Iron Oxide Nanoparticles Exposure Research Articles

Investigating the toxic mechanism of iron oxide nanoparticles-induced oxidative stress in tadpole (Duttaphrynus melanostictus): A combined biochemical and molecular study

Metal oxide nanomaterials have toxicity towards aquatic organisms, especially microbes and invertebrates, but little is known about their impact on amphibians. We conducted a study on Duttaphrynus melanostictus (D. melanostictus) tadpoles to explore the chronic toxicity effects of iron oxide nanoparticles (IONPs) and the underlying mechanisms of IONPs-induced oxidative stress. IONPs exposure led to increased iron accumulation in the blood, liver, and kidneys of tadpoles, significantly affecting blood parameters and morphology. Higher IONPs concentrations (10 and 50 mg L−1) triggered reactive oxygen species generation, resulting in lipid peroxidation, oxidative stress, and pronounced toxicity in tadpoles. The activity levels of antioxidant enzymes/proteins (SOD, CAT, albumin, and lysozyme) decreased after IONPs exposure, and immunological measures in the blood serum were significantly reduced compared to the control group. Molecular docking analysis revealed that IONPs primarily attached to the surface of SOD/CAT/albumin/lysozyme through hydrogen bonding and hydrophobic forces. Overall, this study emphasizes the ability of IONPs to induce oxidative damage by decreasing immunological profiles such as ACH50 (34.58 ± 2.74 U mL−1), lysozyme (6.94 ± 0.82 U mL−1), total Ig (5.00 ± 0.35 g dL−1), total protein (1.20 ± 0.17 g dL−1), albumin (0.52 ± 0.01 g dL−1) and globulin (0.96 ± 0.01 g dL−1) and sheds light on their potential toxic effects on tadpoles.

Effects of iron oxide nanoparticles as T2-MRI contrast agents on reproductive system in male mice

Iron oxide nanoparticles (IONPs)-based contrast agents are widely used for T2-weighted magnetic resonance imaging (MRI) in clinical diagnosis, highlighting the necessity and importance to evaluate their potential systematic toxicities. Although a few previous studies have documented the toxicity concerns of IONPs to major organs, limited data are available on the potential reproductive toxicity caused by IONPs, especially when administrated via intravenous injection to mimic clinical use of MRI contrast agents. Our study aimed to determine whether exposure to IONPs would affect male reproductive system and cause other related health concerns in ICR mice. The mice were intravenously injected with different concentrations IONPs once followed by routine toxicity tests of major organs and a series of reproductive function-related analyses at different timepoints. As a result, most of the contrast agents were captured by reticuloendothelial system (RES) organs such as liver and spleen, while IONPs have not presented adverse effects on the normal function of these major organs. In contrast, although IONPs were not able to enter testis through the blood testicular barrier (BTB), and they have not obviously impaired the overall testicular function or altered the serum sex hormones levels, IONPs exposure could damage Sertoli cells in BTB especially at a relative high concentration. Moreover, IONPs administration led to a short-term reduction in the quantity and quality of sperms in a dose-dependent manner, which might be attributed to the increase of oxidative stress and apoptotic activity in epididymis. However, the semen parameters have gradually returned to the normal range within 14 days after the initial injection of IONPs. Collectively, these results demonstrated that IONPs could cause reversible damage to the reproductive system of male mice without affecting the main organs, providing new guidance for the clinical application of IONPs as T2-MRI contrast agents.Graphical

Effect of Dietary Lactobacillus casei on Physiometabolic Responses and Liver Histopathology in Common Carp (Cyprinus carpio) After Exposure to Iron Oxide Nanoparticles.

A 60-day feeding trial was performed to assess the dietary effect of Lactobacillus casei as a probiotic supplement on some serum biochemical parameters and liver histopathology in common carp fry after exposure to iron oxide nanoparticles (IoNPs). Six treatments were prepared as follows: control (no IoNP exposure and no dietary probiotic), P6: 106CFU/g probiotic diet, P7: 107CFU/g probiotic diet, NPs: 0.15mg/l IoNPs, NPs + P6: 0.15mg/l IoNPs with 106CFU/g probiotic diet, and NPs + P7: 0.15mg/l IoNPs with 107CFU/gprobiotic diet. Based on the results, serum aspartate aminotransferase and alanine aminotransferase levels were significantly increased in 0.15mg/l IoNPs, P7, and NPs + P6 treatments compared to the control group. In addition, the examination of antioxidant enzymes showed a significant increase in the levels of cortisol and glutathione S-transferase as well as malondialdehyde level. IoNPs also caused significant histopathological changes in the fish liver during the experiment such as hyperemia in sinusoidal spaces, hepatocytes vacuolation and necrosis, pyknosis, and disruption of hepatic lobules and atrophy. Results revealed the protective effects of dietary L. casei to mitigate the adverse impacts of IoNPs on the physiological processes of common carp.

