Toxicity Of Nanomaterials Research Articles

Graphene promotes lung cancer metastasis through Wnt signaling activation induced by DAMPs

Graphene has important application prospects in many fields, and is considered a revolutionary material in the future. The biocompatibility of graphene and its safety issues have drawn much attention. Possible toxicities of a nanomaterial might be concerned with cell deaths, releasing of damage-associated molecular patters (DAMPs), inflammation, risks of tumorigenesis etc. In the current study, we investigated the long-term pulmonary exposure model of graphene and carbon black and discovered that long-term pulmonary exposure of the materials led to lung cancer metastasis and progression. Notably, pulmonary exposure of graphene or carbon black induced cell necrosis and the release of the DAMP, namely, mitochondrial DNA (mtDNA), which is a potent stimulator for elevating the secretion of Wnt ligands in alveolar macrophages (AMs). The Wnt-activating macrophages contributed to the formation of premetastatic niches in lung tissues by enhancing the stemness potential of cancer cells and promoting their generation and proliferation. The growth of metastatic cancer induced by exposure of carbon-based nanomaterials could be effectively inhibited by treating mice with a Wnt inhibitor. Taken together, our findings elucidate the how the pulmonary cell deaths induced by graphene reshaped the tumor microenvironment by releasing DAMPs and promoting tumor metastasis, which throws the light on the relationship between nanomaterial toxicity and its tumorigenesis risk.

Liquid exfoliation of TiN nanodots as novel sonosensitizers for photothermal-enhanced sonodynamic therapy against cancer

Ultrasound (US)-activated sonodynamic therapy (SDT), as a non-invasive therapy method, has the advantages of large tissue penetration depth promising for treatment of large internal tumors. However, due to the hypoxic characteristic of tumor microenvironment and lack of effective sonosensitizers, the efficacy of SDT is still not satisfactory. In addition, there is still a lot of space for the exploration of SDT-based collaborative cancer treatment. Herein, ultra-small titanium nitride (TiN) nanodots are successfully synthesized for photothermal-enhanced SDT against cancer. Ultra-small TiN nanodots with an average size of 1.5 nm are prepared by the liquid exfoliation method. The obtained TiN nanodots have satisfactory second near-infrared (NIR II) absorption, which can be used for photoacoustic (PA) imaging and photothermal therapy (PTT) of tumors. Interestingly, TiN nanodots can also be used as efficient sonosensitizers to generate reactive oxygen species (ROS) under US irradiation owing to the special defect structure and surface partial oxidation to TiO2 for sonodynamic cancer therapy. The mild photothermal heating of tumors generated by TiN nanodots under NIR II laser irradiation can facilitate intra-tumoral blood flow and improve tumor oxygenation, thereby achieving a significant synergistic treatment effect by combining PTT and SDT. Importantly, most of these TiN nanodots due to their ultra-small size can be promptly metabolized from the mouse body, thus avoiding the concerns about long-term toxicity of nanomaterials. Our work thus for the first time demonstrates the potential use of metal nitride nanomaterials as a new type of multifunctional nano-agents with intriguing properties for cancer theranostic applications.

Membrane perturbation of fullerene and graphene oxide distinguished by pore-forming peptide melittin

Carbon nanomaterials such as fullerenes (C60) and graphene oxide (GO) are considered as promising candidates for diverse applications in biotechnology and biomedicine. However, their potential toxic effects are still under debate. Herein, by using melittin (Mel), a representative pore-forming peptide, as a testing molecule we demonstrated that even the low-concentrated (usually assumed non-toxic) C60 and GO could still mechanically perturb a cell membrane by adsorption and insertion, and consequently influence the function realization of membrane active proteins/peptides. Such perturbations, however, are particle-property and membrane-environment dependent. GO would sensitize both model bilayers and bacterial membranes to Mel, demonstrated as significantly enhanced membrane permeabilization ability or improved antibacterial performance of Mel. In contrast, C60 activates the permeabilization effect of Mel on model membranes, while produces exactly the reverse effect on living bacteria and mammalian cells. Simulations further provide molecular details of the structural disturbance and probe the residue-specific formation of C60-Mel complex in membrane. This work emphasizes the dependence of biological toxicity of nanomaterials on their physico-chemical properties, provides a facile method to detect the subtle structural perturbation of cell membranes at nanoscale, and suggests a necessity for a careful evaluation of the potential influences of nanomaterials on biological processes.

