Exposure to tungsten particles via inhalation triggers early toxicity marker expression in the rat brain.

OBJECTIVE: Our work is focused on tungsten, considered as an emerging contaminant. Its environmental dispersion is partly due to mining and military activities. Exposure scenario can also be occupational, in areas such as the hard metal industry and specific nuclear facilities. Our study investigated the cerebral effects induced by the inhalation of tungsten particles. METHODS: Inhalation exposure campaigns were carried out at two different concentrations (5 and 80 mg/m3) in single and repeated modes (4 consecutive days) in adult rats within a nose-only inhalation chamber. Processes involved in brain toxicity were investigated 24 h after exposure. RESULTS AND DISCUSSION: Site-specific effects in terms of neuroanatomy and concentration-dependent changes in specific cellular actors were observed. Results obtained in the olfactory bulb suggest a potential early effect on the survival of microglial cells. Depending on the mode of exposure, these cells showed a decrease in density accompanied by an increase in an apoptotic marker. An abnormal phenotype of the nuclei of mature neurons, suggesting neuronal suffering, was also observed in the frontal cortex, and can be linked to the involvement of oxidative stress. The differential effects observed according to exposure patterns could involve two components: local (brain-specific) and/or systemic. Indeed, tungsten, in addition to being found in the lungs and kidneys, was present in the brain of animals exposed to the high concentration. CONCLUSION: Our data question the perceived innocuity of tungsten relative to other metals and raise hypotheses regarding possible adaptive or neurotoxic mechanisms that could ultimately alter neuronal integrity.

Tungsten toxicity on kidney tubular epithelial cells induces renal inflammation and M1-macrophage polarization.

Tungsten is widely used in medical, industrial, and military applications. The environmental exposure to tungsten has increased over the past several years, and few studies have addressed its potential toxicity. In this study, we evaluated the effects of chronic oral tungsten exposure (100 ppm) on renal inflammation in male mice. We found that 30- or 90-day tungsten exposure led to the accumulation of LAMP1-positive lysosomes in renal tubular epithelial cells. In addition, the kidneys of mice exposed to tungsten showed interstitial infiltration of leukocytes, myeloid cells, and macrophages together with increased levels of proinflammatory cytokines and p50/p65-NFkB subunits. In proximal tubule epithelial cells (HK-2) in vitro, tungsten induced a similar inflammatory status characterized by increased mRNA levels of CSF1, IL34, CXCL2, and CXCL10 and NFkB activation. Moreover, tungsten exposure reduced HK-2 cell viability and enhanced reactive oxygen species generation. Conditioned media from HK-2 cells treated with tungsten induced an M1-proinflammatory polarization of RAW macrophages as evidenced by increased levels of iNOS and interleukin-6 and decreased levels of the M2-antiinflammatory marker CD206. These effects were not observed when RAW cells were exposed to conditioned media from HK-2 cells treated with tungsten and supplemented with the antioxidant N-acetylcysteine (NAC). Similarly, direct tungsten exposure induced M1-proinflammatory polarization of RAW cells that was prevented by NAC co-treatment. Altogether, our data suggest that prolonged tungsten exposure leads to oxidative injury in the kidney ultimately leading to chronic renal inflammation characterized by a proinflammatory status in kidney tubular epithelial cells and immune cell infiltration.

Subchronic oral exposure of tungsten induces myofibroblast transformation and various markers of kidney fibrosis.