Assessment of oxidative damage induced by iron oxide nanoparticles on different nervous system cells

Iron oxide nanoparticles (ION) have received much attention for their utility in biomedical applications, such as magnetic resonance imaging, drug delivery and hyperthermia, but concerns regarding their potential harmful effects are also growing. Even though ION may induce different toxic effects in a wide variety of cell types and animal systems, there is a notable lack of toxicological data on the human nervous system, particularly important given the increasing number of applications on this specific system. An important mechanism of nanotoxicity is reactive oxygen species (ROS) generation and oxidative stress. On this basis, the main objective of this work was to assess the oxidative potential of silica-coated (S-ION) and oleic acid-coated (O-ION) ION on human SH-SY5Y neuronal and A172 glial cells. To this aim, ability of ION to generate ROS (both in the absence and presence of cells) was determined, and consequences of oxidative potential were assessed (i) on DNA by means of the 8-oxo-7,8-dihydroguanine DNA glycosylase (OGG1)-modified comet assay, and (ii) on antioxidant reserves by analyzing ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG). Conditions tested included a range of concentrations, two exposure times (3 and 24 h), and absence and presence of serum in the cell culture media. Results confirmed that, even though ION were not able to produce ROS in acellular environments, ROS formation was increased in the neuronal and glial cells by ION exposure, and was parallel to induction of oxidative DNA damage and, only in the case of neuronal cells treated with S-ION, to decreases in the GSH/GSSG ratio. Present findings suggest the production of oxidative stress as a potential action mechanism leading to the previously reported cellular effects, and indicate that ION may pose a health risk to human nervous system cells by generating oxidative stress, and thus should be used with caution.

Toxicological assessment of silica-coated iron oxide nanoparticles in human astrocytes

Iron oxide nanoparticles (ION) have great potential for an increasing number of medical and biological applications, particularly those focused on nervous system. Although ION seem to be biocompatible and present low toxicity, it is imperative to unveil the potential risk for the nervous system associated to their exposure, especially because current data on ION effects on human nervous cells are scarce. Thus, in the present study potential toxicity associated with silica-coated ION (S-ION) exposure was evaluated on human A172 glioblastoma cells. To this aim, a complete toxicological screening testing several exposure times (3 and 24 h), nanoparticle concentrations (5–100 μg/ml), and culture media (complete and serum-free) was performed to firstly assess S-ION effects at different levels, including cytotoxicity – lactate dehydrogenase assay, analysis of cell cycle and cell death production – and genotoxicity – H2AX phosphorylation assessment, comet assay, micronucleus test and DNA repair competence assay. Results obtained showed that S-ION exhibit certain cytotoxicity, especially in serum-free medium, related to cell cycle disruption and cell death induction. However, scarce genotoxic effects and no alteration of the DNA repair process were observed. Results obtained in this work contribute to increase the knowledge on the impact of ION on the human nervous system cells.

Intranasal instillation of iron oxide nanoparticles induces inflammation and perturbation of trace elements and neurotransmitters, but not behavioral impairment in rats.

Over the last decades, engineered nanomaterials have been widely used in various applications due to their interesting properties. Among them, iron oxide nanoparticles (IONPs) are used as theranostic agents for cancer, and also as contrast agents in magnetic resonance imaging. With the increasing production and use of these IONPs, there is an evident raise of IONP exposure and subsequently a higher risk of adverse outcome for humans and the environment. In this work, we aimed to investigate the effects of sub-acute IONP exposure on Wistar rat, particularly (i) on the emotional and learning/memory behavior, (ii) on the hematological and biochemical parameters, (iii) on the neurotransmitter content, and (vi) on the trace element homeostasis. Rats were treated during seven consecutive days by intranasal instillations at a dose of 10mg/kg body weight. The mean body weight increased significantly in IONP-exposed rats. Moreover, several hematological parameters were normal in treated rats except the platelet count which was increased. The biochemical study revealed that phosphatase alkaline level decreased in IONP-exposed rats, but no changes were observed for the other hepatic enzymes (ALT and AST) levels. The trace element homeostasis was slightly modulated by IONP exposure. Sub-acute intranasal exposure to IONPs increased dopamine and norepinephrine levels in rat brain; however, it did not affect the emotional behavior, the anxiety index, and the learning/memory capacities of rats.