Gold Nanoclusters Display Low Immunogenic Effect in Microglia Cells.

Gold nanoparticles hold a great promise for both clinical and preclinical applications. The major factors impeding such applications are toxicity of new nanomaterials including e.g., pro-apoptotic activities or inflammatory effects, but also their potential to accumulate in the body or inadequate absorption, distribution, metabolism and excretion (ADME) profiles. Since such adverse effects depend on the size, form and coating of nanomaterials, the search for new, less toxic nanomaterials with low tendency to accumulate is highly active domain of research. Here, we describe optical and biological properties of Au18 gold nanoclusters (NCs), small gold nanoparticles composed of 18 atoms of gold and stabilized with glutathione ligands. These nanoclusters may be suitable for in vivo applications owing to their low toxicity and biodistribution profile. Specifically, using lactate dehydrogenase (LDH) test in P19 cell line we found that Au18 NCs display low toxicity in vitro. Importantly, using primary microglial cells we showed that at low concentrations Au18 NCs display anti-inflammatory signaling on evidence of reduced interleukin 1-β (IL1-β) levels and unchanged levels of tumor necrosis factor (TNF-α) or Ym1/2. Such effect was dose dependent as higher concentrations of Au18 NCs induced expression of pro-inflammatory cytokines and suppression of anti-inflammatory cytokine Ym1/2, pointing, thus, to global inflammatory activity. Finally, we also showed that within 3 days Au18 NCs can be completely eliminated from the liver reported as the major target organ for accumulation of gold nanoparticles. These data point to a potential of gold nanoparticles for further biomedical studies.

Primary culture macrophages from fish as potential experimental model in toxicity studies with multiwalled carbon nanotubes

Multiwalled carbon nanotube (MWCNT) has been broadly used in several sectors of society. This material when exposed to the environment might reach the aquatic animals and cause toxic effects. Here, it was evaluated the MWCNTs toxicity in melanomacrophages primary culture that was submitted to 1 µ gm L-1 MWCNTs for 24 hours. After exposition to MWCNT, 48 and 59% liver and spleen melanomacrophages were healthy, respectively. The control group presented 85% viability. Phagocytosis activity of melanomacrophages was observed by presence of black inclusions in cytoplasm. The findings indicate MWCNT was cytotoxic to melanomacrophages, where its release and effect into aquatic environment must be more studied. Finally, the melanomacrophages present large potential as experimental model for evaluation of carbon-based nanomaterial toxicity.

Current Strategies in Assessment of Nanotoxicity: Alternatives to In Vivo Animal Testing.

Millions of experimental animals are widely used in the assessment of toxicological or biological effects of manufactured nanomaterials in medical technology. However, the animal consciousness has increased and become an issue for debate in recent years. Currently, the principle of the 3Rs (i.e., reduction, refinement, and replacement) is applied to ensure the more ethical application of humane animal research. In order to avoid unethical procedures, the strategy of alternatives to animal testing has been employed to overcome the drawbacks of animal experiments. This article provides current alternative strategies to replace or reduce the use of experimental animals in the assessment of nanotoxicity. The currently available alternative methods include in vitro and in silico approaches, which can be used as cost-effective approaches to meet the principle of the 3Rs. These methods are regarded as non-animal approaches and have been implemented in many countries for scientific purposes. The in vitro experiments related to nanotoxicity assays involve cell culture testing and tissue engineering, while the in silico methods refer to prediction using molecular docking, molecular dynamics simulations, and quantitative structure–activity relationship (QSAR) modeling. The commonly used novel cell-based methods and computational approaches have the potential to help minimize the use of experimental animals for nanomaterial toxicity assessments.

Nanoimpact in Plants: Lessons from the Transcriptome.

Transcriptomics studies are available to evaluate the potential toxicity of nanomaterials in plants, and many highlight their effect on stress-responsive genes. However, a comparative analysis of overall expression changes suggests a low impact on the transcriptome. Environmental challenges like pathogens, saline, or drought stress induce stronger transcriptional responses than nanoparticles. Clearly, plants did not have the chance to evolve specific gene regulation in response to novel nanomaterials; but they use common regulatory circuits with other stress responses. A shared effect with abiotic stress is the inhibition of genes for root development and pathogen response. Other works are reviewed here, which also converge on these results.

