Comparative hazard identification of nano- and micro-sized cerium oxide particles based on 28-day inhalation studies in rats

There are many uncertainties regarding the hazard of nanosized particles compared to the bulk material of the parent chemical. Here, the authors assess the comparative hazard of two nanoscale (NM-211 and NM-212) and one microscale (NM-213) cerium oxide materials in 28-day inhalation toxicity studies in rats (according to Organisation for Economic Co-operation and Development technical guidelines). All three materials gave rise to a dose-dependent pulmonary inflammation and lung cell damage but without gross pathological changes immediately after exposure. Following NM-211 and NM-212 exposure, epithelial cell injury was observed in the recovery groups. There was no evidence of systemic inflammation or other haematological changes following exposure of any of the three particle types. The comparative hazard was quantified by application of the benchmark concentration approach. The relative toxicity was explored in terms of three exposure metrics. When exposure levels were expressed as mass concentration, nanosized NM-211 was the most potent material, whereas when expression levels were based on surface area concentration, micro-sized NM-213 material induced the greatest extent of pulmonary inflammation/damage. Particles were equipotent based on particle number concentrations. In conclusion, similar pulmonary toxicity profiles including inflammation are observed for all three materials with little quantitative differences. Systemic effects were virtually absent. There is little evidence for a dominant predicting exposure metric for the observed effects.     

Dendritic polyglycerol nanoparticles show charge dependent bio-distribution in early human placental explants and reduce hCG secretion

A thorough understanding of nanoparticle bio-distribution at the feto-maternal interface will be a prerequisite for their diagnostic or therapeutic application in women of childbearing age and for teratologic risk assessment. Therefore, the tissue interaction of biocompatible dendritic polyglycerol nanoparticles (dPG-NPs) with first- trimester human placental explants were analyzed and compared to less sophisticated trophoblast-cell based models. First-trimester human placental explants, BeWo cells and primary trophoblast cells from human term placenta were exposed to fluorescence labeled, ～5?nm dPG-NPs, with differently charged surfaces, at concentrations of 1 µM and 10?nM, for 6 and 24?h. Accumulation of dPGs was visualized by fluorescence microscopy. To assess the impact of dPG-NP on trophoblast integrity and endocrine function, LDH, and hCG releases were measured. A dose- and charge-dependent accumulation of dPG-NPs was observed at the early placental barrier and in cell lines, with positive dPG-NP-surface causing deposits even in the mesenchymal core of the placental villi. No signs of plasma membrane damage could be detected. After 24?h we observed a significant reduction of hCG secretion in placental explants, without significant changes in trophoblast apoptosis, at low concentrations of charged dPG-NPs. In conclusion, dPG-NP’s surface charge substantially influences their bio-distribution at the feto-maternal interface, with positive charge facilitating trans-trophoblast passage, and in contrast to more artificial models, the first-trimester placental explant culture model reveals potentially hazardous influences of charged dPG-NPs on early placental physiology.     

Effect of soluble copper released from copper oxide nanoparticles solubilisation on growth and photosynthetic processes of Lemna gibba L

Copper oxide nanoparticles (CuO NPs) are used as a biocide in paints, textiles and plastics. Their application may lead to the contamination of aquatic ecosystems, where potential environmental effects remain to be determined. Toxic effects may be related to interactions of NPs with cellular systems or to particles' solubilisation releasing metal ions. In this report, we evaluated CuO NPs and soluble copper effects on photosynthesis of the aquatic macrophyte Lemna gibba L to determine the role of particle solubility in NPs toxicity. When L. gibba plants were exposed 48 h to CuO NPs or soluble copper, inhibition of photosynthetic activity was found, indicated by the inactivation of Photosystem II reaction centers, a decrease in electron transport and an increase of thermal energy dissipation. Toxicity of CuO NPs was mainly driven by copper ions released from particles. However, the bioaccumulation of CuO NPs in plant was shown, indicating the need to evaluate organisms of higher trophic level.     

Utilization of solid nanomaterials for drug delivery

Background: Solid nanostructures are versatile platforms for constructing hybrid drug delivery systems that have tremendous potential for improving disease prevention and treatment. The rationale and application of solid nanostructures in the context of drug delivery are explored in this article. Objective: The purpose of this paper is to provide a concise review of the major attributes of solid nanostructures as they relate to drug delivery and to describe the outstanding issues that need to be addressed in order to develop these materials into clinically useful reagents. Methods: The scope of this opinion has been restricted to solid nanostructures, where solid nanostructures are defined as those that are not biodegradable. The opinion has been further limited to the three primary types of nanostructures: nanoparticles, nanowires and nanotubes. Results/conclusion: There is a need for cross-disciplinary training and standardized protocols for developing and evaluating the efficacy of solid nanomaterials.     

