Mechanisms of titanium dioxide nanoparticle‐induced oxidative stress and modulation of plasma glucose in mice

Titanium dioxide nanoparticles (TiO₂ NPs) are reported to increase plasma glucose levels in mice at specific doses. The production and accumulation of reactive oxygen species (ROS) is potentially the most important factor underlying the biological toxicity of TiO₂ NPs but the underlying mechanisms are unclear at present. Data from genome‐wide analyses showed that TiO₂ NPs induce endoplasmic reticulum (ER) stress and ROS generation, leading to the inference that TiO₂ NP‐induced ER stress contributes to enhancement of ROS in mice. Resveratrol (Res) effectively relieved TiO₂ NP‐induced ER stress and ROS generation by ameliorating expression of a common set of activated genes for both processes, signifying that ER stress and ROS are closely related. TiO₂ NP‐induced ER stress occurred earlier than ROS generation. Upon treatment with 4‐phenylbutyric acid to relieve ER stress, plasma glucose levels tended toward normal and TiO₂ NP increased ROS production was inhibited. These results suggest that TiO2 NP‐induced ER stress promotes the generation of ROS, in turn, triggering increased plasma glucose levels in mice. In addition, Res that displays the ability to reduce ER stress presents a dietary polyphenol antioxidant that can effectively prevent the toxicological effects of TiO₂ NPs on plasma glucose metabolism.     

The effects of endoplasmic reticulum stress inducer thapsigargin on the toxicity of ZnO or TiO2 nanoparticles to human endothelial cells

It was recently shown that ZnO nanoparticles (NPs) could induce endoplasmic reticulum (ER) stress in human umbilical vein endothelial cells (HUVECs). If ER stress is associated the toxicity of ZnO NPs, the presence of ER stress inducer thapsigargin (TG) should alter the response of HUVECs to ZnO NP exposure. In this study, we addressed this issue by assessing cytotoxicity, oxidative stress and inflammatory responses in ZnO NP exposed HUVECs with or without the presence of TG. Moreover, TiO₂ NPs were used to compare the effects. Exposure to 32?μg/mL ZnO NPs (p?2 NPs (p?>?0.05), significantly induced cytotoxicity as assessed by WST-1 and neutral red uptake assay, as well as intracellular ROS. ZnO NPs dose-dependently increased the accumulation of intracellular Zn ions, and ZnSO₄ induced similar cytotoxic effects as ZnO NPs, which indicated a role of Zn ions. The release of inflammatory proteins tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) or the adhesion of THP-1 monocytes to HUVECs was not significantly affected by ZnO or TiO₂ NP exposure (p?>?0.05). The presence of 250?nM TG significantly induced cytotoxicity, release of IL-6 and THP-1 monocyte adhesion (p?p?>?0.05). ANOVA analysis indicated no interaction between exposure to ZnO NPs and the presence of TG on almost all the endpoints (p?>?0.05) except neutral red uptake assay (p?相似文献   

Evaluation of distribution,redox parameters,and genotoxicity in Wistar rats co-exposed to silver and titanium dioxide nanoparticles

ABSTRACT

The increasing production of silver nanoparticles (AgNPs) and titanium dioxide nanoparticles (TiO₂NPs) has resulted in their elevated concentrations in the environment. This study was, therefore, aimed at determining the distribution, redox parameters, and genotoxic effects in male Wistar rats that were treated with either AgNP or TiO₂NP individually, as well as under a co-exposure scenario. Animals were exposed via oral gavage to either sodium citrate buffer (vehicle), 0.5 mg/kg/day TiO₂NP, 0.5 mg/kg/day AgNP or a mixture of TiO₂NPs and AgNPs. Exposure lasted 45 days after which rats were sacrificed, and tissue biodistribution of Ag and Ti measured. The blood concentration of glutathione (GSH) and activities of glutathione peroxidase (GPx) and catalase (CAT) were determined while the genotoxicity was analyzed using the comet assay in peripheral blood and liver cells. The tissue concentrations of Ag followed the order; blood > liver > kidneys while for Ti the order was kidneys > liver > blood. There was no significant change in the measured redox parameters in animals that were exposed to TiO₂NPs. However, there was a significant increase in GSH levels accompanied by a reduction in the GPx activity in AgNP-treated and co-exposed groups. The individual or co-exposure to TiO₂NP and AgNP did not markedly induce genotoxicity in blood or liver cells. Data showed that TiO₂NP did not produce significant oxidative stress or genotoxicity in rats at the dose used in this study while the same dose level of AgNPs resulted in oxidative stress, but no noticeable adverse genotoxic effects.     

