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Reprotoxicité des nanoparticules
Abstract
Nanoparticles (NPs) are sized between 1 and 100 nm. Their size allows new nanoscale properties of particular interest for industrial and scientific purpose. Over the past twenty years, nanotechnology conquered many areas of use (electronic, cosmetic, textile…). While, human is exposed to an increasing number of nanoparticles sources, health impacts and, particularly on reproductive function, remains poorly evaluated. Indeed, traceability of nanoparticles use is lacking and nanotoxicology follows different rules than classical toxicology. This review focuses on the impact of NPs on health and particularly on fertility and addresses potential risks of chronic exposure to NPs on human fertility.
... Nanoparticles (NPs) are defined as particles with at least one spatial dimension of less than 100 nm [24]. Their nanometric size gives them new physical and chemical properties that are different from the conventional materials and make them attractive from both industrial and scientific point of views [42]. The scope for NPs is very wide and includes many fields, such as healthcare, environmental, pharmaceuticals, cosmetics, food processing, agriculture, electronic and computer engineering [10]. ...
... Results showed a significant increase in reactive oxygen species formation when the epithelial cells were exposed to 30 ppm of pure TiO 2 [83]. Other studies also reported cytotoxicity and genotoxicity of some NPs, such as silver, gold, zinc, titanium, carbon and silica NPs on gonad cells, germ cells and somatic cells involved in the animal reproduction [42]. ...
Nano-pollutants (NPLTs) have recently raised global concerns due to their possible harmful impact on environment and human health. However, until date, information on the occurrence, fate and toxicity of NPLTs in environment is scant. The knowledge gap can be attributed to the lack of advanced and sophisticated methodologies for the precise detection and characterization of NPLTs at lower concentration in complex matrices, such as surface water, wastewater, soil and food. This review briefly discusses the performance of classical methods for characterization and study of the properties of NPLTs. The important properties include shape, size, aggregation state, chemical composition and structure. Chromatographic, microscopic and spectroscopic techniques have been developed for detection and quantitative estimation of fabricated or naturally existed NPLTs in different matrices. Often, combination of these techniques is required for the separation, purification and accurate estimation. For better detection and understanding of the initial steps of interaction with the environmental matrices, pollution sources, such as wastewater and industrial discharges, must be selected as sampling points. Understanding the dynamics of agglomeration, and decantation will allow to estimate the plume of transport to delimit the potential effects.
This thesis focuses on the study of proteins from samples containing less than one microgram. It concentrates on the evaluation of new sample preparation protocols and the automation of one of them, the SP3. Acquisition methods in ddaPASEF and diaPASEF were evaluated using an innovative mass spectrometer with an ion mobility separation dimension. Bioinformatics tools dedicated to quantitative proteomics allowing to process these data with an atypical format were evaluated. Finally, different analytical strategies were developed to study protein-protein interactions, to better understand the mechanisms of cholesterol accumulation and its role in atherosclerosis as well as to study ribosome biogenesis and mRNA regulation. Finally, a last project allowed us to evaluate the impact of nanoparticles of medical interest on human immune cells.
Male reproductive health is deteriorating, and fertility is largely affected by environmental factors. This study aims to investigate the potential mechanism underlying mitochondrial division and mitochondrial autophagy in the male...
Zinc oxide nanoparticles (ZnO NPs) demonstrate potential positive effects on reproduction. However, their protective role against the reproductive toxicity pollutants has not yet been adequately studied at the molecular level. This study was designed to assess this objective using Benzo[α]pyrene B[a]P as reproductive toxic agent . Forty-eight mature male rats were randomly distributed into six groups: Group1 (negative control); Groups 2 and 3 (positive control I and II, wherein the animals were treated with 10 and 30 mg ZnO NPs/kg BW, respectively); Group 4 (B[a]P group; treated with 150 mg B[a]P/kg BW); and Groups 5 and 6 (subjected to B[a]P treatment co-administered with different concentrations of ZnO NPs). We investigated oxidative stress biomarkers; cholesterol side-chain cleavage enzyme (CYP11A1), steroidogenic acute regulatory protein (StAR), and 3β-hydroxysteroid dehydrogenase (3β-HSD) gene expression; testosterone levels; and histopathology of the liver, kidney, and testicles. The B[a]P-treated group showed significant deterioration in all reproductive parameters and displayed induced oxidative stress. ZnO NPs remarkably reduced oxidative stress, effectively upregulated the mRNA levels of CY11A1, StAR, and 3β-HSD, and improved the histological pictures in the examined organs. At their investigated doses and given their NPs properties, ZnO NPs demonstrated a marked ameliorative effect against the reproductive toxic effects of B[a]P. Further studies are needed to thoroughly investigate the molecular mechanisms of ZnO NPs.
Green synthesis of nanoparticles (NPs) had shown the positive effects on various parameters of human health. However, this can vary depending on plant category, NPs nature, doses of green synthesized NPs and type of cell or tissue taken for experiment. The aim of this study is to evaluate the effects of Allium cepa (A. cepa)-mediated zinc oxide ZnO NPs on male reproductive tissues and aberrations in sperm structure of albino mice. The green-synthesized NPs were synthesized with A. cepa and further characterized through ultraviolet–visible spectroscopy, scanning electron microscopy (SEM), zeta potential and FTIR analysis. Various doses (75 mg, 150 mg, 225 mg and 300 mg/kg) were given orally to adult albino mice by keeping them in various groups for 28 days. Epididymis and testis were removed for assessment of spermatogenesis and histopathological analysis of testicular tissues was performed. The synthesized NPs showed absorption at 330 nm and size ranging from 50 to 90 nm through SEM. Dose-dependent significant decrease (P < 0.05) in sperm calculation, increased in sperm abnormalities and sperm motility were observed by the A. cepa mediated ZnO NPs compared to control group. Similarly, testicular tissues showed vacuolization and detachment in seminiferous tubules and degenerative sperm cells in experimental groups provided with synthesized ZnO NPs. The study concluded that ZnO NPs adversely effect on epididymal sperm parameters and testicular tissues of male albino mice.
Resumen
La reacción cutánea más frecuente ante la exposición solar es una respuesta inflamatoria llamada quemadura solar o eritema actínico. Es una reacción muy frecuente, puesto que cerca del 100% de la población habría sufrido una quemadura solar moderada y más del 50% una quemadura solar importante. En una persona sana, puede desencadenarse por una exposición demasiado importante o por la utilización de sustancias fotosensibilizadoras. El médico, habitualmente enfrentado a esta situación, debe guiar su prescripción según la extensión y la profundidad de las lesiones. La búsqueda posterior de la causa (fotoprotección inadecuada, contacto con sustancias fotosensibilizadoras, dermatosis agravada por el sol) es el elemento primordial que permitirá evitar la recidiva, que conduciría potencialmente a aumentar el riesgo de aparición de un melanoma maligno en la edad adulta.
Silver nanoparticles (AgNPs) have been widely produced for different industrial purposes. Recently, biogenic synthesis of AgNPs has emerged although the extent of effects from exposure, oral exposure in particular, to nanomaterials synthesized in such a manner remains elusive. The main objective of this study was to evaluate the effects of oral administration of a dose of 50 mg/Kg body weight AgNPs biosynthesized in baker’s yeast (Saccharomyces cerevisiae) over a period of eight weeks on the reproductive performance and the possibility of a protective effect through co-administration of morin. Forty-eight male Sprague-Dawley rats were used in four experimental groups (control, morin-treated group, AgNP-treated, and AgNP + morin co-treatment). AgNPs produced no significant alteration in daily food intake or body weight. Both the absolute and relative testicular weights were significantly reduced but not the epididymal weight. Also, serum levels of urea, creatinine, uric acid, and liver enzymes were significantly elevated. Furthermore, AgNPs significantly downregulated the hypothalamic–pituitary–gonadal axis. This corresponds to lower motility and viability percent, reduced sperm concentration, and a higher abnormality ratio as well as a prominent alteration in the blood–testis barrier (BTB) and testicular histology and induction of testicular apoptosis and oxidative stress. The supplementation of morin evidently restored most of the reproductive characters to its physiological range. We can conclude that exposure to the biologically synthesized AgNPs for an extended period of time has proven to be a health risk that can be ameliorated via oral administration of some bioactive agents including morin.