Analysis of cobalt ferrite nanoparticles induced genotoxicity on human peripheral lymphocytes: comparison of size and organic grafting-dependent effects

We aimed to detect the potential genotoxic effects of CoFe₂O₄ particles (CoFe), of different size, by means of the micronucleus test (MN) in human lymphocytes for the possible use in hyperthermic treatments. CoFe of 5.6 nm (CoFe06) showed a significant decrease of the cytokinesis blocked proliferation index (CBPI) (p<0.05), in parallel to a significant increase in the frequency of micronucleated binucleated lymphocytes (BNMN) (p<0.05). For CoFe of 10 µm (CoFe10) a significant increase in BNMN was found, but any cytotoxic effect. For larger CoFe particles of 120 µm (CoFe120) any significant effect in both indices was detected. To verify if these effects could be triggered by the release in the medium of Co²⁺ source, we organically grafted CoFe06 (CoFe06Lig) to analyze if there was a reduction of the Co⁺²-induced toxic effect. CoFe06Lig showed still a statistically significant genotoxic effect (p<0.05), but 4-fold less than that observed for the same NP, but ‘naked’.     

Effect of BSA on carbon nanotube dispersion for in vivo and in vitro studies

Carbon nanotubes (CNT) are one of the most promising nanomaterials because of their intrinsic properties. So, it becomes urgent to assess their toxicity. However, CNT are insoluble in aqueous media required for toxicological studies. Thus, we propose a simple method to disperse CNT for toxicological studies using a biomolecule: The albumin. To evaluate this method, several nanotubes were suspended in saline solution (NaCl 0.9%) without or with albumin at a concentration of 0.5 mg/ml or equal as CNT concentration. These suspensions were visually compared to suspensions obtained with classical dispersing methods using Tween 80 or serum. Homogeneity of the suspensions with or without BSA and CNT structure were analyzed by TEM, agglomerates quantification and total carbon dosage. The effect of coupled albumin-CNT was then tested on A549 and U937 cells in vitro and on rats in vivo. Total carbon dosage, agglomerates quantification and TEM revealed that, in the presence of albumin, the tested nanotubes were better dispersed without any modification of their structure. The CNT suspension was tested in vitro and in vivo in rats. Albumin solution alone induced no modification of the biological responses studied (i.e., cell viability in vitro and inflammatory response and histopathology in vivo) compared to the saline. CNT in NaCl or BSA altered cellular viability in vitro in a similar way but results obtained with CNT suspension in the presence of albumin showed a better reproducibility that can be explained by the better homogeneity of the suspensions. CNT in BSA but not in NaCl significantly increased the cell number in BAL and also the number of apparent CNT-containing cells. Taken together, these results highlight the potential importance of CNT dispersion (and thus of the vehicle) for the toxicological studies.     

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

Titanium dioxide nanoparticles (TiO₂ NPs) were usually consumed with a high content of sugar, and children were identified as having the highest exposures due to sweet food preferences. Research on the combined effect of ingested TiO₂ NPs and glucose has great significance, particularly in young people. We examined young Sprague-Dawley rats administered TiO₂ NPs (0, 2, 10 and 50 mg/kg) orally with and without glucose (1.8 g/kg) for 90 days. Blood glucose homeostasis was assessed by monitoring blood glucose and detecting glycoproteins. Glucose tolerance was also evaluated by the oral glucose tolerance test. The levels of blood glucose-related hormones such as insulin, C-peptide and glucagon were measured. We found that subchronic co-exposure of TiO₂ NPs and glucose caused slight imbalance of blood glucose homeostasis in vivo. Mild and temporary hypoglycemia, impaired glucose tolerance and changes of glucose-regulating hormones were shown in the exposure groups. The combined effect of TiO₂ NPs and glucose was more apparent than that of TiO₂ NPs alone, which may be due to the effects of excess glucose and the interactions between TiO₂ NPs and glucose. The antagonistic effect of TiO₂ NPs with glucose did exist in the level of glycosylated hemoglobin in female rats. Gender differences were apparent in these effects induced by TiO₂ NPs and glucose. Female rats seemed to be more susceptible for blood glucose disorders. Co-exposure of TiO₂ NPs and excessive glucose could induce gender-dependent imbalance of blood glucose homeostasis in rats. It may be the reason that these consumers face greater health risks glycosylated hemoglobin.     