Overestimation of nanoparticles-induced DNA damage determined by the comet assay

The increasing use of engineered nanoparticles (NPs) in a wide range of commercial products raises concern about the possible risks that NPs pose to human health. Many aspects of the interaction between living cells and NPs are still unclear, and a reliable assessment of NP genotoxicity would be important. One of the most common tests used for genotoxicity is the comet assay, a sensitive method measuring DNA damage in individual cells. The assay was originally developed for soluble molecules, but it is also used in the assessment of genotoxicity of NPs. However, concerns have been raised recently about the reliability of this test in the case of NPs, but no conclusive results have been presented. Using nuclei isolated from human epithelial cells incubated with NPs, we obtained clear evidence of overestimation of NP genotoxicity by the comet assay in the case of CeO₂, TiO_2, SiO₂, and polystyrene NPs. Removal of the NPs in the cytoplasm was effective in eliminating this genotoxicity overestimation (ex post damage) and determining the actual damage produced by the NPs during incubation with the cells (ex ante damage). This method could improve significantly the determination of NP genotoxicity in eukaryotic cells.     

Evaluation of cytotoxic,genotoxic and inflammatory response in human alveolar and bronchial epithelial cells exposed to titanium dioxide nanoparticles

The toxicity of titanium dioxide nanoparticles (TiO₂‐NPs), used in several applications, seems to be influenced by their specific physicochemical characteristics. Cyto‐genotoxic and inflammatory effects induced by a mixture of 79% anatase/21% rutile TiO₂‐NPs were investigated in human alveolar (A549) and bronchial (BEAS‐2B) cells exposed to 1–40 µg ml^–1 30 min, 2 and 24 h to assess potential pulmonary toxicity. The specific physicochemical properties such as crystallinity, NP size and shape, agglomerate size, surface charge and specific surface area (SSA) were analysed. Cytotoxic effects were studied by evaluating cell viability using the WST1 assay and membrane damage using LDH analysis. Direct/oxidative DNA damage was assessed by the Fpg‐comet assay and the inflammatory potential was evaluated as interleukin (IL)‐6, IL‐8 and tumour necrosis factor (TNF)‐α release by enzyme‐linked immunosorbant assay (ELISA). In A549 cells no significant viability reduction and moderate membrane damage, only at the highest concentration, were detected, whereas BEAS‐2B cells showed a significant viability reduction and early membrane damage starting from 10 µg ml^–1. Direct/oxidative DNA damage at 40 µg ml^–1 and increased IL‐6 release at 5 µg ml^–1 were found only in A549 cells after 2 h. The secretion of pro‐inflammatory cytokine IL‐6, involved in the early acute inflammatory response, and oxidative DNA damage indicate the promotion of early and transient oxidative‐inflammatory effects of tested TiO₂‐NPs on human alveolar cells. The findings show a higher susceptibility of normal bronchial cells to cytotoxic effects and higher responsiveness of transformed alveolar cells to genotoxic, oxidative and early inflammatory effects induced by tested TiO₂‐NPs. This different cell behaviour after TiO₂‐NPs exposure suggests the use of both cell lines and multiple end‐points to elucidate NP toxicity on the respiratory system. Copyright © 2014 John Wiley & Sons, Ltd.     

Titanium dioxide nanoparticles translocate through differentiated Caco‐2 cell monolayers,without disrupting the barrier functionality or inducing genotoxic damage