Background
Cerium oxide nanoparticles (CeO2 NPs) have potential application for use in biomedical and in various consumer products. However, it is largely unclear whether CeO2 NPs have effects on male reproductive function.
Methods
In this study, male mice were examined for toxicity, if any, following chronic oral administration of CeO2 NPs for 32 days. In each animal, epididymides were examined for sperm motility and DNA integrity. Bloods were tested for testosterone levels. Testicular tissues were collected to determine the element Ce content, the daily sperm production (DSP), marker enzymes such as ACP, G6PD, γ-GT and SDH, mRNA expression levels of steroidogenesis genes Star, P450scc, P450c17, 3β-Hsd, and 17β-Hsd, as well as steroidogenic factor-1 (SF-1) gene/protein levels.
Results
The results showed that CeO2 NPs (20 mg/kg and 40 mg/kg) increased the element Ce content in testis, the testis histopathological patterns and sperm DNA damage whereas decreased the testis weight, DSP and sperm motility. There were also remarkable reduction in testosterone levels and marker enzymes activities, down-regulated mRNA expression levels of several steroidogenesis genes such as Star, P450scc, P450c17, 3β-Hsd, and 17β-Hsd, as well as altered gene and protein expressions of SF-1.
Conclusion
These results reveal the male reproductive toxicity of chronic exposure of CeO2 NPs in mice, hinting that the utilization of CeO2 NPs need to be carefully evaluated about their potential reproductive toxicity on the human health.
Electronic supplementary material
The online version of this article (10.1186/s12951-019-0474-2) contains supplementary material, which is available to authorized users.
Several in vitro studies have convincingly demonstrated that SiO2NPs mediated cytotoxicity, which was dose-, time- and size-dependent. The data on in vivo toxicity of SiO2NPs are even more contradictory. In the present study, we investigated the effects of sub-acute exposure to SiO2-NPs on spatial learning and memory, the biochemical parameters and the histology of organs. Rats were injected intravenously with a single dose of SiO2- NPs (20mg/kg) during five consecutive days. The analysis of spatial memory in the Morris water maze showed that SiO2-NPs disrupt the cognitive abilities of rats. Moreover, SiO2-NPs could changes the blood counts. However, biochemical markers remained unchanged. Histological examination showed that SiO2-NPs induced pathological changes in rat organs. In this finding NPs were shown to cause granuloma formation and inflammatory cells infiltration in the liver.
SERENADE is a French project which aims to develop and apply the "safer by design" process to create safer nano-products. It achieves this goal by combining knowledge and scientific approaches from a range of disciplines towards this common goal. This tutorial review presents the conceptual approach to "Safer by Design" and provides several examples of case studies primarily for TiO2 (anatase) present in paints and cements to demonstrate how the approach can inform design decisions. Particular attention is paid to chronic low dose exposure scenarios.
Whatever their origin, natural or manufactured, the nanometer-sized particles are known to play a crucial role in natural media. An overview of the terminology, fate and main effects of nanoparticles is given. The main physicochemical characteristics are presented as well as the biophysicochemical processes that depend. The issue of analytical strategy is then discussed. The possible methods of sample preparation are presented. Additionally the main methods for the dimensional characterization and the determination of the composition and concentration of nanoparticles are reviewed. Coupling and multitechnique approach are also discussed.
It has been demonstrated that exposure to silver nanoparticles (AgNPs) can induce toxicological effects in rodents. In this study, we investigated whether sub-chronic oral exposure to different doses of polyvinil pyrrolidone (PVP)-coated AgNPs (PVP-AgNPs) (50, 100 and 200mg/kg/day) could induce harmful effects on epididymal sperm rat parameters. Sperm motility, viability and morphology were examined. Moreover, a histological evaluation of testis and epididymis was also performed. High doses of PVP-AgNPs showed higher sperm morphology abnormalities, while a progressive, but not significant effect, was observed in other sperm parameters. The current results suggest that oral sub-chronic exposure to PVP-AgNPs induces slight toxicological effects in sperm rat parameters.
Nanotechnology starts to be an important field of biomedical and clinical research and the application of nanoparticles in disease may offer promising advances in treatment of many diseases, especially cancer. Malignant melanoma is one of the most aggressive forms of cancer and its incidence is rapidly increasing. Redox-active cerium oxide nanoparticles (CNP) are known to exhibit significant anti-tumor activity in cells derived from human skin tumors in vitro and in vivo, whereas CNP is non- toxic and beyond that even protective (antioxidative) in normal, healthy cells of the skin. As the application of conventional chemotherapeutics is associated with harmful side effects on healthy cells and tissues, the clinical use is restricted. In this study, the question was addressed of whether CNP supplement a classical chemotherapy thereby enhancing its efficiency without additional damage of normal cells. The anthracycline Doxorubicin, one of the most effective cancer drugs, was chosen as reference for a classical chemotherapeutic agent in this study. Herein, we show that CNP enhance the anti-tumor activity of Doxorubicin in human melanoma cells. Synergistic effects on cytotoxicity, ROS generation and oxidative damage in tumor cells were observed after co-incubation. In contrast to Doxorubicin, CNP do not cause DNA damage and even protect human dermal fibroblasts from Doxorubicin-induced cytotoxicity. A combination of classical chemotherapeutics with non-genotoxic, but anti-tumor active cerium oxide nanoparticles may provide a new strategy against cancer by improving therapeutic outcome and benefit for patients.
The response of the mouse male germ cells exposed to gold nanoparticles (~2.5 nm) was studied.
Our investigation demonstrates that treatment with Au nanoparticles for four days does not impair the archi
tecture of the spermatogenic epithelium. Cytogenetic
evaluation using micronucleus assay showed that gold
nanoparticles can affect the chromosomes of early pr
imary spermatocytes. However, gold nanoparticles did
not induce chromosome abnormalities in spermatogoni
al stem cells. Further, the cauda epididymal sperm
was isolated on the 14th day after treatment and wa
s incubated in SDS solution (Na dodecyl sulphate) and
then in a solution containing DTT (dithiothreitol)
to induce nuclear chromatin decondensation. Observa
tions showed that after four days of treatment of sperm
iogenic (postmeiotic) cells with gold nanoparticles the
decondensation process had no differences from the control. On the contrary, in the experiment with the
same cells and period of fixation but with a single
exposure to gold nanoparticles, the number of mature
gametes with totally decondensed nuclei reached 100% as opposed to 44% in the controls.
Cerium dioxide nanoparticles (CeO2 ENPs) are on the priority list of nanomaterials requiring evaluation. We performed in vitro assays on mature mouse oocytes incubated with CeO2 ENPs to study (1) physicochemical biotransformation of ENPs in culture medium; (2) ultrastructural interactions with follicular cells and oocytes using Transmission Electron Microscopy (TEM); (3) genotoxicity of CeO2 ENPs on follicular cells and oocytes using a comet assay. DNA damage was quantified as Olive Tail Moment. We show that ENPs aggregated, but their crystal structure remained stable in culture medium. TEM showed endocytosis of CeO2 ENP aggregates in follicular cells. In oocytes, CeO2 ENP aggregates were only observed around the zona pellucida (ZP). The comet assay revealed significant DNA damage in follicular cells. In oocytes, the comet assay showed a dose-related increase in DNA damage and a significant increase only at the highest concentrations. DNA damage decreased significantly both in follicular cells and in oocytes when an anti-oxidant agent was added in the culture medium. We hypothesise that at low concentrations of CeO2 ENPs oocytes could be protected against indirect oxidative stress due to a double defence system composed of follicular cells and ZP.
