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.     

3‐Hydroxyflavone enhances the toxicity of ZnO nanoparticles in vitro

It is recently shown that flavonoids might reduce the toxicity of nanoparticles (NPs) due to their antioxidative properties. In this study, the influence of 3‐hydroxyflavone (H3) on the toxicity of ZnO NPs was investigated. H3 increased hydrodynamic size, polydispersity index and absolute value of the zeta potential of ZnO NPs, which indicated that H3 could influence the colloidal aspects of NPs. Surprisingly, H3 markedly decreased the initial concentration of ZnO NPs required to induce cytotoxicity to Caco‐2, HepG2, THP‐1 and human umbilical vein endothelial cells, which suggested that H3 could promote the toxicity of ZnO NPs to both cancerous and normal cells. For comparison, 6‐hydroxyflavone did not show this effect. H3 remarkably increased cellular Zn elements and intracellular Zn ions in HepG2 cells following ZnO NP exposure, and co‐exposure to H3 and NPs induced a relatively higher intracellular reactive oxygen species. Exposure to ZnO NPs at 3 hours induced the expression of endoplasmic reticulum stress markers DDIT3 and XBP‐1 s, which was suppressed by H3. The expression of apoptotic genes BAX and CASP3 was significantly induced by ZnO NP exposure after 3 and 5 hours, respectively, and H3 further significantly promoted CASP3 expression at 5 hours. In combination, the results from this study suggested that H3 affected colloidal stability of ZnO NPs, promoted the interactions between NPs and cells, and altered the NP‐induced endoplasmic reticulum stress–apoptosis signaling pathway, which finally enhanced the cytotoxicity of ZnO NPs.     

In vitro mechanistic study towards a better understanding of ZnO nanoparticle toxicity

Abstract

ZnO nanoparticles (NPs) elicit significant adverse effects in various cell types, organisms and in the environment. The toxicity of nanoscale ZnO has often been ascribed to the release of zinc ions from the NPs but it is not yet understood to which extent these ions contribute to ZnO NP toxicity and what are the underlying mechanisms. Here, we take one step forward by demonstrating that ZnO-induced Jurkat cell death is largely an ionic effect involving the extracellular release of high amounts of Zn(II), their rapid uptake by the cells and the induction of a caspase-independent alternative apoptosis pathway that is independent of the formation of ROS. In addition, we identified novel coating strategies to reduce ZnO NP dissolution and subsequent adverse effects.     

Aerosolized ZnO nanoparticles induce toxicity in alveolar type II epithelial cells at the air-liquid interface

The majority of in vitro studies characterizing the impact of engineered nanoparticles (NPs) on cells that line the respiratory tract were conducted in cells exposed to NPs in suspension. This approach introduces processes that are unlikely to occur during inhaled NP exposures in vivo, such as the shedding of toxic doses of dissolved ions. ZnO NPs are used extensively and pose significant sources for human exposure. Exposures to airborne ZnO NPs can induce adverse effects, but the relevance of the dissolved Zn(2+) to the observed effects in vivo is still unclear. Our goal was to mimic in vivo exposures to airborne NPs and decipher the contribution of the intact NP from the contribution of the dissolved ions to airborne ZnO NP toxicity. We established the exposure of alveolar type II epithelial cells to aerosolized NPs at the air-liquid interface (ALI) and compared the impact of aerosolized ZnO NPs and NPs in suspension at the same cellular doses, measured as the number of particles per cell. By evaluating membrane integrity and cell viability 6 and 24 h post-exposure, we found that aerosolized NPs induced toxicity at the ALI at doses that were in the same order of magnitude as doses required to induce toxicity in submersed cultures. In addition, distinct patterns of oxidative stress were observed in the two exposure systems. These observations unravel the ability of airborne ZnO NPs to induce toxicity without the contribution of dissolved Zn(2+) and suggest distinct mechanisms at the ALI and in submersed cultures.     

