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Archives of Toxicology (v.85, #7)
Toxicity of nanocrystal quantum dots: the relevance of surface modifications by Akiyoshi Hoshino; Sanshiro Hanada; Kenji Yamamoto (pp. 707-720).
With the development of nanotechnology, nanometer-sized products smaller than several 100 nm have been applied for all areas of science and technology. The nanometer-sized products, including carbon nanotubes, fullerene derivatives, and nanocrystals made of various materials, are widely employed as novel tools in various fields, not only in material engineering, electronics, plastics, automobile, aviation, and aerospace industries, but also even in cellular biology, molecular biology, and basic and clinical medical fields. In particular, nanocrystal quantum dots (QDs) have been widely used in biological and medical studies because of their far brighter photoemission and photostability. The physical and chemical properties of QDs have been circumstantially investigated, but little is known about the potential harmful effects of QDs on human health. In addition to the physical and chemical properties of the QDs, their toxicity and biological behavior are generally regulated by three other conditions: (1) the QD core material itself, (2) the surface modifications of the QD, and (3) the external environmental condition of the QDs. We herein report on the in vitro and in vivo toxicity and biological behavior of nanocrystals such as QDs. Accumulating evidence suggests that the QD-capping material, rather than the core metalloid complex, is responsible for the majority of their toxicity and biological activity. For example, molecules covered with a toxic agent showed cytotoxicity, whereas QDs conjugated with biomolecules retained the biological effects of the conjugate.
Keywords: Nanoparticle; Toxicity; Surface modification
Erratum to: Toxicity of nanocrystal quantum dots: the relevance of surface modifications
by Akiyoshi Hoshino; Sanshiro Hanada; Kenji Yamamoto (pp. 721-721).
Nanotoxicology: a perspective and discussion of whether or not in vitro testing is a valid alternative by Martin J. D. Clift; Peter Gehr; Barbara Rothen-Rutishauser (pp. 723-731).
Despite the many proposed advantages related to nanotechnology, there are increasing concerns as to the potential adverse human health and environmental effects that the production of, and subsequent exposure to nanoparticles (NPs) might pose. In regard to human health, these concerns are founded upon the plethora of knowledge gained from research relating to the effects observed following exposure to environmental air pollution. It is known that increased exposure to environmental air pollution can cause reduced respiratory health, as well as exacerbate pre-existing conditions such as cardiovascular disease and chronic obstructive pulmonary disease. Such disease states have also been associated with exposure to the NP component contained within environmental air pollution, raising concerns as to the effects of NP exposure. It is not only exposure to accidentally produced NPs however, which should be approached with caution. Over the past decades, NPs have been specifically engineered for a wide range of consumer, industrial and technological applications. Due to the inevitable exposure of NPs to humans, owing to their use in such applications, it is therefore imperative that an understanding of how NPs interact with the human body is gained. In vivo research poses a beneficial model for gaining immediate and direct knowledge of human exposure to such xenobiotics. This research outlook however, has numerous limitations. Increased research using in vitro models has therefore been performed, as these models provide an inexpensive and high-throughput alternative to in vivo research strategies. Despite such advantages, there are also various restrictions in regard to in vitro research. Therefore, the aim of this review, in addition to providing a short perspective upon the field of nanotoxicology, is to discuss (1) the advantages and disadvantages of in vitro research and (2) how in vitro research may provide essential information pertaining to the human health risks posed by NP exposure.
Keywords: Nanotechnology; Nanoparticle; In vitro testing strategies; Human health; Toxicity; Nanotoxicology; Environmental air pollution; NP exposure
Nanoparticles: molecular targets and cell signalling by Francelyne Marano; Salik Hussain; Fernando Rodrigues-Lima; Armelle Baeza-Squiban; Sonja Boland (pp. 733-741).