Metal and alloy nanoparticles are increasingly developed for biomedical applications, while a firm understanding of their biocompatibility is still missing. Various properties have been reported to influence the toxic potential of nanoparticles. This study aimed to assess the impact of nanoparticle size, surface ligands and chemical composition of gold, silver or gold-silver alloy nanoparticles on mammalian gametes. An in vitro assay for porcine gametes was developed, since these are delicate primary cells, for which well-established culture systems exist and functional parameters are defined. During coincubation with oocytes for 46 h neither any of the tested gold nanoparticles nor the gold-silver alloy particles with a silver molar fraction of up to 50% showed any impact on oocyte maturation. Alloy nanoparticles with 80% silver molar fraction and pure silver nanoparticles inhibited cumulus-oocyte maturation. Confocal microscopy revealed a selective uptake of gold nanoparticles by oocytes, while silver and alloy particles mainly accumulated in the cumulus cell layer surrounding the oocyte. Interestingly sperm vitality parameters (motility, membrane integrity and morphology) were not affected by any of the tested nanoparticles. Only sporadic association of nanoparticles with the sperm plasma membrane was found by transmission electron microscopy. In conclusion, mammalian oocytes were sensitive to silver containing nanoparticles. Likely, the delicate process of completing meiosis in maternal gametes features high vulnerability towards nanomaterial derived toxicity. The results imply that released Ag(+)-ions are responsible for the observed toxicity, but the compounding into an alloy seemed to alleviate the toxic effects to a certain extent.
Targeted therapy is becoming an increasingly important component in the treatment of cancer. How to accurately monitor targeted therapy has been crucial in clinical practice. The traditional approach to monitor treatment through imaging has relied on assessing the change of tumor size by refined World Health Organization criteria, or more recently, by the Response Evaluation Criteria in Solid Tumors. However, these criteria, which are based on the change of tumor size, show some limitations for evaluating targeted therapy. Currently, genetic alterations are identified with prognostic as well as predictive potential concerning the use of molecularly targeted drugs. Conversely, considering the limitations of invasiveness and the issue of expression heterogeneity, molecular imaging is better able to assay in vivo biologic processes noninvasively and quantitatively, and has been a particularly attractive tool for monitoring treatment in clinical cancer practice. This review focuses on the applications of different kinds of molecular imaging including positron emission tomography-, magnetic resonance imaging-, ultrasonography-, and computed tomography-based imaging strategies on monitoring targeted therapy. In addition, the key challenges of molecular imaging are addressed to successfully translate these promising techniques in the future.
In recent years, nanoparticles have been increasingly used in several industrial, consumer and medical applications because of their unique physico-chemical properties. However, in vitro and in vivo studies have demonstrated that these properties are also closely associated with detrimental health effects. There is a serious lack of information on the potential nanoparticle hazard to human health, particularly on their possible toxic effects on the endocrine system. This topic is of primary importance since the disruption of endocrine functions is associated with severe adverse effects on human health. Consequently, in order to gather information on the hazardous effects of nanoparticles on endocrine organs, we reviewed the data available in the literature regarding the endocrine effects of in vitro and in vivo exposure to different types of nanoparticles. Our aim was to understand the potential endocrine disrupting risks posed by nanoparticles, to assess their underlying mechanisms of action and identify areas in which further investigation is needed in order to obtain a deeper understanding of the role of nanoparticles as endocrine disruptors. Current data support the notion that different types of nanoparticles are capable of altering the normal and physiological activity of the endocrine system. However, a critical evaluation of these findings suggests the need to interpret these results with caution since information on potential endocrine interactions and the toxicity of nanoparticles is quite limited.
The diverse abilities of cerium oxide nanoparticles (CONPs) have encouraged researchers to pursue CONPs as a therapeutic agent to treat a number of diseases, including cancer. In vitro and in vivo studies have shown CONPs to be toxic to cancer cells, inhibit invasion, and sensitize cancer cells to radiation therapy. However, CONPs display minimal toxicity to normal tissues and provide protection from various forms of reactive oxygen species (ROS) generation. The antioxidant capabilities of CONPs, which enable radiation protection, have also resulted in the exploration of these particles as a potential treatment for other disorders characterized by ROS accumulation, such as diabetes and macular degeneration. While critical information regarding the uptake, retention, and clearance of these particles is incomplete and conflicting reports exist about in vitro toxicity, most research into the various applications of CONPs has yielded promising data. This review highlights the current research into cerium oxide nanoparticles as a novel therapeutic for the treatment of cancer and other diseases.
Recent studies have demonstrated nanosized titanium dioxide (nano-TiO2)-induced fertility reduction and ovary injury in animals. To better understand how nano-TiO2 act in mice, female mice were exposed to 2.5, 5, and 10 mg/kg nano-TiO2 by intragastric administration for 90 consecutive days; the ovary injuries, fertility, hormone levels, and inflammation-related or follicular atresia-related cytokine expression were investigated. The results showed that nano-TiO2 was deposited in the ovary, resulting in significant reduction of body weight, relative weight of ovary and fertility, alterations of hematological and serum parameters and sex hormone levels, atretic follicle increases, inflammation, and necrosis. Furthermore, nano-TiO2 exposure resulted in marked increases of insulin-like growth factor-binding protein 2, epidermal growth factor, tumor necrosis factor-α, tissue plasminogen activator, interleukin-1β, interleukin -6, Fas, and FasL expression, and significant decreases of insulin-like growth factor-1, luteinizing hormone receptor, inhibin α, and growth differentiation factor 9 expression in mouse ovary. These findings implied that fertility reduction and ovary injury of mice following exposure to nano-TiO2 may be associated with alteration of inflammation-related or follicular atresia-related cytokine expressions, and humans should take great caution when handling nano-TiO2.
In this study, we extended previous work to evaluate the oral toxicity of ZnO nanoparticles and their possible effects on different serum-elements and sexual hormones in the mouse. The histopathological changes have also been examined. Significant recorded increases in alanine aminotransferase and aspartate aminotransferase activity in all mice exposed to ZnO nanoparticles suggest that these nanoparticles can cause hepatic injury. Hepatocyte necrosis and other pathological observations also confirmed liver damage. Moreover, Glomeruli segmentation, hydropic degeneration in epithelial cells, necrosis of epithelial cells in tubules and swelling in epithelial cells of proximal tubules were found in all kidney tissues, which demonstrated that ZnO nanoparticles have severe toxicological effects on kidney. Serous inflammation, severe hyperemia in alveoli, and edema were observed as pathological findings in the lung which suggest that the lung is the third target tissue of the ZnO nanoparticles.
The physical, chemical and biological properties of various nanomaterials differ substantially – as do the potential risks they pose. We argue that nanomaterials must be categorized based on the location of the nanoscale structure in the system/material before their hazards can be assessed and propose a categorization framework that enables scientists and regulators to identify the categories of nanomaterials systematically. The framework is applied to a suggested hazard identification approach aimed at identifying causality between inherent physical and chemical properties and observed adverse effects reported in the literature. We tested the workability of the proposed procedure using nanoparticles as an illustrative case study. A database was generated noting the reported inherent physical and chemical properties of the nanoparticles tested and the main effects observed. 428 studies were noted in the database reporting on a total of 965 nanoparticles. We found that although a limited number of studies have been reported on ecotoxicity, more than 120 and 270 have been reported on mammalian toxicity and cytotoxicity, respectively. In general there was a lack of characterization of the nanoparticles studied and it was not possible to link specific properties of nanoparticles to the observed effects. Our study shows that future research strategies must have a strong focus on characterization of the nanoparticles tested.