Tissue distribution following 28 day repeated oral administration of aluminum‐based nanoparticles with different properties and the in vitro toxicity

The tissue distribution and toxicity of nanoparticles (NPs) depend on their physical and chemical properties both in the manufactured condition and within the biological system. We characterized three types of commercially available aluminum‐based NPs (Al‐NPs), two rod‐type aluminum oxide NPs (Al₂O₃, AlONPs), with different aspect ratios (short [S]‐ and long [L]‐AlONPs), and spherical aluminum cerium oxide NPs (AlCeO₃, AlCeONPs). The surface area was in order of the S‐AlONPs > L‐AlONPs > AlCeONPs. Very importantly, we found that AlCeONPs is Al₂O₃‐coated CeO₂ NPs, but not AlCeO₃ NPs, and that the Al level in AlCeONPs is approximately 20% of those in S‐ and L‐AlONPs. All three types of Al‐NPs were slightly ionized in gastric fluid and rapidly particlized in the intestinal fluid. There were no significant differences in the body weight gain following 28 days of repeated oral administration of the three different types of Al‐NPs. All Al‐NPs elevated Al level in the heart, spleen, kidney and blood at 24 hours after the final dose, accompanied by the altered tissue level of redox reaction‐related trace elements. Subsequently, in four types of cells derived from the organs which Al‐NPs are accumulated, H9C2 (heart), HEK‐293 (kidney), splenocytes and RAW264.7 (blood), S‐AlONPs showed a very low uptake level and did not exert significant cytotoxicity. Meanwhile, cytotoxicity and uptake level were the most remarkable in cells treated with AlCeONPs. In conclusion, we suggest that the physicochemical properties of NPs should be examined in detail before the release into the market to prevent unexpected adverse health effects.     

Improving the selective cancer killing ability of ZnO nanoparticles using Fe doping

This work reports a new method to improve our recent demonstration of zinc oxide (ZnO) nanoparticles (NPs) selectively killing certain human cancer cells, achieved by incorporating Fe ions into the NPs. Thoroughly characterized cationic ZnO NPs (～6 nm) doped with Fe ions (Zn(1-x )Fe (x) O, x = 0-0.15) were used in this work, applied at a concentration of 24 μg/ml. Cytotoxicity studies using flow cytometry on Jurkat leukemic cancer cells show cell viability drops from about 43% for undoped ZnO NPs to 15% for ZnO NPs doped with 7.5% Fe. However, the trend reverses and cell viability increases with higher Fe concentrations. The non-immortalized human T cells are markedly more resistant to Fe-doped ZnO NPs than cancerous T cells, confirming that Fe-doped samples still maintain selective toxicity to cancer cells. Pure iron oxide samples displayed no appreciable toxicity. Reactive oxygen species generated with NP introduction to cells increased with increasing Fe up to 7.5% and decreased for >7.5% doping.     

The toxicology of ion-shedding zinc oxide nanoparticles

Zinc oxide nanoparticles (ZnO NPs) are nanomaterials that are widely used in many fields. ZnO NPs are ion-shedding particles, and zinc ions produce important and potent effects that differ from those of other metal or metal oxide NPs. Several studies have reported the toxicological effects of ZnO NPs administered via several different routes, including orally, dermally, by pulmonary absorption, intraperitoneally, and intravenously. Some potential routes for human exposure have produced various toxic effects in animal models. Moreover, several in vitro studies using a range of cell lines have reported the mechanisms underlying ZnO NP toxicity. Zinc ions play a very important role in ZnO NP toxicity, although the effects of the particulate form cannot be excluded. A crucial determinant of toxicity is the solubility of ZnO NPs, which is influenced by various factors, including the pH of the environment in tissues, cells, and organelles. In addition to the inflammatory responses and oxidative stress known to be induced by ZnO NPs, these NPs also exhibit some positive anti-inflammatory, anti-diabetic, and pro-coagulant effects at sub-toxic doses; these effects are probably induced by zinc ions, which are an essential element in cell homeostasis. It is highly likely that there are additional distinct mechanisms at sub-toxic doses and concentrations, which may be concealed or altered by the toxic effects observed at higher levels of ZnO NPs. Furthermore, many signaling pathway molecules associated with necrosis and apoptosis can be activated, leading to cell death. This review presents the status of ZnO NP toxicology and highlights areas requiring further investigation.     