Increasing evidence linking nanoparticles (NPs) with different cellular outcomes necessitate an urgent need for the better understanding of cellular signalling pathways triggered by NPs. Oxidative stress has largely been reported to be implicated in NP-induced toxicity. It could activate a wide variety of cellular events such as cell cycle arrest, apoptosis, inflammation and induction of antioxidant enzymes. These responses occur after the activation of different cellular pathways. In this context, three groups of MAP kinase cascades [ERK (extracellular signal-regulated kinases), p38 mitogen-activated protein kinase and JNK (c-Jun N-terminal kinases)] as well as redox-sensitive transcription factors such as NFκB and Nrf-2 were specially investigated. The ability of NPs to interact with these signalling pathways could partially explain their cytotoxicity. The induction of apoptosis is also closely related to the modulation of signalling pathways induced by NPs. Newly emerged scientific areas of research are the studies on interactions between NPs and biological molecules in body fluids, cellular microenvironment, intracellular components or secreted cellular proteins such as cytokines, growth factors and enzymes and use of engineered NPs to target various signal transduction pathways in cancer therapy. Recently published data present the ability of NPs to interact with membrane receptors leading to a possible aggregation of these receptors. These interactions could lead to a sustained modulation of specific signalling in the target cells or paracrine and even “by-stander” effects of the neighbouring cells or tissues. However, oxidative stress is not sufficient to explain specific mechanisms which could be induced by NPs, and these new findings emphasize the need to revise the paradigm of oxidative stress to explain the effects of NPs.
Keywords: Nanoparticle; Oxidative stress; Cell signalling; Inflammation; Nano–bio interactions; Apoptosis
Cytotoxicity and genotoxicity of silver nanoparticles in the human lung cancer cell line, A549 by Rasmus Foldbjerg; Duy Anh Dang; Herman Autrup (pp. 743-750).
Nanomaterials, especially silver nanoparticles (Ag NPs), are used in a rapidly increasing number of commercial products. Accordingly, the hazards associated with human exposure to nanomaterials should be investigated to facilitate the risk assessment process. A potential route of exposure to NPs is through the respiratory system. In the present study, we investigated the effects of well-characterized PVP-coated Ag NPs and silver ions (Ag+) in the human, alveolar cell line, A549. Dose-dependent cellular toxicity caused by Ag NPs and Ag+ was demonstrated by the MTT and annexin V/propidium iodide assays, and evidence of Ag NP uptake could be measured indirectly by atomic absorption spectroscopy and flow cytometry. The cytotoxicity of both silver compounds was greatly decreased by pretreatment with the antioxidant, N-acetyl-cysteine, and a strong correlation between the levels of reactive oxygen species (ROS) and mitochondrial damage (r s = −0.8810; p = 0.0039) or early apoptosis (r s = 0.8857; p = 0.0188) was observed. DNA damage induced by ROS was detected as an increase in bulky DNA adducts by 32P postlabeling after Ag NP exposure. The level of bulky DNA adducts was strongly correlated with the cellular ROS levels (r s = 0.8810, p = 0.0039) and could be inhibited by antioxidant pretreatment, suggesting Ag NPs as a mediator of ROS-induced genotoxicity.
Keywords: Silver; Nanoparticles; Reactive oxygen species; Apoptosis; Bulky DNA adducts
Radiolabelling of engineered nanoparticles for in vitro and in vivo tracing applications using cyclotron accelerators by N. Gibson; U. Holzwarth; K. Abbas; F. Simonelli; J. Kozempel; I. Cydzik; G. Cotogno; A. Bulgheroni; D. Gilliland; J. Ponti; F. Franchini; P. Marmorato; H. Stamm; W. Kreyling; A. Wenk; M. Semmler-Behnke; S. Buono; L. Maciocco; N. Burgio (pp. 751-773).