The toxicity of QD has been extensively studied over the past decade. However, the potential toxicity of QDs impedes its use for clinical research. In this work, we established a preantral follicle in vitro culture system to investigate the effects of QD-Transferrin (QDs-Tf) bioconjugates on follicle development and oocyte maturation. The preantral follicles were cultured and exposed to CdTe/ZnTe QDs-Tf bioconjugates with various concentrations and the reproductive toxicity was assessed at different time points post-treatment. The invasion of QDs-Tf for oocytes was verified by laser scanning confocal microscope. Steroid production was evaluated by immunoassay. C-band Giemsa staining was performed to observe the chromosome abnormality of oocytes. The results showed that the QDs-Tf bioconjugates could permeate into granulosa cells and theca cells, but not into oocyte. There are no obvious changes of oocyte diameter, the mucification of cumulus-oocyte-complexes and the occurrence of aneulpoidy as compared with the control group. However, delay in the antrum formation and decrease in the ratio of oocytes with first polar body were observed in QDs-Tf-treated groups. The matured oocytes with first polar body decreased significantly by ~16% (from 79.6±10 % to 63±2.9 %) when the concentration of QDs-Tf bioconjugates exceeded 2.89 nmol·L(-1) (P < 0.05). Our results implied that the CdTe/ZnTe QDs-Tf bioconjugates were reproductive toxic for follicle development, and thus also revealed that this in vitro culture system of preantral follicle is a highly sensitive tool for study on the reproductive toxicity of nanoparticles.
One industrially important metal oxide nanoparticle (NP) is cadmium oxide (CdO). A study was performed using timed-pregnant CD-1 mice to determine if Cd associated with inhaled CdO NP could reach the placenta and adversely affect the developing fetus and/or neonate. Pregnant mice were exposed by inhalation either every other day to 100 μg of freshly generated CdO/m(3) (exposure 1) or daily to 230 μg CdO/m(3) (exposure 2). In each exposure, mice were exposed to CdO NP or carrier gas (control) for 2.5 h from 4.5 days post coitus (dpc) through 16.5 dpc. At 17.5 dpc, fetuses and placentas from both exposures 1 and 2 were collected, measured, and weighed. A subgroup from the second exposure was allowed to give birth, and neonates were weighed daily until weaning. Cadmium in the uterus and placenta, as well as in other maternal organs, was elevated in NP-treated mice, but was undetectable in fetuses at 17.5 dpc. Daily inhalation of 230 μg CdO NP/m(3) decreased the incidence of pregnancy (i.e., no evidence of implantation) by 23%, delayed maternal weight gain, altered placental weight, and decreased fetal length, as well as delayed neonatal growth. This study demonstrates that inhalation of CdO NP during pregnancy adversely affects reproductive fecundity and alters fetal and postnatal growth of the developing offspring.
Diseases such as tuberculosis, hepatitis, and HIV/AIDS are caused by intracellular pathogens and are a major burden to the global medical community. Conventional treatments for these diseases typically consist of long-term therapy with a combination of drugs, which may lead to side effects and contribute to low patient compliance. The pathogens reside within intracellular compartments of the cell, which provide additional barriers to effective treatment. Therefore, there is a need for improved and more effective therapies for such intracellular diseases. This review will summarize, for the first time, the intracellular compartments in which pathogens can reside and discuss how nanomedicine has the potential to improve intracellular disease therapy by offering properties such as targeting, sustained drug release, and drug delivery to the pathogen's intracellular location. The characteristics of nanomedicine may prove advantageous in developing improved or alternative therapies for intracellular diseases.
The rapid expansion of nanotechnology promises to have great benefits for society, yet there is increasing concern that human and environmental exposure to engineered nanomaterials may result in significant adverse effects. That is why the field of nanotoxicology – dealing with effects and potential risks of particulate structures
The increasing use of nanomaterials has raised concerns about their potential risks to human health. Recent studies have shown that nanoparticles can cross the placenta barrier in pregnant mice and cause neurotoxicity in their offspring, but a more detailed understanding of the effects of nanoparticles on pregnant animals remains elusive. Here, we show that silica and titanium dioxide nanoparticles with diameters of 70 nm and 35 nm, respectively, can cause pregnancy complications when injected intravenously into pregnant mice. The silica and titanium dioxide nanoparticles were found in the placenta, fetal liver and fetal brain. Mice treated with these nanoparticles had smaller uteri and smaller fetuses than untreated controls. Fullerene molecules and larger (300 and 1,000 nm) silica particles did not induce these complications. These detrimental effects are linked to structural and functional abnormalities in the placenta on the maternal side, and are abolished when the surfaces of the silica nanoparticles are modified with carboxyl and amine groups.
Many neurodegenerative diseases are known to occur and progress because of oxidative stress, the presence of reactive oxygen species (ROS) in excess of the cellular defensive capabilities. Age related macular degeneration (AMD), diabetic retinopathy (DR) and inherited retinal degeneration share oxidative stress as a common node upstream of the blinding effects of these diseases. Knockout of the Vldlr gene results in a mouse that develops intraretinal and subretinal neovascular lesions within the first month of age and is an excellent model for a form of AMD called retinal angiomatous proliferation (RAP). Cerium oxide nanoparticles (nanoceria) catalytically scavenge ROS by mimicking the activities of superoxide dismutase and catalase. A single intravitreal injection of nanoceria into the Vldlr-/- eye was shown to inhibit: the rise in ROS in the Vldlr-/- retina, increases in vascular endothelial growth factor (VEGF) in the photoreceptor layer, and the formation of intraretinal and subretinal neovascular lesions. Of more therapeutic interest, injection of nanoceria into older mice (postnatal day 28) resulted in the regression of existing vascular lesions indicating that the pathologic neovessels require the continual production of excessive ROS. Our data demonstrate the unique ability of nanoceria to prevent downstream effects of oxidative stress in vivo and support their therapeutic potential for treatment of neurodegenerative diseases such as AMD and DR.
In the last years, increasing biological interest is emerging for nanotechnology that can improve pharmacological treatments, by using nanomaterials. In particular, cerium oxide nanoparticles, considered one of the most interesting nanomaterials for their catalytic properties, show a promise for application in therapy. Due to the presence of oxygen vacancies on its surface and autoregenerative cycle of its two oxidation states, Ce3+ and Ce4+, nanoceria can be used as an antioxidant agent. Because many disorders are associated with oxidative stress and inflammation, cerium oxide nanoparticles may be a tool for the treatment of these pathologies. In this review we analyze the opinions, sometimes conflicting, of the scientific community about nanoceria, together with its capability to protect from various damages that induce cells to death, and to reduce oxidative stress, associated with a consequent reduction of inflammation.
To develop and validate an efficient comet assay on mouse oocytes without depellucidation.
In vitro experiments using a murine model.
Biogenotoxicology research laboratory in Aix-Marseille II University, France.
CD1 prepubescent female mice.
DNA lesions in oocytes were evaluated by the alkaline comet assay. After oocyte retrieval, we first studied the effect of zona pellucida (ZP) on comet morphology. For this study, we applied the comet assay to mature oocytes with and without ZP after exposure to simulated sunlight irradiation (SSI) compared with negative controls. Next, nondepellucidated mouse oocytes were exposed to three well-known genotoxic agents (SSI, methylmethanesulfonate [MMS], and hydrogen peroxide [H(2)O(2)]) and compared with negative controls. Images of oocytes were analyzed with Komet software.
DNA damages were quantified and expressed as olive tail moment (OTM), defined as the product of the tail length and the fraction of total DNA in the tail. OTMχ(2) were calculated from OTM; they corresponded to the degrees of freedom (n) of each OTM distribution obtained from at least 50 oocytes. OTMχ(2) is an indicator of DNA lesions. The test was considered positive and statistically significant when OTMχ(2) increased in oocytes compared with the medium-only control cells.
There was no difference in comet aspect between oocyte groups with and without ZP. The three genotoxic agents significantly increased DNA damages as compared with the control groups. The OTMχ(2) values were (mean ± SD): 2.1 ± 0.07, 7.73 ± 0.35, 3.35 ± 0.15, and 12.4 ± 0.51 in control, SSI, MMS, and H(2)O(2) groups, respectively.
Comet assay on non depellucidated mouse oocytes is a rapid and easy test. This assay would be useful to assess the genotoxicity on female germ cells of chemicals, drugs, or environmental pollutants and the efficiency of antioxidant molecules.