Multiple toxicity endpoints induced by carbon nanofibers in Amazon turtle juveniles: Outspreading warns about toxicological risks to reptiles

The toxicity of carbon-based nanomaterials (CNs) has been observed in different organisms; however, little is known about the impact of water polluted with carbon nanofibers (CNFs) on reptiles. Thus, the aim of the current study was to assess the chronic effects (7.5months) of 1 and 10mg/L of CNF on Podocnemis expansa (Amazon turtle) juveniles (4months old) based on different biomarkers. Increased total organic carbon (TOC) concentrations observed in the liver and brain (which suggests CNF uptake) were closely correlated to changes in REDOX systems of turtles exposed to CNFs, mainly to higher nitrite, hydrogen peroxide and lipid peroxidation levels. Increased levels of antioxidants such as total glutathione, catalase and superoxide dismutase in the exposed animals were also observed. The uptake of CNFs and the observed biochemical changes were associated with higher frequency of erythrocyte nuclear abnormalities (assessed through micronucleus assays), as well as with both damage in erythrocyte DNA (assessed through comet assays) and higher apoptosis and necrosis rates in erythrocytes of exposed turtles. Cerebral and hepatic acetylcholinesterase (AChE) increased in turtles exposed to CNFs, and this finding suggested the neurotoxic effect of these nanomaterials. Data in the current study reinforced the toxic potential of CNFs and evidenced the biochemical, mutagenic, genotoxic, cytotoxic, and neurotoxic effects of CNFs on P. expansa.

Skin Sensitization Evaluation of Carbon-Based Graphene Nanoplatelets.

Graphene nanoplatelets (GNPs) are one of the major types of carbon based nanomaterials that have different industrial and biomedical applications. There is a risk of exposure to GNP material in individuals involved in their large-scale production and in individuals who use products containing GNPs. Determining the exact toxicity of GNP nanomaterials is a very important agenda. This research aimed to evaluate the skin sensitization potentials induced by GNPs using two types of alternative to animal testing. We analyzed the physicochemical characteristics of the test material by selecting a graphene nanomaterial with a nano-size on one side. Thereafter, we evaluated the skin sensitization effect using an in vitro and an in vivo alternative test method, respectively. As a result, we found that GNPs do not induce skin sensitization. In addition, it was observed that the administration of GNPs did not induce cytotoxicity and skin toxicity. This is the first report of skin sensitization as a result of GNPs obtained using alternative test methods. These results suggest that GNP materials do not cause skin sensitization, and these assays may be useful in evaluating the skin sensitization of some nanomaterials.

Chemical conjugation of FITC to track silica nanoparticles in vivo and in vitro: An emerging method to assess the reproductive toxicity of industrial nanomaterials

Previous studies have demonstrated that silica nanoparticle (SiNP) exposure induces pulmonary and cardiovascular diseases, yet their transportation and degradation in vivo have not been fully elucidated. From the perspective of reproduction, this study was implemented to examine the uterine accumulation of SiNP and explore its reproductive toxicity and pathogenic mechanisms. First, we coupled FITC onto SiNPs and intratracheally instilled them into pregnant mice on the fifth gestational day, and the toxic effect of SiNP was evaluated in vitro and in vivo. It was found that SiNP penetrated the trophoblast membrane, leading to apoptosis and suppression of cell proliferation, tube formation, and invasion in a dose-dependent manner. Mechanistically, SiNP dysregulated the expression of Scd1, Slc27a1, and Cpt1a, and induced over synthesis and efflux obstruction of fatty acid through the PPARγ signaling pathway. The downregulation of Caspase-3 triggered apoptosis of trophoblast, which was causally associated with intracellular fatty acid accumulation as revealed by the correlation analysis. Besides, SiNP induced uterine inflammation in vivo, which aggravated with the observation prolongation within 24 h. Overall, SiNPs were visualized by coupling with FITC, and the uterine accumulation of SiNP induced fatty acid metabolic disorder, biological dysfunction, and trophoblast apoptosis, which were mediated in part by the PPARγ signaling pathway. These findings would contribute to understanding the environmental impacts of SiNP better, as well as the development of control measures for environmental pollution.