Influence of bovine serum albumin pre-incubation on toxicity and ER stress-apoptosis gene expression in THP-1 macrophages exposed to ZnO nanoparticles

When entering a biological environment, proteins could be adsorbed onto nanoparticles (NPs), which can potentially influence the toxicity of NPs. This study used bovine serum albumin (BSA) as the model for serum protein and investigated its interactions with three different types of ZnO NPs, coded as XFI06 (pristine NPs of 20?nm), NM110 (pristine NPs of 100?nm) and NM111 (hydrophobic NPs of 130?nm). Atomic force microscope indicated the adsorption of BSA to ZnO NPs, leading to the increase of NP diameters. Pre-incubation with BSA did not significantly affect hydrodynamic size but decreased Zeta potential of NM110 and NM111. The fluorescence and synchronous fluorescence of BSA were quenched after pre-incubation with ZnO NPs, and the quenching effects were more obvious for XFI06 and NM110. Exposure to all types of ZnO NPs significantly induced cytotoxicity and lysosomal destabilization, which was slightly alleviated when NPs were pre-incubated with BSA. However, ZnO NPs with or without pre-incubation of BSA resulted in comparable intracellular Zn ions, glutathione and reactive oxygen species in THP-1 macrophages. Exposure to ZnO NPs promoted the expression of endoplasmic reticulum (ER) stress markers (DDIT3 and XBP-1s) and apoptosis genes (CASP9 and CASP12). Pre-incubation with BSA had minimal impact on ER stress gene expression but decreased apoptosis gene expression. Combined, these results suggested that pre-incubation with BSA could modestly alleviate the cytotoxicity and reduce ER stress related apoptosis gene expression in THP-1 macrophages after ZnO NP exposure.     

The effects of baicalein or baicalin on the colloidal stability of ZnO nanoparticles (NPs) and toxicity of NPs to Caco-2 cells

Recent study suggested that the presence of phytochemicals in food could interact with nanoparticles (NPs) and consequently reduce the toxicity of NPs, which has been attributed to the antioxidant properties of phytochemicals. In this study, we investigated the interactions between ZnO NPs and two flavonoids baicalein (Ba) or baicalin (Bn) as well as the influence of the interactions on the toxicity of ZnO NPs to Caco-2 cells. The antioxidant properties of Ba and Bn were confirmed by 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) assays, with Ba being stronger. However, the presence of Ba or Bn did not significantly affect cytotoxicity, intracellular superoxide or release of inflammatory cytokines of Caco-2 cells after ZnO NP exposure. When Ba was present, the cellular viability of Caco-2 cells after exposure to ZnO NPs was slightly increased, associated with a modest decrease of intracellular Zn ions, but these effects were not statistically different. Ba was more effective than Bn at changing the hydrodynamic sizes, Zeta potential and UV–Vis spectra of ZnO NPs, which indicated that Ba might increase the colloidal stability of NPs. Taken together, the results of the present study indicated that the anti-oxidative phytochemical Ba might only modestly protected Caco-2 cells from the exposure to ZnO NPs associated with an insignificant reduction of the accumulation of intracellular Zn ions. These results also indicated that when assessing the combined effects of NPs and phytochemicals to cells lining gastrointestinal tract, it might be necessary to evaluate the changes of colloidal stability of NPs altered by phytochemicals.     

Pulmonary toxicity of inhaled nanoscale and fine zinc oxide particles: mass and surface area as an exposure metric

The total surface area is known to be an effective exposure metric for predicting the lung toxicity of low solubility nanoparticles (NPs). However, if NPs are dissolved quickly enough in the lungs, the mass may be correlated with the toxicity. Recent studies have found that the toxicity of zinc oxide (ZnO) NPs was caused by the release of zinc ions. Thus, we hypothesized that mass could be used as an exposure metric for the toxicity of ZnO NPs. Healthy Sprague-Dawley rats were exposed to a low, moderate, or high dose of 35 and 250?nm ZnO particles or filtered air. Bronchoalveolar lavage fluid was collected to determine lung inflammation, injury and oxidative stress. The lung inflammation induced by ZnO particles according to different concentration metrics, including number, mass and surface area, was compared. The mass concentration was significantly correlated with the percentage of neutrophils (R(2)?=?0.84), number of neutrophils (R(2)?=?0.84) and total cells (R(2)?=?0.73). Similarly, surface area concentration was significantly correlated with the percentage of neutrophils (R(2)?=?0.94), number of neutrophils (R(2)?=?0.81) and total cells (R(2)?=?0.76). There was no correlation between the number and lung inflammation. We found that both mass and surface area were effective as metrics for the toxicity of ZnO NPs, although only surface area was previously indicated to be an effective metric. Our results are also consistent with recent study results that ZnO NPs and released zinc ions may play a role mediating the toxicity of NPs.     