The development of an environmental health and safety risk management system for nanoscale particle-types requires a base set of hazard data. Accurate determination of health and environmental risks of nanomaterials is a function of the integration of hazard and exposure datasets. Recently, a nanoparticle risk assessment strategy was promulgated and the components are described in a document entitled “Nanorisk framework” (www.nanoriskframework.com). A major component of the hazard evaluation includes a proposed minimum base set of toxicity studies. Included in the suggested studies were substantial particle characterization, a variety of acute hazard and environmental tests, concomitant with screening-type genotoxicity studies. The implementation of well-accepted genotoxicity assays for testing nanomaterials remains a controversial issue. This is because many of these genotoxicity tests were designed for screening general macroparticle chemicals and might not be suitable for the screening of nanomaterials (even of the same compositional material). Furthermore, no nanoparticle-type positive controls have been established or universally accepted for these tests. Although it is the comparative results of the test material vs. the negative or vehicle control that forms the basis for interpreting the results and potency of test materials in genetic toxicology assays, the lack of a nanoparticle-type positive control questions the suitability of the tests to identify nanomaterials with genotoxic properties. It is also not possible to establish historical positive control ranges that would confirm the sensitivity of the tests. Although several genetic toxicology tests have been validated for chemicals according to the Organisation for Economic Co-operation and Development (OECD) test guidelines, the relevance of these assays for nanoparticulate materials remains to be determined. In an attempt to remedy this issue, the OECD has established current projects designed to evaluate the relevance and reproducibility of safety hazard tests for representative nanomaterials, including genotoxicity assays (i.e., Steering Group 3 – Safety Testing of Representative Nanomaterials). In this article, we discuss our past approaches and experience in conducting genotoxicity assays (1) for a newly developed ultrafine TiO₂ particle-type; and (2) in a recent inhalation study, evaluating micronucleus formation in rat erythrocytes following exposures to engineered amorphous nanosilica particles. It seems clear that the development of standardized approaches will be necessary in order to determine whether exposures to specific nanoparticle-types are associated with genotoxic events. The appropriateness of available genotoxicity test systems for nanomaterials requires confirmation and standardization. Accordingly, it seems reasonable to conclude that any specific regulatory testing requirements for nanoparticles would be premature at this time.
Silver nanoparticles (Ag-NPs) are being utilized in an increasing number of fields and are components of antibacterial coatings, antistatic materials, superconductors, and biosensors. A number of reports have now described the toxic effects of silver nanoparticles on somatic cells; however, no study has examined their effects on the germ line at the molecular level. Spermatogenesis is a complex biological process that is particularly sensitive to environmental insults. Many chemicals, including ultrafine particles, have a negative effect on the germ line, either by directly affecting the germ cells or by indirectly acting on the somatic cells of the testis. In the present study, we have assessed the impact of different doses of Ag-NPs, as well as their size and biocompatible coating, on the proliferation of mouse spermatogonial stem cells (SSCs), which are at the origin of the germ line in the adult testis. At concentrations >OR= 10 microg/ml, Ag-NPs induced a significant decline in SSCs proliferation, which was also dependent on their size and coating. At the concentration of 10 microg/ml, reactive oxygen species production and/or apoptosis did not seem to play a major role; therefore, we explored other mechanisms to explain the decrease in cell proliferation. Because glial cell line-derived neurotrophic factor (GDNF) is vital for SSC self-renewal in vitro and in vivo, we evaluated the effects of Ag-NPs on GDNF-mediated signaling in these cells. Although the nanoparticles did not reduce GDNF binding or Ret receptor activity, our data revealed that already at a concentration of 10 microg/ml, silver nanoparticles specifically interact with Fyn kinase downstream of Ret and impair SSC proliferation in vitro. In addition, we demonstrated that the particle coating was degraded upon interaction with the intracellular microenvironment, reducing biocompatibility.
Titanium dioxide (TiO(2)) is included in some sunscreen formulations to physically block ultraviolet radiation. A dermal penetration study was conducted in minipigs with three TiO(2) particles (uncoated submicron sized, uncoated nano-sized, and dimethicone/methicone copolymer-coated nanosized) applied 5% by weight in a sunscreen. These and control formulations were topically applied to minipigs at 2 mg cream/cm(2) skin (4 applications/day, 5 days/week, 4 weeks). Skin (multiple sites), lymph nodes, liver, spleen, and kidneys were removed, and the TiO(2) content was determined (as titanium) using inductively coupled plasma mass spectroscopy. Titanium levels in lymph nodes and liver from treated animals were not increased over the values in control animals. The epidermis from minipigs treated with sunscreens containing TiO(2) showed elevated titanium. Increased titanium was detected in abdominal and neck dermis of minipigs treated with uncoated and coated nanoscale TiO(2). Using electron microscopy-energy dispersive x-ray analysis, all three types of TiO(2) particles were found in the stratum corneum and upper follicular lumens in all treated skin samples (more particles visible with coated nanoscale TiO(2)). Isolated titanium particles were also present at various locations in the dermis of animals treated with all three types of TiO(2)-containing sunscreens; however, there was no pattern of distribution or pathology suggesting the particles could be the result of contamination. At most, the few isolated particles represent a tiny fraction of the total amount of applied TiO(2). These findings indicate that there is no significant penetration of TiO(2) nanoparticles through the intact normal epidermis.
The Kunming mice immatured oocytes in vitro maturation culture system are established to investigate the reproductive toxicity of CdSe/CdS/ZnS quantum dots (QDs). QDs stock solution is added into oocyte culture medium at a final concentration of 28.90 nmol/L. Then, QDs and oocytes are co-cultured at 37 °C, 5% CO2 for 4, 8 and 20 h, respectively. The morphological information of oocytes are observed and analyzed under phase-contrast fluorescence microscope. The results demonstrate that QDs enter cumulus cells and accumulate with co-culture time. QDs can not penetrate oocytes zona pellucida, which is confirmed by laser scanning confocal microscope with high spatial resolution. After being treated for 20 h and being rejected by oocytes, QDs decrease the ratio of oocyte in vitro maturation dramatically.
Abstract As silver nanoparticles (AgNPs) have antimicrobial properties and potentiate the activity of some antibiotics, they are broadly used in both medical and nonmedical applications. In this study, prepubertal male Wistar rats were orally treated with 15 or 30 µg/kg/day AgNPs from postnatal day 23 (PND23) to PND58 and sacrificed at PND102. The acrosome integrity, plasma membrane integrity, mitochondrial activity and morphological alterations of the sperm were analyzed. Sexual partner preference, sexual behavior and the serum concentrations of FSH, LH, testosterone and estradiol were also recorded. The results were evaluated following the appropriate statistical analyses, and differences among the groups were considered significant when p < 0.05. AgNPs reduced the acrosome and plasma membrane integrities, reduced the mitochondrial activity and increased the abnormalities of the sperm in both treatment groups. AgNP exposure also delayed the onset of puberty, although no changes in body growth were observed in either treatment group. The animals did not show changes in sexual behavior or serum hormone concentrations. This study shows for the first time that prepubertal exposure to AgNPs causes alterations in adult sperm parameters. Importantly, the sperm appeared to be more sensitive to the toxic effects of AgNPs and demonstrated adverse effects following exposure to lower doses. Consequently, the effects of AgNPs on sperm should be considered in order to establish safety limits for the use of these particles.
To evaluate targeted superoxide dismutase (SOD)-loaded biodegradable nanoparticles' (NPs) ability to protect Sertoli cells from hydrogen peroxide (H2O2)-induced oxidative stress.
Cell culture controlled experimental study.
Research laboratory.
Mouse testis Sertoli cells (TM4).
Sertoli cells were exposed to 0-200 μg/mL plain media, unconjugated NPs, or FSH peptide-conjugated NPs for 2 or 24 hours to assess uptake. Next, Sertoli cells were exposed to 0-50 mmol H2O2 with 0-1 mg/mL unconjugated SOD-loaded NPs, FSH-conjugated SOD-loaded NPs, or equivalent units of SOD in solution as a control for 2-6 hours to assess influence on cell survival after oxidative stress.
Cell viability, flow cytometry, and microscopy.