Nano-Medicine in the Cardiovascular System.

Nano-medicines that include nanoparticles, nanocomposites, small molecules, and exosomes represent new viable sources for future therapies for the dysfunction of cardiovascular system, as well as the other important organ systems. Nanomaterials possess special properties ranging from their intrinsic physicochemical properties, surface energy and surface topographies which can illicit advantageous cellular responses within the cardiovascular system, making them exceptionally valuable in future clinical translation applications. The success of nano-medicines as future cardiovascular theranostic agents requires a comprehensive understanding of the intersection between nanomaterial and the biomedical fields. In this review, we highlight some of the major types of nano-medicine systems that are currently being explored in the cardiac field. This review focusses on the major differences between the systems, and how these differences affect the specific therapeutic or diagnostic applications. The important concerns relevant to cardiac nano-medicines, including cellular responses, toxicity of the different nanomaterials, as well as cardio-protective and regenerative capabilities are discussed. In this review an overview of the current development of nano-medicines specific to the cardiac field is provided, discussing the diverse nature and applications of nanomaterials as therapeutic and diagnostic agents.

Crystal Phase-Related Toxicity of One-Dimensional Titanium Dioxide Nanomaterials on Kidney Cells.

One-dimensional (1D) nanomaterials are widely used in different fields, and the increased application of 1D nanomaterials has drawn concerns about their unknown toxicity. 1D titanium oxide (TiO2) nanomaterials in different crystal phases are commonly applied in environmental remediation and solar energy conversion fields, but these materials pose a threat to human health, especially to the kidneys, an organ with abundant blood flow. To systematically evaluate the cytotoxicity to the kidneys, TiO2 nanofibers with TiO2(B), anatase, and rutile phases, as well as nanorods with anatase and rutile phases were synthesized and added to the culture medium of HK2 cells. Cell counting kit-8 assay, 2',7'-dichlorofluorescin diacetate assay, Hoechst 33342 staining experiments, and quantitative real-time reverse transcription polymerase chain reaction tests were used to explore the renal effects of the as-prepared TiO2 nanomaterials in the short term or long term. In the short-term evaluation, all the added TiO2 nanomaterials were toxic to HK2 cells, and the cytotoxicity was dose-dependent. Rutile TiO2 can widely attach to the cell surface and displays the most serious cell-killing and proapoptotic ability, while anatase induces the most serious oxidative stress. In long-term evaluation, all the as-prepared TiO2 nanomaterials led to epithelial mesenchymal transition (EMT), a mechanism of renal fibrosis. Consistent with the short-term results, rutile induced the most serious EMT. This study indicated that the renal toxicity of 1D TiO2 nanomaterials is crystal phase-dependent and that rutile induced the most significant renal cell injury. Oxidative stress is a crucial but not the only contributor to the renal toxicity of TiO2 nanomaterials in the short term.

A Fumigation-Based Surface Sterilization Approach for Plant Tissue Culture.

Plant tissue culture has led to breakthroughs in understanding and applying the fundamental knowledge towards harnessing more from plants. Microbial contamination is one of the serious problems limiting the successful extrapolation of plant tissue culture practices. Sources of in vitro contamination include culture containers, media, explants, equipment, the environment of the culture room and transfer area, and operating personnel. The successful initiation of in vitro culture mostly depends on surface sterilization of explants because this is the primary source. Usually, surface sterilization is done using chemicals, or toxic nanomaterials, this is the first time such an approach has been demonstrated. Numerous surface microflora attached to plant surfaces grow faster than the cultured explants and release phytotoxic substances into the culture media, hindering positive outcomes. In the current work, for the first time, the applicability of turmeric and benzoin resin-based fumigation of explants is demonstrated. The results showed that fumigation methods for surface sterilization were promising and could lead to fifty and even 100% contamination-free plant tissue culture. Nanoparticulate carbon was identified in the turmeric and benzoin smoke and coined the key player in the surface sterilization effect. These studies open a whole new avenue for the use of fumigation-based methods for riddance of microbial contamination.