The widespread use of titanium dioxide nanoparticles (TiO₂NPs) in commercial food products makes intestinal cells a suitable target. Accordingly, we have used the human colon adenocarcinoma Caco‐2 cells to detect their potential harmful effects. Caco‐2 cells can differentiate in to enterocytic‐like cells, forming consistent cell monolayers and are used as a model of the intestinal barrier. Using both undifferentiated and differentiated Caco‐2 cells, we have explored a set of biomarkers, aiming to evaluate undesirable effects associated to TiO₂NP exposure. Results indicate non‐toxic effects in exposures ranging 1‐200 μg ml^?1. Significant differences were observed in cell uptake, with a higher amount of incorporated TiO₂NPs in undifferentiated cells, as visualized using confocal microscopy. In well‐established monolayers, translocation was detected using both confocal microscopy and transmission electron microscopy with energy‐dispersive X‐ray spectroscopy. In spite of the observed uptake and translocation, TiO₂NP exposures did not modify the integrity of the monolayer, as measured using the transepithelial electrical resistance and Lucifer yellow methods. The potential genotoxic effects in differentiated cells were evaluated in the comet assay, with and without formamidopyrimidine DNA glycosylase enzyme to detect oxidatively the damaged DNA bases. Although some changes were detected at the lower dose (10 μg ml^?1), no effects were observed at higher doses.     

In vitro evaluation of the toxicity and underlying molecular mechanisms of Janus Fe3O4‐TiO2 nanoparticles in human liver cells

Recent studies show that Janus Fe₃O₄‐TiO₂ nanoparticles (NPs) have potential applications as a multifunctional agent of magnetic resonance imaging (MRI) and photodynamic therapy (PDT) for the diagnosis and therapy of cancer. However, little work has been done on their biological effects. To evaluate the toxicity and underlying molecular mechanisms of Janus Fe₃O₄‐TiO₂ nanoparticles, an in vitro study using a human liver cell line HL‐7702 cells was conducted. For comparison, the Janus Fe₃O₄‐TiO₂ NPs parent material TiO₂ NPs was also evaluated. Results showed that both Fe₃O₄‐TiO₂ NPs and TiO₂ NPs decreased cell viability and ATP levels when applied in treatment, but increased malonaldehyde (MDA) and reactive oxygen species (ROS) generation. Mitochondria JC‐1 staining assay showed that mitochondrial membrane permeability injury occurred in both NPs treated cells. Cell viability analysis showed that TiO₂ NPs induced slightly higher cytotoxicity than Fe₃O₄‐TiO₂ NPs in HL7702 cells. Western blotting indicated that both TiO₂ NPs and Fe₃O₄‐TiO₂ NPs could induce apoptosis, inflammation, and carcinogenesis related signal protein alterations. Comparatively, Fe₃O₄‐TiO₂ NPs induced higher signal protein expressions than TiO₂ NPs under a high treatment dose. However, under a low dose (6.25 μg/cm²), neither NPs had any significant toxicity on HL7702 cells. In addition, our results suggest both Fe₃O₄‐TiO₂ NPs and TiO₂ NPs could induce oxidative stress and have a potential carcinogenetic effect in vitro. Further studies are needed to elaborate the detailed mechanisms of toxicity induced by a high dose of Fe₃O₄‐TiO₂ NPs.     

Cytotoxicity,oxidative stress and inflammation induced by ZnO nanoparticles in endothelial cells: interaction with palmitate or lipopolysaccharide

Recent studies showed that ZnO nanoparticles (NPs) might induce the toxicity to human endothelial cells. However, little is known about the interaction between ZnO NPs and circulatory components, which is likely to occur when NPs enter the blood. In this study, we evaluated ZnO NP‐induced cytotoxicity, oxidative stress and inflammation in human umbilical vein endothelial cells (HUVECs), with the emphasis on the interaction with palmitate (PA) or lipopolysaccharide (LPS), because PA and LPS are normal components in human blood that increase in metabolic diseases. Overall, ZnO NPs induced cytotoxicity and intracellular reactive oxygen species (ROS) at a concentration of 32 μg ml⁻¹, but did not significantly affect the release of inflammatory cytokines or adhesion of THP‐1 monocytes to HUVECs. In addition, exposure to ZnO NPs dose‐dependently promoted intracellular Zn ions in HUVECs. PA and LPS have different effects. Two hundred μm PA significantly induced cytotoxicity and THP‐1 monocyte adhesion, but did not affect ROS or release of inflammatory cytokines. In contrast, 1 μg ml⁻¹ LPS significantly induced ROS, release of inflammatory cytokines and THP‐1 monocyte adhesion, but not cytotoxicity. The presence of ZnO NPs did not significantly affect the toxicity induced by PA or LPS. In addition, the accumulation of Zn ions after ZnO NP exposure was not significantly affected by the presence of PA or LPS. We concluded that there was no interaction between ZnO NPs and PA or LPS on toxicity to HUVECs in vitro . Copyright © 2016 John Wiley & Sons, Ltd.     