We present in this article an outline of some cyclotron-based irradiation techniques that can be used to directly radiolabel industrially manufactured nanoparticles, as well as two techniques for synthesis of labelled nanoparticles using cyclotron-generated radioactive precursor materials. These radiolabelled nanoparticles are suitable for a range of different in vitro and in vivo tracing studies of relevance to the field of nanotoxicology. A basic overview is given of the relevant physics of nuclear reactions regarding both ion-beam and neutron production of radioisotopes. The various issues that determine the practicality and usefulness of the different methods are discussed, including radioisotope yield, nuclear reaction kinetics, radiation and thermal damage, and radiolabel stability. Experimental details are presented regarding several techniques applied in our laboratories, including direct light-ion activation of dry nanoparticle samples, neutron activation of nanoparticles and suspensions using an ion-beam driven activator, spark-ignition generation of nanoparticle aerosols using activated electrode materials, and radiochemical synthesis of nanoparticles using cyclotron-produced isotopes. The application of these techniques is illustrated through short descriptions of some selected results thus far achieved. It is shown that these cyclotron-based methods offer a very useful range of options for nanoparticle radiolabelling despite some experimental difficulties associated with their application. For direct nanoparticle radiolabelling, if care is taken in choosing the experimental conditions applied, useful activity levels can be achieved in a wide range of nanoparticle types, without causing substantial thermal or radiation damage to the nanoparticle structure. Nanoparticle synthesis using radioactive precursors presents a different set of issues and offers a complementary and equally valid approach when laboratory generation of the nanoparticles is acceptable for the proposed studies, and where an appropriate radiolabel can be incorporated into the nanoparticles during synthesis.
Keywords: Nanoparticles; Toxicity; Radiolabelling; Radiotracer; Ion beam irradiation; Neutron irradiation
Aspect ratio has no effect on genotoxicity of multi-wall carbon nanotubes by Jin Sik Kim; Kyu Lee; Young Hee Lee; Hyun Sun Cho; Ki Heon Kim; Kyung Hee Choi; Sang Hee Lee; Kyung Seuk Song; Chang Soo Kang; Il Je Yu (pp. 775-786).
Carbon nanotubes (CNTs) have specific physico-chemical and electrical properties that are useful for telecommunications, medicine, materials, manufacturing processes and the environmental and energy sectors. Yet, despite their many advantages, it is also important to determine whether CNTs may represent a hazard to the environment and human health. Like asbestos, the aspect ratio (length:diameter) and metal components of CNTs are known to have an effect on the toxicity of carbon nanotubes. Thus, to evaluate the toxic potential of CNTs in relation to their aspect ratio and metal contamination, in vivo and in vitro genotoxicity tests were conducted using high-aspect-ratio (diameter: 10–15 nm, length: ~10 μm) and low-aspect-ratio multi-wall carbon nanotubes (MWCNTs, diameter: 10–15 nm, length: ~150 nm) according to OECD test guidelines 471 (bacterial reverse mutation test), 473 (in vitro chromosome aberration test), and 474 (in vivo micronuclei test) with a good laboratory practice system. To determine the treatment concentration for all the tests, a solubility and dispersive test was performed, and a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) solution found to be more suitable than distilled water. Neither the high- nor the low-aspect-ratio MWCNTs induced any genotoxicity in a bacterial reverse mutation test (~1,000 μg/plate), in vitro chromosome aberration test (without S9: ~6.25 μg/ml, with S9: ~50 μg/ml), or in vivo micronuclei test (~50 mg/kg). However, the high-aspect-ratio MWCNTs were found to be more toxic than the low-aspect-ratio MWCNTs. Thus, while high-aspect-ratio MWCNTs do not induce direct genotoxicity or metabolic activation–mediated genotoxicity, genotoxicity could still be induced indirectly through oxidative stress or inflammation.