Interaction mechanisms between α-Fe2O3, γ-Fe2O3 and Fe3O4 nanoparticles and Citrus maxima seedlings

The interactions between α-Fe2O3, γ-Fe2O3, and Fe3O4 nanoparticles (NPs) and Citrus maxima seedlings were examined so as to better understand possible particle applications as an Fe source for crop plants. NPs toxicity to the exposed plant was investigated as well. The α- and γ-Fe2O3 NPs were accumulated by plant root cells through diapirism and endocytosis, respectively, but translocation to the shoots was negligible. Analysis of malondialdehyde (MDA), soluble protein content, and antioxidant enzyme activity revealed that Fe deficiency induced strong oxidative stress in Citrus maxima seedlings, which followed an order of Fe deficiency>Fe3+>α-Fe2O3, γ-Fe2O3 NPs>Fe3O4 NPs. However, the chlorophyll leaf content of plants exposed to α-Fe2O3, γ-Fe2O3, Fe3O4 NPs and Fe3+ were significantly reduced by 31.1%, 14.8%, 18.8% and 22.0%, respectively, relative to the control. Furthermore, RT-PCR analysis revealed no up-regulation of AHA and Nramp3 genes in Citrus maxima roots; however, the relative FRO2 gene expression upon exposure to iron oxide NPs was 1.4–2.8-fold higher than the control. Ferric reductase activity was consistently enhanced upon iron oxide NPs exposure. These findings advance understanding of the interaction mechanisms between metal oxide NPs and plants, and provide important knowledge need for the possible application of these materials in agriculture.

Potential Toxicity and Underlying Mechanisms Associated with Pulmonary Exposure to Iron Oxide Nanoparticles: Conflicting Literature and Unclear Risk.

Fine/micron-sized iron oxide particulates are incidentally released from a number of industrial processes, including iron ore mining, steel processing, welding, and pyrite production. Some research suggests that occupational exposure to these particulates is linked to an increased risk of adverse respiratory outcomes, whereas other studies suggest that iron oxide is biologically benign. Iron oxide nanoparticles (IONPs), which are less than 100 nm in diameter, have recently surged in use as components of novel drug delivery systems, unique imaging protocols, as environmental catalysts, and for incorporation into thermoplastics. However, the adverse outcomes associated with occupational exposure to IONPs remain relatively unknown. Relevant in vivo studies suggest that pulmonary exposure to IONPs may induce inflammation, pulmonary fibrosis, genotoxicity, and extra-pulmonary effects. This correlates well with in vitro studies that utilize relevant dose, cell type(s), and meaningful end points. A majority of these adverse outcomes are attributed to increased oxidative stress, most likely caused by particle internalization, dissolution, release of free iron ions, and disruption of iron homeostasis. However, because the overall toxicity profile of IONPs is not well understood, it is difficult to set safe exposure limit recommendations that would be adequate for the protection of at-risk workers. This review article will focus on known risks following IONPs exposure supported by human, animal, and cell culture-based studies, the potential challenges intrinsic to IONPs toxicity assessment, and how these may contribute to the poorly characterized IONPs toxicity profile.

Erratum to: Magnetic iron oxide nanoparticles accelerate osteogenic differentiation of mesenchymal stem cells via modulation of long noncoding RNA INZEB2

Nanomaterials are increasingly used for biomedical applications; thus, it is important to understand their biological effects. Previous studies suggested that magnetic iron oxide nanoparticles (IONPs) have tissue-repairing effects. In the present study, we explored cellular effects of IONPs in mesenchymal stem cells (MSCs) and identified the underlying molecular mechanisms. The results showed that our as-prepared IONPs were structurally stable in MSCs and promoted osteogenic differentiation of MSCs as whole particles. Moreover, at the molecular level, we compared the gene expression of MSCs with or without IONP exposure and showed that IONPs upregulated long noncoding RNA INZEB2, which is indispensable for maintaining osteogenesis by MSCs. Furthermore, overexpression of INZEB2 downregulated ZEB2, a factor necessary to repress BMP/Smad-dependent osteogenic transcription. We also demonstrated that the essential role of INZEB2 in osteogenic differentiation was ZEB2-dependent. In summary, we elucidated the molecular basis of IONPs’ effects on MSCs; these findings may serve as a meaningful theoretical foundation for applications of stem cells to regenerative medicine.