Overview of the toxic effects of titanium dioxide nanoparticles in blood,liver, muscles,and brain of a Neotropical detritivorous fish

The toxicity of titanium dioxide nanoparticles (TiO₂‐NP) in the blood, liver, muscle, and brain of a Neotropical detritivorous fish, Prochilodus lineatus, was tested. Juvenile fish were exposed to 0, 1, 5, 10, and 50 mg L^?1 of TiO₂‐NP for 48 hours (acute exposure) or 14 days (subchronic exposure) to evaluate changes in hematology, red blood cell (RBC) genotoxicity/mutagenicity, liver function (reactive oxygen species (ROS) production, antioxidant responses, detoxification, and histopathology), acetylcholinesterase (AChE) activity in muscles and brain, and Ti bioaccumulation. TiO₂‐NP did not cause genetic damage to RBC, but acutely decreased white blood cells (WBC) and increased monocytes. Subchronically, RBC decreased, mean cell volume and hemoglobin increased, and WBC and lymphocytes decreased. Therefore, NP has the potential to affect immune system and increase energy expenditure, reducing the fish's ability to avoid predator and to resist pathogens. In the liver, acute exposure decreased ROS and increased glutathione (GSH) content, while subchronic exposure decreased superoxide dismutase activity and increased glutathione‐S‐transferase (GST) activity and GSH content. GSH and GST seem to play an essential role in metabolizing NP and ROS, likely increasing hepatocytes' metabolic rate, which may be the cause of observed cell hypertrophy, disarrangement of hepatic cords and degenerative morphological alterations. Although most studies indicate that the kidney is responsible for metabolizing and/or eliminating TiO₂‐NP, this study shows that the liver also has a main role in these processes. Nevertheless, Ti still accumulated in the liver, muscle, and brain and decreased muscular AChE activity after acute exposure, showing neurotoxic potential. More studies are needed to better understand the biochemical pathways TiO₂‐NP are metabolized and how its bioaccumulation may affect fish homeostasis and survival in the environment.     

Amplification of arsenic genotoxicity by TiO2 nanoparticles in mammalian cells: new insights from physicochemical interactions and mitochondria

Titanium dioxide nanoparticles (TiO₂ NPs) have shown great adsorption capacity for arsenic (As); however, the potential impact of TiO₂ NPs on the behavior and toxic responses of As remains largely unexplored. In the present study, we focused on the physicochemical interaction between TiO₂ NPs and As(III) to clarify the underlying mechanisms involved in their synergistic genotoxic effect on mammalian cells. Our data showed that As(III) mainly interacted with TiO₂ NPs by competitively occupying the sites of hydroxyl groups on the surface of TiO₂ NP aggregates, resulting in more aggregation of TiO₂ NPs. Although TiO₂ NPs at concentrations used here had no cytotoxic or genotoxic effects on cells, they efficiently increased the genotoxicity of As(III) in human-hamster hybrid (A_L) cells. The synergistic genotoxicity of TiO₂ NPs and As(III) was partially inhibited by various endocytosis pathway inhibitors while it was completely blocked by an As(III)-specific chelator. Using a mitochondrial membrane potential fluorescence probe, a reactive oxygen species (ROS) probe together with mitochondrial DNA-depleted ρ⁰ A_L cells, we discovered that mitochondria were essential for mediating the synergistic DNA-damaging effects of TiO₂ NPs and As(III). These data provide novel mechanistic proof that TiO₂ NPs enhanced the genotoxicity of As(III) via physicochemical interactions, which were mediated by mitochondria-dependent ROS.     

Evaluation of cytogenotoxicity and oxidative stress parameters in male Swiss mice co-exposed to titanium dioxide and zinc oxide nanoparticles