FSH peptide targeting improved uptake of NPs by Sertoli cells. FSH-conjugated SOD-NPs significantly protected Sertoli cells at 6 hours of H2O2-induced oxidative stress, with 100% survival with FSH-conjugated SOD-NPs compared with unconjugated SOD-NPs (45%) or SOD in solution (36%).
Conjugation of NPs with FSH peptide improves cellular uptake and survival when SOD-loaded NPs are coincubated with Sertoli cells undergoing oxidative stress. This study represents a step toward developing NPs for the targeted treatment of testicular oxidative stress.
Abstract To examine gold nanoparticle reprotoxicity, bovine spermatozoa were challenged with ligand-free or oligonucleotide-conjugated gold nanoparticles synthesized purely without any surfactants by laser ablation. Sperm motility declined at nanoparticle mass dose of 10 µg/ml (corresponding to ∼14 000 nanoparticles per sperm cell) regardless of surface modification. Sperm morphology and viability remained unimpaired at all concentrations. Transmission electron microscopy showed an modification dependant attachment of nanoparticles to the cell membrane of spermatozoa, but provided no evidence for nanoparticle entrance into sperm cells. A molecular examination revealed a reduction of free thiol residues on the cell membrane after nanoparticle exposure, which could explain the decrease in sperm motility. Sperm fertilising ability decreased after exposure to 10 µg/ml of ligand-free nanoparticles indicating that agglomerated ligand-free nanoparticles interfere with membrane properties necessary for fertilisation. In conclusion, nanoparticles may impair key sperm functions solely by interacting with the sperm surface membrane.
The incidence of male reproductive pathologies, such as hypospadias, cryptorchidism, testicular cancer, and low sperm production in adulthood, is increasing and may be related to exposure to environmental contaminants. The silver nanoparticles (AgNP) are a new class of chemical compounds commonly used in both medical and nonmedical settings, and they affect development of spermatogonial stem cells in vitro. The aim of this study was to examine the adverse productive toxic effects of AgNPs in male Wistar rats exposed during the prepubertal period and sacrificed at postnatal day (PND) 53 and PND90. Growth was assessed by daily weighing. The progress of puberty in the rats was measured by preputial separation, while spermatogenesis was assayed by (1) measuring the sperm count in testes and epididymis and (2) examining the morphology and morphometry of seminiferous epithelium using stereological analysis. In addition, testosterone and estradiol levels were assayed by radioimmunoassay. The weight of the animals at PND90 did not change markedly, but growth was less in the group treated with AgNP at 50 μg/kg from PND34 to PND53. AgNP exposure produced a delay in puberty in both treated groups. Decreased sperm reserves in the epididymis and diminished sperm transit time were observed at PND53, while a reduction in sperm production occurred at PND90. The morphology of the seminiferous epithelium was markedly altered. Data demonstrated that prepubertal exposure to AgNP altered reproductive development in prepubertal male Wistar rats, as evidenced by impairment in spermatogenesis and a lower sperm count in adulthood.
Nanoparticles are important in natural environments due to their size, tunable properties and accessible surfaces and our control over these properties can be exploited to create or add value to a variety of technologies. Many consumer products that incorporate nanoparticles, such as sunscreens and clothing, are already in the marketplace, and the industry is growing fast. This book highlights also the many valuable environmental technologies that can come from the applications of unique nanomaterial properties. As this nascent technology area matures, the debate about the whether the unknown risks of nanomaterial use balances its established benefits will only intensify.
Objective: To study the influence of titanium dioxide nanoparticle(TiO 2) on follicle development and oocyte maturation of rats using in vitro rat preantral follicle culture system, so as to know whether TiO 2 can cause female reproductive toxicity and provide evidences for evaluating its safety. Methods: Rat ovaries were mechanically dissected to obtain preantral follicles and the individual preantral follicle was cultured in 96-well plates. The study was divided into 5 groups: three 25 nm TiO 2 groups (12.5 μg/ml, 25 μg/ml and 50 μg/ml), one negative control group (treated with culture medium), and one micron TiO2 control group. Ten days after culture, the ovulation was induced and the follicle development and oocyte maturation were observed. Results: The survival rate of follicles, formation rate of antral follicles and release rate of cumulus-oocyte cell complexes (COCs) all decreased with the increase of 25 nm TiO2 (P<0.05). Compared with the negative control group, micron TiO2 group had no obvious changes in the follicle development and oocyte maturation. Compared with the two control groups, 25 nm TiO2 caused obvious morphological changes of follicles and obvious decrease in follicle survival and formation rate of antral follicles. 50 μg/ml 25 nm TiO2 reduced the number of mature oocytes. Conclusion: 25 nm TiO 2 at 25 μg/ml or above can inhibit rat follicle development and oocyte maturation in vitro, while the micron TiO2 at the same dose has no obvious influence on follicle development and oocyte maturation, suggesting different toxic properties between nmTiO2 and micron TiO2. Titanium dioxide nanoparticle may have female reproductive toxicity and should be given more attention.
The aerogel catalysts investigated are constituted by two chemically different nanoparticle systems consisting of the gold phase and the iron oxide support. High-resolution transmission electronic microscopy (HRTEM) showed an increased surface roughness for aerogel particles with higher gold loading. X-ray photoelectron spectroscopy (XPS) revealed increases in the surface coverage of hydroxyl groups and the Fe2+/Fe3+ ratio due to the addition of gold, and showed the transition of gold from oxidized to metallic states due to calcination. In the presence of gold species, the Fe3+ satellite structure in XPS was not produced. The crystallinity of maghemite as the support was found quite stable with respect to gold addition and thermal treatment. The aerogels were evaluated for methanol oxidation carried out in an ambient flow reactor. The oxidation activity enhanced with decreasing catalyst pretreatment temperatures and with increasing gold loadings up to 5wt%. A wide selectivity pattern formed between dimethyl ether and carbon dioxide products. The size of gold particles and the status of surface gold species played a crucial role in the catalytic conversion of methanol. The oxidized gold was more active than the metallic gold towards the total combustion to carbon dioxide. The surface nature has been proven to transform from strong Lewis acidic to high basic characters due to the formation of reactive hydroxyl groups near by the gold sites.
Context:
One of the leading causes of cancer-associated deaths in most men and women in the Western world is lung cancer. There are various types of treatments depending on the type and the stage of the cancer. A recent type of therapy is targeted gene therapy which aims to target genes that cause lung cancer. However, this therapy has some drawbacks including lack of proper vectors for delivery. These drawbacks can potentially be overcome by using various types of nanoparticles.
Objective:
To review current literature on the treatment of lung cancer with nanoparticles.
Methods:
Researchers have attempted to treat lung cancer with a variety of types of nanoparticle matrices including lipid, polylactide-co-glycolide, albumin, poly (ω-pentadecalactone-co-butylene-co-succinate), cerium oxide, gold, ultra-small superparamagnetic iron oxide nanoparticles, super paramagnetic iron oxide, lipid-polycation-DNA, N-[1-(2,3- dioleoyloxyl)propyl]-NNN-trimethylammoniummethylsulfate, silica-overcoated magnetic cores, and polyethyleneglycol phosphatidylethanolamine. There are various ways in which nanoparticles enhance drug delivery, and these include encapsulation against immune response, tissue penetration, target selectivity and specificity, delivery monitoring, promoting apoptosis, and blocking pathways for cancer initiation and progression.
Conclusion:
In the past decade, a lot has been said about targeting of NPs for lung and other cancers, but little has been actually successfully delivered to date. Nevertheless, nanoparticles can act as good vectors for delivering drug to the target neoplastic lesions within the lung, increase cellular uptake, increase tissue penetration and help in tracking the drug. In the future, combination therapies may play a key role in the treatment of lung cancer using the existing therapies.