Assessment of Immunotoxicity and Oxidative Stress Induced by Zinc Selenium/Zinc Sulphide Quantum Dots

Although ZnSe/ZnS quantum dots (QDs) have emerged as apparently less hazardous substitute to cadmium-based QDs, their toxicity has not been fully understood. Huge levels of ROS production and associated difficulties comprise the underlying reason for nanomaterial toxicity in cells. This will cause both immunotoxicity and genotoxicity. In the current work, Zinc Selenium/Zinc Sulphide (ZnSe/ZnS) QDs was synthesized, characterized and analyzed for its role in oxidative stress induction in two cell lines (HepG2 and HEK) and Swiss Albino mice. ROS production and influence of catalase activity in ROS production measured by DCFHDA assay in both HepG2 and HEK cells after exposure to ZnSe/ZnS QDs. Assessment of nitrile radical formation carried out by griess reagent. Level of GSH is assessed as a marker for oxidative stress induced by QDs. Cell death induced after exposure to ZnSe/ZnS QDs investigated by Calcein AM-PI live dead assay. Apoptotic DNA ladder assay carried out for studying the potential of ZnSe/ZnS QDs to induce DNA fragmentation. In vivo bio-nano interaction was studied by exposing Swiss Albino mice to ZnSe/ZnS QDs via i.v. and i.p. injection. Antioxidant assays were carried out in brain and liver homogenates to study the oxidative stress. LPO, GSH, GPx, GR and SOD are considered as biomarkers for the stress analysis. Blood brain barrier (BBB) integrity also studied. Spleenocytes proliferation assay was carried out to study the immunotoxicity response. ZnSe/ZnS QDs do not induce visible oxidative stress upto a concentration of 50 μg/ml. Cell death occurs at higher concentration (100 μg/ml) caused by ROS production. Overall study apparently provide attentive information that ZnSe/ZnS QDs is not capable of eliciting any serious damages to liver and brain tissues which in turn substantiates its applicability in biomedical applications.

Machine learning predictions of concentration-specific aggregate hazard scores of inorganic nanomaterials in embryonic zebrafish

The possibility of employing computational approaches like nano-QSAR or nano-read-across to predict nanomaterial hazard is attractive from both a financial, and most importantly, where in vivo tests are required, ethical perspective. In the present work, we have employed advanced Machine Learning techniques, including stacked model ensembles, to create nano-QSAR tools for modeling the toxicity of metallic and metal oxide nanomaterials, both coated and uncoated and with a variety of different core compositions, tested at different dosage concentrations on embryonic zebrafish. Using both computed and experimental descriptors, we have identified a set of properties most relevant for the assessment of nanomaterial toxicity and successfully correlated these properties with the associated biological responses observed in zebrafish. Our findings suggest that for the group of metal and metal oxide nanomaterials, the core chemical composition, concentration and properties dependent upon nanomaterial surface and medium composition (such as zeta potential and agglomerate size) are significant factors influencing toxicity, albeit the ranking of different variables is sensitive to the exact analysis method and data modeled. Our generalized nano-QSAR ensemble models provide a promising framework for anticipating the toxicity potential of new nanomaterials and may contribute to the transition out of the animal testing paradigm. However, future experimental studies are required to generate comparable, similarly high quality data, using consistent protocols, for well characterized nanomaterials, as per the dataset modeled herein. This would enable the predictive power of our promising ensemble modeling approaches to be robustly assessed on large, diverse and truly external datasets.

Comparative study of response of four crop species exposed to carbon nanotube contamination in soil

Crop plants are exposed to a variety of contaminants through sewage sludge spreading but very little is known about the impact of emerging contaminants such as nanomaterials. To date their impact on plants is still very controversial with many works claiming negative impacts while some authors suggest their use as plant growth regulator in agriculture. In this study, aiming to better understand where these discrepancies may come from, we investigated the influence of plant species (tomato, rapeseed, cucumber and maize) on plant response to a carbon nanotube contamination in soil condition. Our results demonstrate that the same CNT contamination can lead to different effects depending on plant species with positive impacts on cucumber and rapeseed (more than 50% increase in leaf biomass and surface area and 29% increase in chlorophyll for cucumber) but negative impact on maize (−14% for plant height), while tomato was insensitive. FTIR analysis of biomacromolecule composition suggested that these differences could be related with plant cell wall composition (in particular: pectins, xyloglucans and lignins). As a summary, no overall conclusion can be drawn about the toxicity of a specific nanomaterial for all plant species.

