3 months. A whole [...] Read more.

We investigated the transcriptomic response and epigenetic changes in the lungs of mice exposed to inhalation of copper(II) oxide nanoparticles (CuO NPs) (8 × 10⁵ NPs/m³) for periods of 3 days, 2 weeks, 6 weeks, and 3 months. A whole genome transcriptome and miRNA analysis was performed using next generation sequencing. Global DNA methylation was assessed by ELISA. The inhalation resulted in the deregulation of mRNA transcripts: we detected 170, 590, 534, and 1551 differentially expressed transcripts after 3 days, 2 weeks, 6 weeks, and 3 months of inhalation, respectively. Biological processes and pathways affected by inhalation, differed between 3 days exposure (collagen formation) and longer treatments (immune response). Periods of two weeks exposure further induced apoptotic processes, 6 weeks of inhalation affected the cell cycle, and 3 months of treatment impacted the processes related to cell adhesion. The expression of miRNA was not affected by 3 days of inhalation. Prolonged exposure periods modified miRNA levels, although the numbers were relatively low (17, 18, and 38 miRNAs, for periods of 2 weeks, 6 weeks, and 3 months, respectively). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis based on miRNA–mRNA interactions, revealed the deregulation of processes implicated in the immune response and carcinogenesis. Global DNA methylation was not significantly affected in any of the exposure periods. In summary, the inhalation of CuO NPs impacted on both mRNA and miRNA expression. A significant transcriptomic response was already observed after 3 days of exposure. The affected biological processes and pathways indicated the negative impacts on the immune system and potential role in carcinogenesis. Full article

(This article belongs to the Special Issue Lung Cell Toxicity of Metal-containing Nanoparticles)

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16 pages, 1506 KiB

Open AccessArticle

Understanding Dissolution Rates via Continuous Flow Systems with Physiologically Relevant Metal Ion Saturation in Lysosome

by Johannes G. Keller, Willie Peijnenburg, Kai Werle, Robert Landsiedel and Wendel Wohlleben

Nanomaterials 2020, 10(2), 311; https://doi.org/10.3390/nano10020311 - 12 Feb 2020

Cited by 32 | Viewed by 3249

Abstract

Dissolution rates of nanomaterials can be decisive for acute in vivo toxicity (via the released ions) and for biopersistence (of the remaining particles). Continuous flow systems (CFSs) can screen for both aspects, but operational parameters need to be adjusted to the specific physiological [...] Read more.

Dissolution rates of nanomaterials can be decisive for acute in vivo toxicity (via the released ions) and for biopersistence (of the remaining particles). Continuous flow systems (CFSs) can screen for both aspects, but operational parameters need to be adjusted to the specific physiological compartment, including local metal ion saturation. CFSs have two adjustable parameters: the volume flow-rate and the initial particle loading. Here we explore the pulmonary lysosomal dissolution of nanomaterials containing the metals Al, Ba, Zn, Cu over a wide range of volume flow-rates in a single experiment. We identify the ratio of particle surface area (SA) per volume flow-rate (SA/V) as critical parameter that superimposes all dissolution rates of the same material. Three complementary benchmark materials—ZnO (quick dissolution), TiO₂ (very slow dissolution), and BaSO₄ (partial dissolution)—consistently identify the SA/V range of 0.01 to 0.03 h/μm as predictive for lysosomal pulmonary biodissolution. We then apply the identified method to compare against non-nanoforms of the same substances and test aluminosilicates. For BaSO₄ and TiO₂, we find high similarity of the dissolution rates of their respective nanoform and non-nanoform, governed by the local ion solubility limit at relevant SA/V ranges. For aluminosilicates, we find high similarity of the dissolution rates of two Kaolin nanoforms but significant dissimilarity against Bentonite despite the similar composition. Full article

(This article belongs to the Special Issue Lung Cell Toxicity of Metal-containing Nanoparticles)

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13 pages, 1689 KiB

Open AccessArticle

Genotoxicity and Cytotoxicity of Gold Nanoparticles In Vitro: Role of Surface Functionalization and Particle Size

by Gerard Vales, Satu Suhonen, Kirsi M. Siivola, Kai M. Savolainen, Julia Catalán and Hannu Norppa

Nanomaterials 2020, 10(2), 271; https://doi.org/10.3390/nano10020271 - 6 Feb 2020

Cited by 52 | Viewed by 3594

Abstract

Several studies suggested that gold nanoparticles (NPs) could be genotoxic in vitro and in vivo. However, gold NPs have currently produced present a wide range of sizes and functionalization, which could affect their interactions with the environment or with biological structures and, thus, [...] Read more.