Although numerous studies have described the accumulation of titanium dioxide nanoparticles (TiO(2) NPs) in the liver, kidneys, lung, spleen, and brain, and the corresponding damage, it is unclear whether or not TiO(2) NPs can be translocated to the ovary and cause ovarian injury, thus impairing fertility. In the current study, ovarian injury and gene-expressed characteristics in female mice induced by intragastric administration of TiO(2) NPs (10mg/kg) for 90 consecutive days were investigated. Our findings indicated that TiO(2) NPs can accumulate in the ovary and result in ovarian damage, cause an imbalance of mineral element distribution and sex hormones, decrease fertility or the pregnancy rate and oxidative stress in mice. Microarray analysis showed that in ovaries from mice treated with TiO(2) NPs compared to controls, 223 genes of known function were up-regulated, while 65 ovarian genes were down-regulated. The increased expression of Cyp17a1 following TiO(2) NPs treatment suggested that the increase in estradiol biosynthesis may be a consequence of increased TiO(2) NPs. In addition, the elevated expression of Akr1c18 implied that progesterone metabolism was accelerated, thus causing a decrease in the progesterone concentration. Taken together, the apparent regulation of key ovarian genes supports the hypothesis that TiO(2) NPs directly affects ovarian function.
The response of the mouse male germ cells exposed to gold nanoparticles (approximately 2.5 nm) was studied. Our investigation demonstrates that treatment with Au nanoparticles for four days does not impair the architecture of the spermatogenic epithelium. Cytogenetic evaluation using micronucleus assay showed that gold nanoparticles can affect the chromosomes of early primary spermatocytes. However, gold nanoparticles did not induce chromosome abnormalities in spermatogonial stem cells. Further, the cauda epididymal sperm was isolated on the 14th day after treatment and was incubated in SDS solution (Na sodium dodecyl) and then in a solution containing DTT (dithiothreitol) to induce nuclear chromatin decondensation. Observations showed that after four days of treatment of spermiogenic (postmeiotic) cells with gold nanoparticles the decondensation process had no differences from the control. On the contrary, in the experiment with the same cells and period of fixation but with a single exposure to gold nanoparticles, the number of mature gametes with totally decondensed nuclei reached 100% as opposed to 44% in the controls.
Toxicity of nanoparticles depends on many factors including size, shape, chemical composition, surface area, surface charge, and others. In this study, we compared the toxicity of different sized-silver nanoparticles (AgNPs) which are being widely used in consumer products due to its unique antimicrobial activity. When mice were treated with AgNPs 1 mg/kg for 14 days by oral administration, small-sized AgNPs (22 nm, 42 nm, and 71 nm) were distributed to the organs including brain, lung, liver, kidney, and testis while large-sized AgNPs (323 nm) were not detected in those tissues. The levels of TGF-β in serum were also significantly increased in the treated group of small-sized AgNPs but not in large-sized AgNPs. In addition, B cell distribution was increased in small-sized AgNPs but not in large-sized-AgNPs by the phenotype analysis. However, body weight or in the ratio of organ/body weight were not different between the control group and all the AgNPs-treated groups. The repeated-dose toxicity of AgNPs (42 nm) was also investigated in mice by oral administration for 28 days. By the administration of AgNPs (0.25 mg/kg, 0.50 mg/kg, 1.00 mg/kg), adverse impacts on liver and kidney were observed in a high dose-treated group (1.00 mg/kg), when determined by blood chemistry and histipathological analysis. Cytokines including IL-1, IL-6, IL-4, IL-10, IL-12, and TGF-β were also increased in a dose-dependent manner by repeated oral administration. In addition, B cell distribution in lymphocyte and IgE production were increased. Based on these results, it is suggested that repeated oral administration of nano-sized AgNPs may cause organ toxicity and inflammatory responses in mice.
Unlabelled:
Cerium oxide nanoparticles (nanoceria) have recently received attention from the scientific community due to their unique free radicals (specially superoxide radical and hydrogen peroxide) scavenging property in biological system, both in vitro and in vivo. It is suggested that free radicals play an important role in the pathogenesis of endometriosis. In this study we have shown that nanoceria mitigate the endometrial lesions induced in mice model by decreasing oxidative stress and inhibiting angiogenesis. Moreover, nanoceria were also observed to protect endometriosis-related adverse effects on the oocytes, which is critical for successful pregnancy. Summarizing, nanoceria have shown promising efficacy against endometriosis related pathogenesis.
From the clinical editor:
Free radicals have been implemented in the pathogenesis of endometriosis. In a murine model the authors demonstrated successful treatment of endometriosis with nanoceria, and protection of endometriosis-related adverse effects on the oocytes, paving the way to potential clinical translational applications in the future.
Contents
Metal nanoparticles play an increasing role in consumer products, biomedical applications and in the work environment. Therefore, the effects of nanomaterials need to be properly understood. This applies especially to their potential reproductive toxicology (nanoreprotoxicity), because any shortcomings in this regard would be reflected into the next generation. This review is an attempt to summarize the current knowledge regarding the effects of nanoparticles on reproductive outcomes. A comprehensive collection of significant experimental nanoreprotoxicity data is presented, which highlight how the toxic effect of nanoparticles can be influenced, not only by the particles’ chemical composition, but also by particle size, surface modification, charge and to a considerable extent on the experimental set‐up. The period around conception is characterized by considerable cytological and molecular restructuring and is therefore particularly sensitive to disturbances. Nanoparticles are able to penetrate through biological barriers into reproductive tissue and at least can have an impact on sperm vitality and function as well as embryo development. Particularly, further investigations are urgently needed on the repetitively shown effect of the ubiquitously used titanium dioxide nanoparticles on the development of the nervous system. It is recommended that future research focuses more on the exact mechanism behind the observed effects, because such information would facilitate the production of nanoparticles with increased biocompatibility.
Titanium dioxide (TiO2) nanoparticles were prepared by the oxidation of titanium tetrachloride (TiCl4) in a diffusion flame reactor. The average diameter of particles was 15–30 nm and mass fraction of anatase ranged from 40% to 80%. Effects of particle size and phase composition of those TiO2 nanoparticles on photocatalytic properties such as decomposition of methylene blue, bacteria and ammonia gas were investigated. The degree of decomposition of methylene blue by the TiO2 nanoparticles under the illumination of the black light was directly proportional to the anatase mass fraction, but inversely to the particle size. The decomposition of bacteria and ammonia gas by the TiO2 nanoparticles under the illumination of the fluorescent light showed the same trend as in the case of the methylene blue.
As the fullerene studies progress, two trends become more visible: the incorporation of the smaller cages of C60 type into organic chemistry and the increasing interest in the elongated fullerene species, carbon nanotubes. The latter turn out to be of interest for structural materials and for the submicro-electronics application. The mechanical strength of these molecular fibers combines with electronic properties, that are uniquely tunable by the molecular symmetry of nanotubes. We outline the basic features of fullerene nanotubes and the more recent findings in their mechanical and electrical properties.
Polymethyl (2-14C) methacrylate nanoparticles of a diameter of 130±30 nm were administered to Wistar rats as a single dose by oral gavage either in form of a suspension in saline, in saline with an additional content of 5% of polysorbate 80 or poloxamine 908, or suspended in peanut oil without or with addition of 5% oleic acid. The animals were sacrificed after 30 min, 1, 2, 4, 8 h, 1, and 4 days, the blood was collected, and different organs and tissues were removed. The gastrointestinal (GI)-tract was separated into stomach, small intestine, and colon. The contents of those parts were collected and the remaining GI-tract sections thoroughly rinsed. The radioactivity in the above organs, tissues, and GI-tract contents were determined using a scintillation counter. The radioactivity concentrations were highest in the GI-tract content and decreased rather rapidly (between 2 h and 1 day). Rather high concentrations (up to 10% of the administered dose at a given time point) also were seen in the GI-tract walls. These concentration did not correlate totally to those in the GI-tract contents. The concentration in the residual body reached 1–3% of the administered dose at a given time point. The highest concentrations in the body were observed between 15 and 60 min but remained at considerable levels for 4 days. By far the highest uptake (about 200–300% of the other preparations) was seen with the saline preparation containing 5% polysorbate 80. No significant difference appeared between saline without surfactants and peanut oil. The addition of oleic acid to the peanut oil increased the uptake of the nanoparticles by about 50%.