The endoplasmic reticulum stress inducer thapsigargin enhances the toxicity of ZnO nanoparticles to macrophages and macrophage-endothelial co-culture

It was recently shown that exposure to ZnO nanoparticles (NPs) could induce endoplasmic reticulum (ER) stress both in vivo and in vitro, but the role of ER stress in ZnO NP induced toxicity remains unclear. Because macrophages are sensitive to ER stress, we hypothesized that stressing macrophages with ER stress inducer could enhance the toxicity of ZnO NPs. In this study, the effects of ER stress inducer thapsigargin (TG) on the toxicity of ZnO NPs to THP-1 macrophages were investigated. The results showed that TG enhanced ZnO NP induced cytotoxicity as revealed by water soluble tetrazolium-1 (WST-1) and neutral red uptake assays, but not lactate dehydrogenase (LDH) assay. ZnO NPs dose-dependently enhanced the accumulation of intracellular Zn ions without the induction of reactive oxygen species (ROS), and the presence of TG did not significantly affect these effects. In the co-culture, exposure of THP-1 macrophages in the upper chamber to ZnO NPs and TG significantly reduced the viability of human umbilical vein endothelial cells (HUVECs) in the lower chamber, but the release of tumor necrosis factor α (TNFα) was not induced. In summary, our data showed that stressing THP-1 macrophages with TG enhanced the cytotoxicity of ZnO NPs to macrophages and macrophage-endothelial co-cultures.     

No evidence of the genotoxic potential of gold,silver, zinc oxide and titanium dioxide nanoparticles in the SOS chromotest

Gold nanoparticles (Au NPs), silver nanoparticles (Ag NPs), zinc oxide nanoparticles (ZnO NPs) and titanium dioxide nanoparticles (TiO₂ NPs) are widely used in cosmetic products such as preservatives, colorants and sunscreens. This study investigated the genotoxicity of Au NPs, Ag NPs, ZnO NPs and TiO₂ NPs using the SOS chromotest with Escherichia coli PQ37. The maximum exposure concentrations for each nanoparticle were 3.23 mg l^–1 for Au NPs, 32.3 mg l^–1 for Ag NPs and 100 mg l^–1 for ZnO NPs and TiO₂ NPs. Additionally, in order to compare the genotoxicity of nanoparticles and corresponding dissolved ions, the ions were assessed in the same way as nanoparticles. The genotoxicity of the titanium ion was not assessed because of the extremely low solubility of TiO₂ NPs. Au NPs, Ag NPs, ZnO NPs, TiO₂ NPs and ions of Au, Ag and Zn, in a range of tested concentrations, exerted no effects in the SOS chromotest, evidenced by maximum IF (IFmax) values of below 1.5 for all chemicals. Owing to the results, nanosized Au NPs, Ag NPs, ZnO NPs, TiO₂ NPs and ions of Au, Ag and Zn are classified as non‐genotoxic on the basis of the SOS chromotest used in this study. To the best of our knowledge, this is the first study to evaluate the genotoxicity of Au NPs, Ag NPs, ZnO NPs and TiO₂ NPs using the SOS chromotest. Copyright © 2012 John Wiley & Sons, Ltd.     

Zinc oxide nanoparticles induced oxidative stress in mouse bone marrow mesenchymal stem cells

Engineered nanoparticles are developed for various applications in industrial, electrical, agricultural, pharmaceutical and medical fields due to their unique properties. Nanoparticles such as TiO₂ and ZnO are widely used in cosmetics for UV protection. The toxicological investigations of ZnO NPs are highly recommended because of the increasing use in various industrial and consumer products. The toxic potential of ZnO NPs was assumed to be caused by the release of free Zn+ ions in the medium. Many of the in vivo studies suggest the toxic nature of ZnO NPs, the in vitro studies are certainly important to elucidate the mechanism of toxicity. This study examined the toxicity of ZnO NPs with the average size of 6–8?nm on the isolated mice bone marrow mesenchymal stem cells. The study focuses on the cytotoxicity and oxidative stress-mediated cellular responses upon exposure to ZnO NPs. The results indicated that the exposure to ZnO NPs significantly affects cellular viability in a dose-dependent manner. Formation of reactive oxygen species (ROS) was found to be the mechanism of cellular toxicity. The release of Zn⁺ ions from the nanoparticles, due to the instability of ZnO NPs in the acidic compartment of lysosomes, also increases the ROS generation. In addition to increased ROS production, damage of lysosomal membrane and the activation of executioner caspase-3 and caspase-7 were observed, which eventually ends in apoptosis.     