A number of studies have investigated the adverse toxic effects of titanium dioxide (TiO₂) nanoparticles (NPs) or zinc oxide (ZnO) NPs. Information on the potential genotoxic effects of the interactions of TiO₂ NPs and ZnO NPs in vivo is lacking. Therefore, this study was designed to investigate the cytogenotoxicity of TiO₂ NPs or ZnO NPs alone or their mixtures using the bone marrow micronucleus assay, and mechanism of damage through the evaluation of oxidative stress parameters in the liver and kidney tissues of Swiss mice. Intraperitoneal administration of doses between 9.38 and 150.00 mg/kg of TiO₂ NPs or ZnO NPs or TiO₂ NPs + ZnO NPs was performed for 5 and 10 days, respectively. TiO₂ NPs alone induced a significant (P < 0.05) increase in micronucleated (Mn) polychromatic erythrocytes (PCEs) at the applied doses compared with the negative controls, with a significant difference between 5 and 10 days for TiO₂ NPs alone and TiO₂ NPs + ZnO NPs. Concurrently, TiO₂ NPs alone for 5 days and TiO₂ NPs and TiO₂ NPs + ZnO NPs for 10 days significantly (P < 0.05) decreased the percentage PCE: normochromatic erythrocyte (NCE) indicating cytotoxicity; with a significant difference between the two periods. Significant (P < 0.001) changes in the activities of superoxide dismutase (SOD) and catalase (CAT), and levels of reduced glutathione (GSH) and malondialdehyde (MDA) were observed in the liver and kidney of mice exposed to TiO₂ NPs or ZnO NPs alone or their mixtures. These results suggest that TiO₂ NPs alone was genotoxic; TiO₂ NPs and TiO₂ NPs + ZnO NPs were noticeably cytotoxic while ZnO NPs was not cytogenotoxic. The individual NPs or their mixtures induced oxidative stress.     

Nrf2 protects the lung against inflammation induced by titanium dioxide nanoparticles: A positive regulator role of Nrf2 on cytokine release

Titanium dioxide nanoparticles (TiO₂ NPs) have been classified as possibly carcinogenic to humans and they are an important nanomaterial widely used in pharmaceutical and paint industries. Inhalation is one of the most important routes of exposure in occupational settings. Several experimental models have shown that oxidative stress and inflammation are key mediators of cell damage. In this regard, Nrf2 modulates cytoprotection against oxidative stress and inflammation, however, its role in inflammation induced by TiO₂ NPs exposure has been less investigated. The aim of this work was to investigate the role of Nrf2 in the cytokines produced after 4 weeks of TiO₂ NPs exposure (5 mg/kg/2 days/week) using wild‐type and Nrf2 knockout C57bl6 mice. Results showed that Nrf2 protects against inflammation and oxidative damage induced by TiO₂ NPs exposure, however, Nrf2 is a positive mediator in the expression of IFN‐γ, TNF‐α, and TGF‐β in bronchial epithelium and alveolar space after 4 weeks of exposure. These results suggest that Nrf2 has a central role in up‐regulation of cytokines released during inflammation induced by TiO₂ NPs and those cytokines are needed to cope with histological alterations in lung tissue. © 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 782–792, 2015.     

Chromium oxide nanoparticle‐induced genotoxicity and p53‐dependent apoptosis in human lung alveolar cells

Chromium oxide (Cr₂O₃) nanoparticles (NPs) are being increasingly used as a catalyst for aromatic compound manufacture, abrading agents and as pigments (e.g., Viridian). Owing to increased applications, it is important to study the biological effects of Cr₂O₃ NPs on human health. The lung is one of the main exposure routes to nanomaterials; therefore, the present study was designed to determine the genotoxic and apoptotic effect of Cr₂O₃ NPs in human lung epithelial cells (A549). The study also elucidated the molecular mechanism of its toxicity. Cr₂O₃ NPs led to DNA damage, which was deduced by comet assay and cytokinesis block micronucleus assay. The damage could be mediated by the increased levels of reactive oxygen species. Further, the oxygen species led to a decrease in mitochondrial membrane potential and an increase in the ratio of BAX/Bcl‐2 leading to mitochondria‐mediated apoptosis induced by Cr₂O₃ NPs, which ultimately leads to cell death. Hence, there is a need of regulations to be imposed in NP usage. The study provided insight into the caspase‐dependent mechanistic pathway of apoptosis. Copyright © 2015 John Wiley & Sons, Ltd.     