The present study has examined the effects of ZnO and TiO2 nanoparticles (40-70 nm range) in the presence and absence of UVA light in human sperm and human lymphocytes in the dark (D), after pre-irradiation with UV (PI) and simultaneous irradiation with UV (SI). For both ZnO and TiO2 nanoparticles, the percentage reduction in head DNA was greater for PI and SI samples compared with samples treated in the dark. However with regard to photogenotoxicity, sperm exhibited no significant differences when the results for PI and SI and the dark were compared, except at the lowest concentration for SI samples in the case of ZnO and the lowest concentration for PI in the case of TiO2. However for lymphocytes, responses were statistically significant at the highest concentration for both PI and SI samples. Thus, these studies suggest that there are photogenotoxic events in these cells in the absence of overt toxicity.
Cerium oxide nanoparticles, nanoceria, are inorganic antioxidants that have catalytic activities which mimic those of the neuroprotective enzymes superoxide dismutase and catalase. We have previously shown that nanoceria preserve retinal morphology and prevent loss of retinal function in a rat light damage model. In this study, the homozygous tubby mutant mouse, which exhibits inherited early progressive cochlear and retinal degeneration, was used as a model to test the ability of nanoceria to slow the progression of retinal degeneration. Tubby mice were injected systemically, intracardially, with 20 μl of 1mM nanoceria in saline, at postnatal day 10 and subsequently at P20 and P30 whereas saline injected and uninjected wild type (or heterozygous tubby) served as injected and uninjected controls, respectively. Assays for retinal function, morphology and signaling pathway gene expression were performed on P34 mice. Our data demonstrate that nanoceria protect the retina by decreasing Reactive Oxygen Species (ROS), up-regulating the expression of neuroprotection-associated genes; down-regulating apoptosis signaling pathways and/or up-regulating survival signaling pathways to slow photoreceptor degeneration. These data suggest that nanoceria have significant potential as global agents for therapeutic treatment of inherited retinal degeneration and most types of ocular diseases.
Unlabelled:
In recent years, nanoparticle exposure risk has drawn increasing attention from the research community and the general public. However, analysis of nanoparticles is hindered by their small size, which prevents the development of methods for their detection in cells and tissues. For risk assessment of nanoparticle exposure, it is important to measure the exact amount of deposited material in pulmonary tissue. Using a nanoparticle exposure device, A/JJmsSlc mice were chronically exposed transtracheally to anatase-type titanium dioxide particles. A microscope-integrated laser Raman spectrometer was used to detect differentially stained macrophages in a pulmonary wash obtained from the mice exposed to the particles. This detection method allowed rapid and easy sample collection and qualitative analysis, and the method may be useful for conducting large-scale evaluations in workers exposed to environments heavily contaminated with nanoparticles.
From the clinical editor:
This paper discusses a microscope-integrated laser Raman spectrometer method to measure the exact amount of nanoparticles deposited in pulmonary tissue. This method allows rapid sample collection, qualitative analysis, and may be useful for large-scale evaluations.
Cerium oxide nanoparticles (nanoceria) have shown great potential as antioxidant and radioprotective agents for applications in cancer therapy. Recently, various polymer-coated nanoceria preparations have been developed to improve their aqueous solubility and allow for surface functionalization of these nanoparticles. However, the interaction of polymer-coated nanoceria with cells, their uptake mechanism, and subcellular localization are poorly understood. Herein, we engineered polymer-coated cerium oxide nanoparticles with different surface charges (positive, negative, and neutral) and studied their internalization and toxicity in normal and cancer cell lines. The results showed that nanoceria with a positive or neutral charge enters most of the cell lines studied, while nanoceria with a negative charge internalizes mostly in the cancer cell lines. Moreover, upon entry into the cells, nanoceria is localized to different cell compartments (e.g., cytoplasm and lysosomes) depending on the nanoparticle's surface charge. The internalization and subcellular localization of nanoceria plays a key role in the nanoparticles' cytotoxicity profile, exhibiting significant toxicity when they localize in the lysosomes of the cancer cells. In contrast, minimal toxicity is observed when they localize into the cytoplasm or do not enter the cells. Taken together, these results indicate that the differential surface-charge-dependent localization of nanoceria in normal and cancer cells plays a critical role in the nanoparticles' toxicity profile.
Contraceptive techniques which target vas deferens have been paid great attention for their good efficacy, safety and reversibility. We have made a filtering-type intra-vas device (IVD) using nano-copper complex/polymer composites. Twenty male adult Beagle dogs and 40 male rabbits were randomly assigned to four groups (sham-operation, IVD, reversal and vasectomy groups). Dogs' semen parameters, concentration of α-glucosidase, copper and zinc ions were tested pre-operation and 1, 3, 6 and 12 months post-operation. The pregnancy rates of the rabbits were evaluated by mating trials after the IVDs were implanted. The histology of testis, epididymides and vas deferens of the animals was examined using an electron microscope. Apoptosis of the cells in the testes, epididymides and vas deferens was detected by TUNEL method. There was no sperm in the semen of dogs, which had been inserted IVD and vasectomized at 1, 3, 6 and 12 months post-operation. The concentration of α-glucosidase in the IVD group, reversal group and sham-operation group was not significantly different between pre- and post-operation. The pregnancy rates of the female rabbits in the vasectomy, IVD and reversal groups were all zero, but the pregnancy rate in the reversal group, after taking out IVD, and that of the sham-operation group was 60% and 80%, respectively. The ultrastructures of the testes, epididymides and vas deferens of the male animals in the IVD group and sham-operation group were in normal ranges compared with the vasectomy group. The apoptosis of the cells in the testes, epididymides and vas deferens in the vasectomy group of both dogs and rabbits was obvious compared with the other groups. No significant changes in the quantities of copper and zinc ions were found in semen of the male dogs both pre- and post-operation. Our studies demonstrated that the filtering-type nano-copper complex/polymer composites intra-vas device may be an efficacious, safe and reversible male contraceptive device.
Nanotechnology, nanomedicine and nanotoxicology are complementary disciplines aimed at the betterment of human life. However, concerns have been expressed about risks posed by engineered nanomaterials (ENMs), their potential to cause undesirable effects, contaminate the environment and adversely affect susceptible parts of the population. Information about toxicity and biokinetics of nano-enabled products combined with the knowledge of unintentional human and environmental exposure or intentional delivery for medicinal purposes will be necessary to determine real or perceived risks of nanomaterials. Yet, results of toxicological studies using only extraordinarily high experimental doses have to be interpreted with caution. Key concepts of nanotoxicology are addressed, including significance of dose, dose rate, and biokinetics, which are exemplified by specific findings of ENM toxicity, and by discussing the importance of detailed physico-chemical characterization of nanoparticles, specifically surface properties. Thorough evaluation of desirable versus adverse effects is required for safe applications of ENMs, and major challenges lie ahead to answer key questions of nanotoxicology. Foremost are assessment of human and environmental exposure, and biokinetics or pharmacokinetics, identification of potential hazards, and biopersistence in cells and subcellular structures to perform meaningful risk assessments. A specific example of multiwalled carbon nanotubes (MWCNT) illustrates the difficulty of extrapolating toxicological results. MWCNT were found to cause asbestos-like effects of the mesothelium following intracavitary injection of high doses in rodents. The important question of whether inhaled MWCNT will translocate to sensitive mesothelial sites has not been answered yet. Even without being able to perform a quantitative risk assessment for ENMs, due to the lack of sufficient data on exposure, biokinetics and organ toxicity, until we know better it should be made mandatory to prevent exposure by appropriate precautionary measures/regulations and practicing best industrial hygiene to avoid future horror scenarios from environmental or occupational exposures. Similarly, safety assessment for medical applications as key contribution of nanotoxicology to nanomedicine relies heavily on nano-specific toxicological concepts and findings and on a multidisciplinary collaborative approach involving material scientists, physicians and toxicologists.