Lysosomal iron liberation is responsible for the vulnerability of brain microglial cells to iron oxide nanoparticles: comparison with neurons and astrocytes

Iron oxide nanoparticles (IONPs) are used for various biomedical and neurobiological applications. Thus, detailed knowledge on the accumulation and toxic potential of IONPs for the different types of brain cells is highly warranted. Literature data suggest that microglial cells are more vulnerable towards IONP exposure than other types of brain cells. To investigate the mechanisms involved in IONP-induced microglial toxicity, we applied fluorescent dimercaptosuccinate-coated IONPs to primary cultures of microglial cells. Exposure to IONPs for 6 h caused a strong concentration-dependent increase in the microglial iron content which was accompanied by a substantial generation of reactive oxygen species (ROS) and by cell toxicity. In contrast, hardly any ROS staining and no loss in cell viability were observed for cultured primary astrocytes and neurons although these cultures accumulated similar specific amounts of IONPs than microglia. Co-localization studies with lysotracker revealed that after 6 h of incubation in microglial cells, but not in astrocytes and neurons, most IONP fluorescence was localized in lysosomes. ROS formation and toxicity in IONP-treated microglial cultures were prevented by neutralizing lysosomal pH by the application of NH4Cl or Bafilomycin A1 and by the presence of the iron chelator 2,2′-bipyridyl. These data demonstrate that rapid iron liberation from IONPs at acidic pH and iron-catalyzed ROS generation are involved in the IONP-induced toxicity of microglia and suggest that the relative resistance of astrocytes and neurons against acute IONP toxicity is a consequence of a slow mobilization of iron from IONPs in the lysosomal degradation pathway.

Effects of iron oxide nanoparticles: cytotoxicity, genotoxicity, developmental toxicity, and neurotoxicity.

Iron oxide nanoparticles (ION) with superparamagnetic properties hold great promise for use in various biomedical applications; specific examples include use as contrast agents for magnetic resonance imaging, in targeted drug delivery, and for induced hyperthermia cancer treatments. Increasing potential applications raise concerns over their potential effects on human health. Nevertheless, very little is currently known about the toxicity associated with exposure to these nanoparticles at different levels of biological organization. This article provides an overview of recent studies evaluating ION cytotoxicity, genotoxicity, developmental toxicity and neurotoxicity. Although the results of these studies are sometimes controversial, they generally indicate that surface coatings and particle size seem to be crucial for the observed ION-induced effects, as they are critical determinants of cellular responses and intensity of effects, and influence potential mechanisms of toxicity. The studies also suggest that some ION are safe for certain biomedical applications, while other uses need to be considered more carefully. Overall, the available studies provide insufficient evidence to fully assess the potential risks for human health related to ION exposure. Additional research in this area is required including studies on potential long-term effects.

Intrinsically green iron oxide nanoparticles? From synthesis via (eco-)toxicology to scenario modelling

Iron oxide nanoparticles (IONP) are currently being studied as green magnet resonance imaging (MRI) contrast agents. They are also used in huge quantities for environmental remediation and water treatment purposes, although very little is known on the consequences of such applications for organisms and ecosystems. In order to address these questions, we synthesised polyvinylpyrrolidone-coated IONP, characterised the particle dispersion in various media and investigated the consequences of an IONP exposure using an array of biochemical and biological assays. Several theoretical approaches complemented the measurements. In aqueous dispersion IONP had an average hydrodynamic diameter of 25 nm and were stable over six days in most test media, which could also be predicted by stability modelling. The particles were tested in concentrations of up to 100 mg Fe per L. The activity of the enzymes glutathione reductase and acetylcholine esterase was not affected, nor were proliferation, morphology or vitality of mammalian OLN-93 cells although exposure of the cells to 100 mg Fe per L increased the cellular iron content substantially. Only at this concentration, acute toxicity tests with the freshwater flea Daphnia magna revealed slightly, yet insignificantly increased mortality. Two fundamentally different bacterial assays, anaerobic activated sludge bacteria inhibition and a modified sediment contact test with Arthrobacter globiformis, both rendered results contrary to the other assays: at the lowest test concentration (1 mg Fe per L), IONP caused a pronounced inhibition whereas higher concentrations were not effective or even stimulating. Preliminary and prospective risk assessment was exemplified by comparing the application of IONP with gadolinium-based nanoparticles as MRI contrast agents. Predicted environmental concentrations were modelled in two different scenarios, showing that IONP could reduce the environmental exposure of toxic Gd-based particles by more than 50%. Application of the Swiss "Precautionary Matrix for Synthetic Nanomaterials" rendered a low precautionary need for using our IONP as MRI agents and a higher one when using them for remediation or water treatment. Since IONP and (considerably more reactive) zerovalent iron nanoparticles are being used in huge quantities for environmental remediation purposes, it has to be ascertained that these particles pose no risk to either human health or to the environment.