Several studies suggested that gold nanoparticles (NPs) could be genotoxic in vitro and in vivo. However, gold NPs have currently produced present a wide range of sizes and functionalization, which could affect their interactions with the environment or with biological structures and, thus, modify their toxic effects. In this study, we investigated the role of surface charge in determining the genotoxic potential of gold NPs, as measured by the induction of DNA damage (comet assay) and chromosomal damage (micronucleus assay) in human bronchial epithelial BEAS-2B cells. The cellular uptake of gold NPs was assessed by hyperspectral imaging. Two core sizes (~5 nm and ~20 nm) and three functionalizations representing negative (carboxylate), positive (ammonium), and neutral (poly(ethylene glycol); (PEG)ylated) surface charges were examined. Cationic ammonium gold NPs were clearly more cytotoxic than their anionic and neutral counterparts, but genotoxicity was not simply dependent on functionalization or size, since DNA damage was induced by 20-nm ammonium and PEGylated gold NPs, while micronucleus induction was increased by 5-nm ammonium and 20-nm PEGylated gold NPs. The 5-nm carboxylated gold NPs were not genotoxic, and evidence on the genotoxicity of the 20-nm carboxylated gold NPs was restricted to a positive result at the lowest dose in the micronucleus assay. When interpreting the results, it has to be taken into account that cytotoxicity limited the doses available for the ammonium-functionalized gold NPs and that gold NPs have earlier been described to interfere with the comet assay procedure, possibly resulting in a false positive result. In conclusion, our findings show that the cellular uptake and cytotoxicity of gold NPs are clearly enhanced by positive surface charge, but neither functionalization nor size can single-handedly account for the genotoxic effects of the gold NPs. Full article

(This article belongs to the Special Issue Lung Cell Toxicity of Metal-containing Nanoparticles)

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17 pages, 8019 KiB

Open AccessArticle

Lung Toxicity Analysis of Nano-Sized Kaolin and Bentonite: Missing Indications for a Common Grouping

by Martin Wiemann, Antje Vennemann and Wendel Wohlleben

Nanomaterials 2020, 10(2), 204; https://doi.org/10.3390/nano10020204 - 24 Jan 2020

Cited by 14 | Viewed by 2985

Abstract

Kaolin and bentonite (nanoclay NM-600) are nanostructured aluminosilicates that share a similar chemical composition, platelet-like morphology, and high binding capacity for biomolecules. To investigate if these material-based criteria allow for a common grouping, we prepared particle suspensions of kaolin and bentonite with a [...] Read more.

Kaolin and bentonite (nanoclay NM-600) are nanostructured aluminosilicates that share a similar chemical composition, platelet-like morphology, and high binding capacity for biomolecules. To investigate if these material-based criteria allow for a common grouping, we prepared particle suspensions of kaolin and bentonite with a similar hydrodynamic diameter and administered them to NR8383 alveolar macrophages in vitro and also to a rat lung using quartz DQ12 as a reference material. Bentonite was far more bioactive in vitro, indicated by a lower threshold for the release of enzymes, tumor necrosis factor α, and H₂O₂. In addition, in the lung, the early effects of bentonite exceeded those of kaolin and even those of quartz, due to strongly increased numbers of inflammatory cells, and elevated concentrations of total protein and fibronectin within the bronchoalveolar lavage fluid. The pro-inflammatory effects of bentonite decreased over time, although assemblies of particle-laden alveolar macrophages (CD68 positive), numerous type-2 epithelial cells (immunopositive for pro-surfactant protein C), and hypertrophic lung epithelia persisted until day 21. At this point in time, kaolin-treated lungs were completely recovered, whereas quartz DQ12 had induced a progressive inflammation. We conclude that bentonite is far more bioactive than equally sized kaolin. This argues against a common grouping of aluminosilicates, previously suggested for different kaolin qualities. Full article

(This article belongs to the Special Issue Lung Cell Toxicity of Metal-containing Nanoparticles)

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