Co-exposure to silver nanoparticles and cadmium induce metabolic adaptation in HepG2 cells

Although multiple studies have reported the toxicological effects and underlying mechanisms of toxicity of silver nanoparticles (AgNP) in a variety of organisms, the interactions of AgNP with environmental contaminants such as cadmium are poorly understood. We used biochemical assays and mass spectrometry-based proteomics to assess the cellular and molecular effects induced by a co-exposure of HepG2 cells to AgNP and cadmium. Cell viability and energy homeostasis were slightly affected after a 4-h exposure to AgNP, cadmium, or a combination of the two; these endpoints were substantially altered after a 24-h co-exposure to AgNP and cadmium, while exposure to one of the two contaminants led only to minor changes. Proteomics analysis followed the same trend: while a 4-h exposure induced minor protein deregulation, a 24-h exposure to a combination of AgNP and cadmium deregulated 43% of the proteome. The toxicity induced by a combined exposure to AgNP and cadmium involved (1) inactivation of Nrf2, resulting in downregulation of antioxidant defense and proteasome-related proteins, (2) metabolic adaptation and ADP/ATP imbalance, and (3) increased protein synthesis possibly to reestablish homeostasis. The adaptation strategy was not sufficient to restore ADP/ATP homeostasis and to avoid cell death.     

Toxicity of pamam‐coated gold nanoparticles in different unicellular models

Polyamidoamine (PAMAM) dendrimers are used for many pharmaceutical and biomedical applications. However, the toxicological risks of several PAMAM‐based compounds are still not fully evaluated, despite evidences of PAMAM deleterious effects on biological membranes, leading to toxicity. In this report, we investigated the toxicity of generation 0 PAMAM‐coated gold nanoparticles (AuG0 NPs) in four different models to determine how different cellular systems are affected by PAMAM‐coated NPs. Toxicity was evaluated in two mammalian cell lines, Neuro 2A and Vero, in the green alga Chlamydomonas reinhardtii and the bacteria Vibrio fischeri. AuG0 NP treatments reduced cell metabolic activity in algal and bacterial cells, measured by esterase enzymatic activity (C. reinhardtii) and luminescence emission (V. fischeri). EC50 value after 30 min of treatment was similar in both organisms, with 0.114 and 0.167 mg mL^?1 for C. reinhardtii and V. fischeri, respectively. On the other hand, AuG0 NPs induced no change of mitochondrial activity in mammalian cells after 24 h of treatment to up to 0.4 mg mL^?1 AuG0 NPs. Change in the absorption spectra of AuG0 NP in the mammalian cell culture media may indicate an alteration of NP properties that contributed to the low toxicity of AuG0 NPs in mammalian cells. For a safe development of PAMAM‐based nanomaterials, the difference of sensitivity between mammalian and microbial cells, as well as the modulation of NPs toxicity by medium properties, should be taken into account when designing PAMAM NPs for applications that may lead to their introduction in the environment. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 328–336, 2014.     

Toxicological evaluation of metal oxide nanoparticles and mixed exposures at low doses using zebra fish and THP1 cell line

Metal and metal oxide nanoparticles are being used in different industries now‐a‐days leading to their unavoidable exposure to humans and animals. In the present study, toxicological testing was done using nanoparticles of copper oxide, cerium oxide and their mixture (1:1 ratio) on zebra fish embryos and THP‐1 cell line. Zebrafish embryos were exposed to 0.01 μg/ml to 50 μg/ml concentrations of dispersed nanoparticles using a 96 well plate and their effects were studied at different hours post fertilization (hpf) i.e. 0 hpf, 24 hpf, 48 hpf, 72 hpf and 96 hpf respectively. Results showed that copper oxide nanoparticles has drastic effects on the morphology and physiology of zebra fish whereas cerium oxide nanoparticles and mixture of these nanoparticles did not show much of the effects. Comparable results were obtained from in vitro study using human monocyte cell line (THP‐1). It is concluded that these nanoparticles may cause toxicological effects to humans and environment.