Combined effect of titanium dioxide nanoparticles and glucose on the cardiovascular system in young rats after oral administration

Titanium dioxide nanoparticles (TiO₂ NPs) have already been used as food additive in various products and are usually consumed with a considerable amount of sugar. Oral consumption of TiO₂ NPs poses concerning health risks; however, research on the combined effect of ingested TiO₂ NPs and glucose is limited. We examined young Sprague‐Dawley rats administrated TiO₂ NPs orally at doses of 0, 2, 10 and 50 mg/kg body weight per day with and without 1.8 g/kg body weight glucose for 30 and 90 days. Heart rate, systolic and diastolic blood pressure, blood biochemical parameters and histopathology of cardiac tissues was assessed to quantify cardiovascular damage. The results showed that oral exposure to TiO₂ NPs and high doses of glucose both could induce cardiovascular injuries. The toxic effects were dose‐, time‐ and gender‐dependent. The interaction effects between oral‐exposed TiO₂ NPs and glucose existed and revealed to be antagonism in most of the biological parameters. However, toxic effects of the high‐dose glucose seemed to be more severe than TiO₂ NPs and the interaction of TiO₂ NPs with glucose. These results suggest that it may be more important to control the sugar intake than TiO₂ NPs for protecting the health of TiO₂ NP consumers.     

Phoxim‐induced damages of Bombyx mori larval midgut and titanium dioxide nanoparticles protective role under phoxim‐induced toxicity

Phoxim (O,O‐diethyl O‐(alpha‐cyanobenzylideneamino) phosphorothioate) is a powerful organophosphorus pesticide with high potential for Bombyx mori larvae of silkworm exposure. However, it is possible that during the phoxim metabolism, there is generation of reactive oxygen species (ROS) and phoxim may produce oxidative stress and neurotoxicity in an intoxicated silkworm. Titanium dioxide nanoparticles (TiO₂ NPs) pretreatment has been demonstrated to increase antioxidant capacity and acetylcholinesterase (AChE) activity in organisms. This study was, therefore, undertaken to determine phoxim‐induced oxidative stress and neurotoxicity to determine whether phoxim intoxication alters the antioxidant system and AChE activity in the B. mori larval midgut, and to determine whether TiO₂ NPs pretreatment attenuates phoxim‐induced toxicity. The findings suggested that phoxim exposure decreased survival of B. mori larvae, increased malondialdehyde (MDA), carbonyl and 8‐OHdG levels, and ROS accumulation in the midgut. Furthermore, phoxim significantly decreased the activities of AChE, superoxide dismutase (SOD), ascorbate peroxidase (APX), glutathione reductase (GR), glutathione‐S‐transferase (GST), and levels of ascorbic acid (AsA), reduced glutathione (GSH), and thiol in the midgut. TiO₂ pretreatment, however, could increase AChE activity, and remove ROS via activating SOD, CAT, APX, GR, and GST, and accelerating AsA–GSH cycle, thus attenuated lipid, protein, and DNA peroxidation and improve B. mori larval survival under phoxim‐induced toxicity. Moreover, this experimental system would help nanomaterials to be applied in the sericulture. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1355–1366, 2014.     

Titanium dioxide nanoparticles impair lung mitochondrial function

Titanium dioxide nanoparticles (TiO₂ NPs) are used in an increasing number of human products such as cosmetics, sunscreen, toothpaste and paints. However, there is clear evidence about effects associated to TiO₂ NPs exposure, which include lung inflammation and tumor formation and these effects are related to reactive oxygen species (ROS) formation. The ROS generation could be attributed to a mitochondrial dysfunction. Even though, it has been shown that TiO₂ NPs exposure can induce some alterations in mitochondria including cytochrome c release to cytosol, change in mitochondrial permeability and decrease of mitochondrial membrane potential (ΔΨ_m), there is no information about the changes in mitochondrial function induced by TiO₂ NPs. We hypothesized that TiO₂ NPs effects are associated with mitochondrial dysfunction and redox unbalance. To test our hypothesis we isolated mitochondria from lung tissue of rats and exposed them to 10 (g TiO₂ NPs (particle size < 25 nm)/mg protein for 1 h. Our results showed that TiO₂ NPs decreases NADH levels and impairs ΔΨ_m and mitochondrial function accompanied by ROS generation during mitochondrial respiration.     