Tungsten is a naturally occurring transition element used in a broad range of applications. As a result of its extensive use, we are increasingly exposed to tungsten from our environment, including potable water, since tungsten can become bioaccessible in ground sources. The kidneys are particularly susceptible to tungsten exposure as this is the main site for tungsten excretion. In this study, we investigated the prolonged effects of tungsten on the kidneys and how this may impact injury and function. When mice were exposed to tungsten in their drinking water for 1 mo, kidney function had not significantly changed. Following 3-mo exposure, mice were presented with deterioration in kidney function as determined by serum and urine creatinine levels. During 3 mo of tungsten exposure, murine kidneys demonstrated significant increases in the myofibroblast marker α-smooth muscle actin (αSMA) and extracellular matrix products: fibronectin, collagen, and matricellular proteins. In addition, Masson's trichrome and hematoxylin-eosin (H&E) staining revealed an increase in fibrotic tissue and vacuolization of tubular epithelial cells, respectively, from kidneys of tungsten-treated mice, indicative of renal injury. In vitro treatment of kidney fibroblasts with tungsten led to increased proliferation and upregulation of transforming growth factor ß1 (TGFß1), which was consistent with the appearance of fibroblast-to-myofibroblast transition (FMT) markers. Our data suggest that continuous exposure to tungsten impairs kidney function that may lead to the development of chronic kidney disease (CKD).

Valorization of Waste Tungsten Filament into mpg-C3N4-WO3 Photocatalyst: A Sustainable e-Waste Management and Wastewater Treatment.

The waste of tungsten filament materials in the environment is one of the reasons for environmental pollution, and it is very dangerous to animals and plants. To date, not much attention has been given to its utility or recyclability. Herein, the present work reported the synthesis of tungsten trioxide nanoparticles (WO3 NPs) by the utilization of cost-free waste tungsten filament by a simple calcination method. A mesoporous graphitic carbon nitride-tungsten trioxide (mpg-C3N4-WO3) composite designed from the WO3 NPs produced from tungsten filament waste and thiourea as a carbon and nitrogen precursor by a one-step calcination method. The synthesized samples were characterized and confirmed by different characterization techniques. The photocatalytic behavior of the synthesized mpg-C3N4-WO3 composite was assessed, with respect to the effect of initial pH, amount of photocatalyst, dye concentration, and reaction time, as well for the degradation of Methylene Blue (MB) dye under sunlight. The best photocatalytic performance (92%) was achieved using mpg-C3N4-WO3 with experimental condition ([photocatalyst] = 100 mg/L, [MB]0 = 10 mg/L, pH 8, and time = 120 min) under sunlight irradiation with excellent photostability than that of isolated mpg-C3N4 and WO3 NPs. The histotoxicological studies also showed that the photodegraded products of MB were found to be nontoxic and did not structurally changes in the gill architecture as well as brain tissues of freshwater fish Labeo rohita.

Long-term impact of the Tyrnyauz tungsten-molybdenum mining and processing factory waste on environmental pollution and children's population.

We studied the consequences of the long-term impact of remediated tailing ponds from the Tyrnyauz tungsten-molybdenum mining and processing factory on the environmental pollution and children living in the area. For more than 60 years, the factory has been engaged in the development of tungsten-molybdenum deposits by open-pit and mine methods and the enrichment of the extracted ore. More than 252,771 thousand tons of waste accumulated in its dumps and tailings ponds. This 170-hectare tailing pond contains more than 125 million tons of waste with arsenic, tungsten, molybdenum and other metals. To examine the possible accumulation of potentially toxic elements in children's bodies, we determined the content of heavy metals in drinking water and in the hair of children. An exfoliated buccal micronucleus test was used to determine the cytogenetic status of children. We did not find significant differences in the content of heavy metals inherent of a tailing pond in children's hair from polluted area compared to the control zone. In buccal cells of children living in the vicinity of the tailings pond, the total number of cytogenetic abnormalities was increased by 4.1 times, the total index of proliferation by 1.5 times, early destruction of the nucleus by 2 times and apoptosis by 1.2 times compared to the clean zone. Thus, we identified a genotoxic and cytotoxic effect on children living in the vicinity of the tailing ponds, which led to an increase in the number of children belonging to the medium- and high-risk groups. No correlations were found between the content of heavy metals in children's hair and the frequency of cells with cytogenetic abnormalities. Weak positive correlation was found between the content of manganese, zinc and copper in children's hair and the indicators of buccal epithelial cell proliferation.

Cobalt-related interstitial lung disease or hard metal lung disease: A case series of Chinese workers.