Keywords: Carbon nanotubes (CNTs); Multi-wall carbon nanotubes (MWCNTs); Genotoxicity; OECD test guidelines; Bacterial reverse mutation test; In vitro chromosome aberration test; In vivo micronuclei test; Good laboratory practice (GLP); Cytotoxicity
Differential stability of lead sulfide nanoparticles influences biological responses in embryonic zebrafish by Lisa Truong; Ian S. Moody; Dylan P. Stankus; Jeffrey A. Nason; Mark C. Lonergan; Robert L. Tanguay (pp. 787-798).
As the number of nanoparticle-based products increase in the marketplace, there will be increased potential for human exposures to these engineered materials throughout the product life cycle. We currently lack sufficient data to understand or predict the inherent nanomaterial characteristics that drive nanomaterial–biological interactions and responses. In this study, we utilized the embryonic zebrafish (Danio rerio) model to investigate the importance of nanoparticle (NP) surface functionalization, in particular as it pertains to nanoparticle stability, on in vivo biological responses. This is a comparative study where two lead sulfide nanoparticles (PbS-NPs) with nearly identical core sizes, but functionalized with either sodium 3-mercaptopropanesulfonate (MT) or sodium 2,3-dimercaptopropanesulfonate (DT) ligand, were used. Developmental exposures and assessments revealed differential biological responses to these engineered nanoparticles. Exposures beginning at 6 h post fertilization (hpf) to MT-functionalized nanoparticles (PbS-MT) led to 100% mortality by 120 hpf while exposure to DT-functionalized nanoparticles (PbS-DT) produced less than a 5% incident in mortality at the same concentration. Exposure to the MT and DT ligands themselves did not produce adverse developmental effects when not coupled to the NP core. Following exposure, we confirmed that the embryos took up both PbS-MT and PbS-DT material using inductively coupled plasma-mass spectrometry (ICP-MS). The stability of the nanoparticles in the aqueous solution was also characterized. The nanoparticles decompose and precipitate upon exposure to air. Soluble lead ions were observed following nanoparticle precipitation and in greater concentration for the PbS-MT sample compared to the PbS-DT sample. These studies demonstrate that in vivo assessments can be effectively used to characterize the role of NP surface functionalization in predicting biological responses.
Keywords: Lead sulfide; Nanoparticle; Nanomaterial–biological interaction; Toxicity; Stability
Platinum nanoparticles and their cellular uptake and DNA platination at non-cytotoxic concentrations by Helge Gehrke; Joanna Pelka; Christian G. Hartinger; Holger Blank; Felix Bleimund; Reinhard Schneider; Dagmar Gerthsen; Stefan Bräse; Marlene Crone; Michael Türk; Doris Marko (pp. 799-812).
Three differently sized, highly dispersed platinum nanoparticle (Pt-NP) preparations were generated by supercritical fluid reactive deposition (SFRD) and deposited on a β-cyclodextrin matrix. The average particle size and size distribution were steered by the precursor reduction conditions, resulting in particle preparations of <20, <100 and >100 nm as characterised by TEM and SEM. As reported previously, these Pt-NPs were found to cause DNA strand breaks in human colon carcinoma cells (HT29) in a concentration- and time-dependent manner and a distinct size dependency. Here, we addressed the question whether Pt-NPs might affect directly DNA integrity in these cells and thus behave analogous to platinum-based chemotherapeutics such as cisplatin. Therefore, DNA-associated Pt as well as the translocation of Pt-NPs through a Caco-2 monolayer was quantified by ICP-MS. STEM imaging demonstrated that Pt-NPs were taken up into HT29 cells in their particulate and aggregated form, but appear not to translocate into the nucleus or interact with mitochondria. The platinum content of the DNA of HT29 cells was found to increase in a time- and concentration-dependent manner with a maximal effect at 1,000 ng/cm2. ICP-MS analysis of the cell culture medium indicated the formation of soluble Pt species, although to a limited extent. The observations suggest that DNA strand breaks mediated by metallic Pt-NPs are caused by Pt ions forming during the incubation of cells with these nanoparticles.