Mechanistic insight into reactivity and (geno)toxicity of well-characterized nanoparticles of cobalt metal and oxides

An increasing use of cobalt (Co)-based nanoparticles (NPs) in different applications and exposures at occupational settings triggers the need for toxicity assessment. Improved understanding regarding the physiochemical characteristics of Co metal NPs and different oxides in combination with assessment of toxicity and mechanisms may facilitate decisions for grouping during risk assessment. The aim of this study was to gain mechanistic insights in the correlation between NP reactivity and toxicity of three different Co-based NPs (Co, CoO, and Co₃O₄) by using various tools for characterization, traditional toxicity assays, as well as six reporter cell lines (ToxTracker) for rapid detection of signaling pathways of relevance for carcinogenicity. The results showed cellular uptake of all NPs in lung cells and induction of DNA strand breaks and oxidative damage (comet assay) by Co and CoO NPs. In-depth studies on the ROS generation showed high reactivity of Co, lower for CoO, and no reactivity of Co₃O₄ NPs. The reactivity depended on the corrosion and transformation/dissolution properties of the particles and the media highlighting the role of the surface oxide and metal speciation as also confirmed by in silico modeling. By using ToxTracker, Co NPs were shown to be highly cytotoxic and induced reporters related to oxidative stress (Nrf2 signaling) and DNA strand breaks. Similar effects were observed for CoO NPs but at higher concentrations, whereas the Co₃O₄ NPs were inactive at all concentrations tested. In conclusion, our study suggests that Co and CoO NPs, but not Co₃O₄, may be grouped together for risk assessment.     

Quantitative evaluation of local pulmonary distribution of TiO2 in rats following single or multiple intratracheal administrations of TiO2 nanoparticles using X‐ray fluorescence microscopy

Uneven pulmonary nanoparticle (NP) distribution has been described when using single‐dose intratracheal administration tests. Multiple‐dose intratracheal administrations with small quantities of NPs are expected to improve the unevenness of each dose. The differences in local pulmonary NP distribution (called microdistribution) between single‐ and multiple‐dose administrations may cause differential pulmonary responses; however, this has not been evaluated. Here, we quantitatively evaluated the pulmonary microdistribution (per mesh: 100 μm × 100 μm) of TiO₂ in lung sections from rats following one, two, three, or four doses of TiO₂ NPs at a same total dosage of 10 mg kg^?1 using X‐ray fluorescence microscopy. The results indicate that: (i) multiple‐dose administrations show lower variations in TiO₂ content (ng mesh^?1) for sections of each lobe; (ii) TiO₂ appears to be deposited more in the right caudal and accessory lobes located downstream of the administration direction of NP suspensions, and less so in the right middle lobes, irrespective of the number of doses; (iii) there are not prominent differences in the pattern of pulmonary TiO₂ microdistribution between rats following single and multiple doses of TiO₂ NPs. Additionally, the estimation of pulmonary TiO₂ deposition for multiple‐dose administrations imply that every dose of TiO₂ would be randomly deposited only in part of the fixed 30–50% of lung areas. The evidence suggests that multiple‐dose administrations do not offer remarkable advantages over single‐dose administration on the pulmonary NP microdistribution, although multiple‐dose administrations may reduce variations in the TiO₂ content for each lung lobe. Copyright © 2016 John Wiley & Sons, Ltd.     

Simultaneous screening of the stability and dosimetry of nanoparticles dispersions for in vitro toxicological studies with static multiple light scattering technique

To evaluate the nanoparticle (NP) toxicity, much efforts have been devoted for developing methods to accurately disperse NPs into aqueous suspensions prior to in vitro toxicological studies. As NP toxicity is strongly dependent on their physicochemical properties, NP characterization is a key step for any in vitro toxicological study. This study demonstrates that the static multiple light scattering (SMLS) technique allows for the simultaneous screening of the NP size, agglomeration state, stability and dosimetry in biological media. Batch dispersions of TiO₂ P25 NPs in water with various bovine serum albumin (BSA) mass fractions (from 0% to 0.5%) and dilutions of these dispersions into cell culture media were characterized with SMLS. In the batch dispersions, TiO₂ NPs are stable and well dispersed for BSA mass fraction lower than 0.2% while agglomeration and rapid settling is observed for higher BSA mass fractions. Paradoxically, when diluted in cell culture media, TiO₂ NPs are well dispersed and stable for BSA mass fractions higher than 0.2%. The TiO₂ NP dosimetry of these dilutions was evaluated experimentally with SMLS and confronted with numerical approaches. The TiO₂ NP bottom concentration evolves far more slowly in the case of the higher BSA mass fraction. Such measurements give valuable insights on the NP fate and transport in biological media to obtain in fine reliable size and dose-cytotoxicity responses.