Hard metal lung disease (HMLD) is rarely diagnosed and is caused by the occupational inhalation of hard metal dust, mainly cobalt. The diagnosis of HMLD is based on a thorough occupational dust exposure combined with clinical-radiological-histological findings. We present a series of four Chinese workers who had occupational exposure to cobalt acid lithium or cobalt and tungsten dust. Four patients all complained of intermittent cough, chest tightness, or shortness of breath on exertion. High-resolution computed tomography scans presented bilateral ground-glass attenuation, consolidations, and/or reticular opacities with diffuse small nodules. Histologic findings showed that interstitial inflammation and fibrotic lesions distributed peribronchioles. The infiltrations by macrophages as well as visible multinucleated giant cells indicated giant cell interstitial pneumonia (GIP). Cobalt was detectable in the lung tissues of two patients measured by inductively-coupled plasma mass spectrometry. The first patient was diagnosed with cobalt-related interstitial lung disease (ILD), while the others were HMLD. GIP is the classic pathology of cobalt-related ILD or HMLD. One of the patients showed spontaneous remission after the cessation of exposure, while the other three recovered within 6-32 weeks after avoiding occupational exposure and using corticosteroids. At follow-up, all four patients showed no recurrence. A multidisciplinary diagnostic panel including occupational cobalt exposure evaluation is beneficial to recognize cobalt-related ILD or HMLD and to indicate the necessity of prevention.

Robust Antibacterial Activity of Tungsten Oxide (WO3-x) Nanodots.

Antibacterial agents are an important tool in the prevention of bacterial infections. Inorganic materials are attractive due to their high stability under a variety of conditions compared to organic antibacterial agents. Herein tungsten oxide nanodots (WO3-x), synthesized by a simple one-pot synthetic approach, were found to exhibit strong antibacterial capabilities. The analyses with colony-forming units (CFU) showed an excellent antibacterial activity of WO3-x against both Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus) strains. The scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images revealed clear damages to the bacterial cell membranes, which was further confirmed by molecular dynamics simulations. Additionally, exposure to simulated sunlight was found to further increase the germicidal activity of WO3-x nanodots, a 30 min exposure to sunlight combined with 50 µg/mL WO3-x nanodots showed a 70% decrease in E. coli viability compared to without exposure. Electron spin resonance spectroscopy (ESR) was used to elucidate the underlying mechanism of this photocatalytic activity through the generation of hydroxyl radical species. The cell counting kit-8 (CCK-8) and the live/dead assay were further employed to evaluate the cytotoxicity of WO3-x nanodots on eukaryotic cells, which demonstrated their general biocompatibility. In summary, our results suggest WO3-x nanodots have considerable potential in antibacterial applications, while also being biocompatible at large.

Comparative study of cyto- and genotoxic potential with mechanistic insights of tungsten oxide nano- and microparticles in lung carcinoma cells.

The exigency of semiconductor and super capacitor tungsten oxide nanoparticles (WO3 NPs) is increasing in various sectors. However, limited information on their toxicity and biological interactions are available. Hence, we explored the underlying mechanisms of toxicity induced by WO3 NPs and their microparticles (MPs) using different concentrations (0-300 µg ml-1 ) in human lung carcinoma (A549) cells. The mean size of WO3 NPs and MPs by transmission electron microscopy was 53.84 nm and 3.88 µm, respectively. WO3 NPs induced reduction in cell viability, membrane damage and the degree of induction was size- and dose-dependent. There was a significant increase in the percentage tail DNA and micronuclei formation at 200 and 300 µg ml-1 after 24 hours of exposure. The DNA damage induced by WO3 NPs could be attributed to increased oxidative stress and inflammation through reactive oxygen species generation, which correlated with the depletion of reduced glutathione content, catalase and an increase in malondialdehyde levels. Cellular uptake studies unveiled that both the particles were attached/surrounded to the cell membrane according to their size. In addition, NP inhibited the progression of the cell cycle in the G2 /M phase. Other studies such as caspase-9 and -3 and Annexin-V-fluorescein isothiocyanate revealed that NPs induced intrinsic apoptotic cell death at 200 and 300 µg ml-1 concentrations. However, in comparison to NPs, WO3 MPs did not incite any toxic effects at the tested concentrations. Under these experimental conditions, the no-observed-significant-effect level of WO3 NPs was determined to be ≤200 µg ml-1 in A549 cells.