Biosafety risk assessment of nanoparticles: Evidence from food case studies.

Nanotechnology provides a wide range of benefits in the food industry in improving food tastes, textures, sensations, quality, shelf life, and food safety. Recently, potential adverse effects such as toxicity and safety concerns have been associated with the increasing use of engineered nanoparticles in food industry. Additionally, very limited information is known concerning the behavior, properties and effects of food nano-materials in the gastrointestinal tract. There is explores the current advances and provides insights of the potential risks of nanoparticles in the food industry. Specifically, characteristics of food nanoparticles and their absorption in the gastrointestinal tract, the effects of food nanoparticles against the gastrointestinal microflora, and the potential toxicity mechanisms in different organs and body systems are discussed. This review would provide references for further investigation of nano-materials toxicity effect in foods and their molecular mechanisms. It will help to develop safer foods and expand nano-materials applications in safe manner.

Quasi-SMILES as a basis for the development of models for the toxicity of ZnO nanoparticles

The application of nanomaterials is expanding. Therefore, it is necessary to investigate the relationship between the structure and toxicity of different nanomaterials. Quasi-SMILES is a line of symbols which are codes of corresponding conditions of experiments aimed to estimate the toxicity of ZnO nanoparticles towards the rat via intraperitoneal injections. By means of the Monte Carlo method, the so-called correlation weights for fragments of quasi-SMILES can be calculated. Having the numerical data on the correlation weights one can build up a one-variable model for the toxicity. The checking up of the approach with five random splits of all available data on results of thirty-six experiments into a sub-system of training and sub-system of validation has confirmed the significance of the statistical quality of models obtained with the above approach. The average determination coefficient equal to 0.957 (dispersion 0.010) and average root mean square error equal to 7.25 [mg/kg] (dispersion 0.59 [mg/kg]).

Nanotechnology risk, toxicity and its effect on safety and human health

Nanotechnology is an interdisciplinary field encompassing a wide and varied range of devices derived from engineering, physics, chemistry and biology, and this field contains a better understanding of the development of medical analysis technologies, biotechnological processes, the development of new and targeted chemicals for delivery. nanomaterials are widely used, especially in biology, biotechnology, and medicine. However, there are limited studies on the potential toxicity of nanomaterials. Therefore, there is a need for varied and systematic toxicological data with new techniques for nanomaterials. To investigate the nanotoxicology of nanoparticles (NPs), the health and safety hazards of nanomaterials include the potential toxicity of various types of nanomaterials, as well as the hazard of dust fire and explosion. As nanotechnology is a recent emergence, the health and safety consequences of nanomaterials exposure, as well as exposure limits, are the subject of ongoing research. Of the potential hazards, inhalation exposure is of greatest concern, with animal studies showing pulmonary effects such as inflammation, fibrosis and carcinogenicity in some nanomaterials. Skin contact and ingestion, as well as a dust explosion hazard, are also of concern.

Different physiological responses of C3 and C4 plants to nanomaterials.

Several studies have previously reported that nanomaterial uptake and toxicity in plants are species dependent. However, the differences between photosynthetic pathways, C3 and C4, following nanomaterial exposure are poorly understood. In the current work, wheat and rice, two C3 pathway species are compared to amaranth and maize, which utilize the C4 photosynthetic mechanism. These plants were cultured in soils which were spiked with CuO, Ag, TiO2, MWCNT, and FLG nanomaterials. Overall, the C4 plant exhibited higher resilience to NM stress than C3 plants. In particular, significant differences were observed in chlorophyll contents with rice returning a 40.9-54.2% decrease compared to 3.5-15.1% for maize. Fv/Fm levels were significantly reduced by up to 51% in rice whereas no significant reductions were observed in amaranth and maize. Furthermore, NM uptake in the C3 species was greater than that in C4 plants, a trend that was also seen in metal concentration. TEM results showed that CuO NPs altered the chloroplast thylakoid structure in rice leaves and a large number of CuO NPs were observed in the vascular sheath cells. In contrast, there were no significant changes in the chloroplasts in the vascular sheath and no significant CuO NPs were found in maize leaves. This study was the first to systematically characterize the effect of metal and carbon-based nanomaterials in soil on C3 and C4 plants, providing a new perspective for understanding the impact of nanomaterials on plants.