Keywords: Cellular localisation; Cytotoxicity; DNA complexes; NP translocation
Uptake and intracellular localization of submicron and nano-sized SiO2 particles in HeLa cells by Marco Al-Rawi; Silvia Diabaté; Carsten Weiss (pp. 813-826).
Engineered amorphous silica nanoparticles (SiO2-NPs) are widely used in dyes, varnishes, plastics and glue, as well as in pharmaceuticals, cosmetics and food. Novel composite SiO2-NPs are promising multifunctional devices and combine labels for subsequent tracking and are functionalized e.g. to specifically target cells to deliver their cargo. However, biological and potential toxic effects of SiO2-NPs are insufficiently understood. The aim of this study was to determine the uptake and fate of SiO2-NPs in mammalian cells. Also, silica submicron particles (SiO2-SMPs) were included in the studies in order to identify effects, which are only observed for nano-sized SiO2 particles. Fluorescently labelled SiO2-NPs (nominal size 70 nm) and SiO2-SMPs (nominal size 200 and 500 nm) were used to examine cytotoxicity, cellular uptake and localization in human cervical carcinoma cells (HeLa). Particle uptake and intracellular localization in mitochondria, endosomes, lysosomes and nuclei were studied by wide field and confocal laser scanning fluorescence microscopy. Physicochemical characterization of SiO2-NPs by transmission electron microscopy and dynamic light scattering revealed a spherical morphology and a monodisperse size distribution. In the presence of serum, all SiO2 particles are non-toxic. However, in the absence of serum SiO2-NPs but not SiO2-SMPs are highly toxic. SiO2 particles, irrespective of size, were detected in the cytosol and accumulated in endosomal compartments of HeLa cells. No accumulation of SiO2 particles in nuclei or mitochondria of HeLa cells could be observed. In contrast to SiO2-SMPs, SiO2-NPs are preferentially localized in lysosomes.
Keywords: SiO2 nanoparticles; Fluorescence imaging; Lysosomes; Endosomes HeLa cells; Toxicity
Nanosized TiO2 caused minor airflow limitation in the murine airways by Maija Leppänen; Anne Korpi; Mirella Miettinen; Jani Leskinen; Tiina Torvela; Elina M. Rossi; Esa Vanhala; Henrik Wolff; Harri Alenius; Veli-Matti Kosma; Jorma Joutsensaari; Jorma Jokiniemi; Pertti Pasanen (pp. 827-839).
The use of nanotechnology is increasing exponentially, whereas the possible adverse health effects of engineered nanoparticles (NPs) are so far less known. Standardized mouse bioassay was used to study sensory and pulmonary irritation, airflow limitation, and inflammation potency of nanosized TiO2. Single exposure (0.5 h) to in situ generated TiO2 (primary particle size 20 nm; geometric mean diameters of 91, 113, and 130 nm at mass concentrations of 8, 20, and 30 mg/m3, respectively; crystal phase anatase + brookite (3:1)) caused airflow limitation in the conducting airways at each studied exposure concentration, which was shown as a reduction in expiratory flow, being at the lowest 73% of baseline. The response was not dose dependent. Repeated exposures (altogether 16 h, 1 h/day, 4 days/week for 4 weeks) to TiO2 at mass concentration of 30 mg/m3 caused as intense airflow limitation effect as the single exposures, and the extent of the responses stayed about the same along the exposure days. Sensory irritation was fairly minor. Pulmonary irritation was more pronounced during the latter part of the repeated exposures compared to the single exposures and the beginning of the repeated exposures. Sensory and pulmonary irritation were observed also in the control group, and, therefore, reaction by-products (NO2 and C3H6) may have contributed to the irritation effects. TiO2 NPs accumulated mainly in the pulmonary macrophages, and they did not cause nasal or pulmonary inflammation. In conclusion, the irritation and inflammation potencies of studied TiO2 seemed to be low.
Keywords: Titanium dioxide; Engineered nanoparticles; Airflow limitation; Irritation; Inflammation