Toxicity of ZnO nanoparticles (NPs) to A549 cells and A549 epithelium in vitro: Interactions with dipalmitoyl phosphatidylcholine (DPPC)

Once inhaled, nanoparticles (NPs) will first interact with lung surfactant system, which may influence the colloidal aspects of NPs and consequently the toxic potential of NPs to pulmonary cells. In this study, we investigated the effects of dipalmitoyl phosphatidylcholine (DPPC), the major component in lung surfactant, on stability and toxicity of ZnO NPs. The presence of DPPC increased the UV–vis spectra, hydrodynamic size, Zeta potential and dissolution rate of ZnO NPs, which indicates that DPPC might interact with NPs and affect the colloidal stability of NPs. Exposure to ZnO NPs induced cytotoxicity associated with increased intracellular Zn ions but not superoxide in A549 cells. In A549 epithelium model, exposure to ZnO NPs induced cytotoxicity and decreased the release of interleukin 6 (IL-6) without a significant effect on epithelial permeability rate. Co-exposure of A549 cells or A549 epithelium model to DPPC and ZnO NPs induced a higher release of lactate dehydrogenase (LDH) and interleukin-6 (IL-6) compared with the exposure of ZnO NPs alone. We concluded that the presence of DPPC could influence the colloidal stability of ZnO NPs and increase the damage of NPs to membrane probably due to the increased positive surface charge.     

Combined effects of low levels of palmitate on toxicity of ZnO nanoparticles to THP-1 macrophages

We have recently proposed that the interaction between food components and nanoparticles (NPs) should be considered when evaluating the toxicity of NPs. In the present study, we used THP-1 differentiated macrophages as a model for immune cells and investigated the combined toxicity of low levels of palmitate (PA; 10 or 50 μM) and ZnO NPs. The results showed that PA especially at 50 μM changed the size, Zeta potential and UV–vis spectra of ZnO NPs, indicating a possible coating effect. Up to 32 μg/mL ZnO NPs did not significantly affect mitochondrial activity, intracellular reactive oxygen species (ROS) or release of interleukin 6 (IL-6), but significantly impaired lysosomal function as assessed by neutral red uptake assay and acridine orange staining. The presence of 50 μM PA, but not 10 μM PA, further promoted the toxic effects of ZnO NPs to lysosomes but did not significantly affect other endpoints. In addition, ZnO NPs dose-dependently increased intracellular Zn ions in THP-1 macrophages, which was not significantly affected by PA. Taken together, the results of the present study showed a combined toxicity of low levels of PA and ZnO NPs especially to lysosomes in THP-1 macrophages.     

Evaluation of the dose metric for acute lung inflammogenicity of fast-dissolving metal oxide nanoparticles

Although surface area metric was suggested as an appropriate dose metric for acute lung inflammation of NPs, it might not be effective for fast-dissolving NPs because they lose their reactive surface when dissolved in the phagolysosomes. Herein, we evaluated the dose metric for fast-dissolving NPs using a rat intratracheal instillation model. A panel of fast-dissolving NPs (CoO, CuO and ZnO) and their constituent metal ions (CoCl₂, CuCl₂ and ZnCl₂) were compiled and each compound was intratracheally instilled into the lungs of female Wistar rats at the same molar concentrations in the NP doses (40, 100 and 400?μg/rat). The toxicity endpoints including cytological and biochemical data in bronchoalveolar lavage fluid were evaluated at 24?h after instillation. To evaluate the dose metric, each toxicity endpoint was plotted against the instilled dose (mass or surface area) or the equivalent dose (mass or surface area) that was weighted by the ratio of specific dose-generated responses between metal chlorides. Dose-response curves of fast-dissolving NPs about percentage of granulocytes, lactate dehydrogenase levels and total protein levels showed similar pattern but slightly less potential than those of their respective metal chlorides. When each toxicity endpoint was plotted against the equivalent mass dose, three types of NPs showed more overlapping dose-response curves than other dose metrics. In conclusion, this study implies that the equivalent mass dose is an appropriate dose metric for fast-dissolving NPs and the main factor determining the slope of the dose-response curve is the intrinsic toxicity of the their constituent ions.     

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   

Soil pH effects on the comparative toxicity of dissolved zinc,non-nano and nano ZnO to the earthworm Eisenia fetida

To determine how soil properties influence nanoparticle (NP) fate, bioavailability and toxicity, this study compared the toxicity of nano zinc oxide (ZnO NPs), non-nano ZnO and ionic ZnCl₂ to the earthworm Eisenia fetida in a natural soil at three pH levels. NP characterisation indicated that reaction with the soil media greatly controls ZnO properties. Three main conclusions were drawn. First that Zn toxicity, especially for reproduction, was influenced by pH for all Zn forms. This can be linked to the influence of pH on Zn dissolution. Secondly, that ZnO fate, toxicity and bioaccumulation were similar (including relationships with pH) for both ZnO forms, indicating the absence of NP-specific effects. Finally, earthworm Zn concentrations were higher in worms exposed to ZnO compared to ZnCl₂, despite the greater toxicity of the ionic form. This observation suggests the importance of considering the relationship between uptake and toxicity in nanotoxicology studies.     

Acute toxicity and tissue distribution of CdSe/CdS‐MPA quantum dots after repeated intraperitoneal injection to mice

Quantum dots (QDs) are novel tools with multiple biological and medical applications because of their superior photoemission and photostability characteristics. However, leaching of toxic metals from QDs is of great concern. Therefore, for the successful application of QDs in bioscience, it is essential to understand their biological fate and toxicity. We investigated toxicological effects and tissue distribution of mercaptopropionic acid‐conjugated cadmium selenide/cadmium sulfide (CdSe/CdS‐MPA) QDs after repeated intraperitoneal injection into BALB/c mice. The mice were injected every 3 days with various doses of QDs (0, 5, 10 and 25 mg kg^?1). The subsequent effects of QDs on plasma levels of various biomarkers were evaluated at different time points (at 0, 1, 4, 7, 10, 13 and 15 days). Various tissue samples (spleen, liver, lung, kidneys, brain, heart and thymus) were collected for toxicity analysis, distribution testing, histopathological examination and inflammation assessment. No abnormal clinical signs or behaviors were recorded but the body weight of mice treated with 25 mg kg^?1 QDs was significantly decreased from day 7 compared with control mice. QDs were observed in the liver, spleen, lung and kidneys, but not in brain or heart. Significantly higher levels of lactate dehydrogenase and nicotinamide adenine dinucleotide phosphate oxidase were found in the plasma, liver and spleen. Histopathological examination did not show any tissue toxicity but the levels of interleukin‐6, a pro‐inflammatory marker, were increased in the plasma, liver and spleen. All of these findings provide insight into the observed toxicological effect levels and tissue‐specific distribution of CdSe/CdS‐MPA QDs. Copyright © 2012 John Wiley & Sons, Ltd.     

Pulmonary toxicity of inhaled nanoscale and fine zinc oxide particles: Mass and surface area as an exposure metric

The total surface area is known to be an effective exposure metric for predicting the lung toxicity of low solubility nanoparticles (NPs). However, if NPs are dissolved quickly enough in the lungs, the mass may be correlated with the toxicity. Recent studies have found that the toxicity of zinc oxide (ZnO) NPs was caused by the release of zinc ions. Thus, we hypothesized that mass could be used as an exposure metric for the toxicity of ZnO NPs. Healthy Sprague-Dawley rats were exposed to a low, moderate, or high dose of 35 and 250?nm ZnO particles or filtered air. Bronchoalveolar lavage fluid was collected to determine lung inflammation, injury and oxidative stress. The lung inflammation induced by ZnO particles according to different concentration metrics, including number, mass and surface area, was compared. The mass concentration was significantly correlated with the percentage of neutrophils (R²?=?0.84), number of neutrophils (R²?=?0.84) and total cells (R²?=?0.73). Similarly, surface area concentration was significantly correlated with the percentage of neutrophils (R²?=?0.94), number of neutrophils (R²?=?0.81) and total cells (R²?=?0.76). There was no correlation between the number and lung inflammation. We found that both mass and surface area were effective as metrics for the toxicity of ZnO NPs, although only surface area was previously indicated to be an effective metric. Our results are also consistent with recent study results that ZnO NPs and released zinc ions may play a role mediating the toxicity of NPs.