Phase-Transition Induced Conversion into a Photothermal Material: Quasi-Metallic WO2.9 Nanorods for Solar Water Evaporation and Anticancer Photothermal Therapy.

Phase transition from WO3 to sub-stoichiometric WO2.9 by a facile method has varied the typical semiconductor to be quasi-metallic with a narrowed band gap and a shifted Femi energy to the conduction band, while maintaining a high crystallinity. The resultant WO2.9 nanorods possess a high total absorption capacity (ca. 90.6 %) over the whole solar spectrum as well as significant photothermal conversion capability, affording a conversion efficiency as high as around 86.9 % and a water evaporation efficiency of about 81 % upon solar light irradiation. Meanwhile, the promising potential of the nanorods for anticancer photothermal therapy have been also demonstrated, with a high photothermal conversion efficiency (ca. 44.9 %) upon single wavelength near-infrared irradiation and a high tumor inhibition rate (ca. 98.5 %). This study may have opened up a feasible route to produce high-performance photothermal materials from well-developed oxides.

Low cytotoxicity of inorganic nanotubes and fullerene-like nanostructures in human bronchial epithelial cells: relation to inflammatory gene induction and antioxidant response.

The cytotoxicity of tungsten disulfide nano tubes (INT-WS2) and inorganic fullerene-like molybdenum disulfide (IF-MoS2) nanoparticles (NPs) used in industrial and medical applications was evaluated in comparison to standard environmental particulate matter. The IF-MoS2 and INT-WS2 reside in vesicles/inclusion bodies, suggestive of endocytic vesicles. In cells representing the respiratory, immune and metabolic systems, both IF-MoS2 and INT-WS2 NPs remained nontoxic compared to equivalent concentrations (up to 100 µg/mL in the medium) of silica dioxide (SiO2), diesel engine-derived and carbon black NPs, which induced cell death. Associating with this biocompatibility of IF-MoS2\INT-WS2, we demonstrate in nontransformed human bronchial cells (NL-20) relative low induction of the pro-inflammatory cytokines IL-1ß, IL-6, IL-8, and TNF-α. Moreover, IF-MoS2 and INT-WS2 activated antioxidant response as measured by the antioxidant response element (ARE) using a luciferase reporter, and induced Nrf2-mediated Phase II detoxification genes. Collectively, our findings suggest that the lower cytotoxicity of IF-MoS2 and INT-WS2 NPs does not reflect general biological inertness. Rather, compared to other NP's, it likely results from decreased pro-inflammatory activation, but a comparable significant capacity to induce protective antioxidant/detoxification defense mechanisms.

Nanotoxicity of tungsten trioxide nanosheets containing oxygen vacancy to human umbilical vein endothelial cells.

Because of the excellent performance in photochemistry, WO3 is increasingly applied in the field of biology and medicine. However, little is known about the mechanism of WO3 cytotoxicity. In this work, WO3 nanosheets with oxygen vacancy are synthesized by solvothermal method, then characterized and added to culture medium of human umbilical vein endothelial cells (HUVECs) with different concentrations. We characterized and analyzed the morphology of nano-WO3 by transmission electron microscopy and calculated the specific data of oxygen vacancy by XPS. It is the first time the effect of WO3-x on cells that WO3-x can cause oxidative stress in HUVEC cells, resulting in DNA damage and thus promoting apoptosis. Transcriptome sequencing is performed on cells treated with low and high concentrations of WO3-x, and a series of key signals affecting cell proliferation and apoptosis are detected in differentially expressed genes, which indicates the research direction of nanotoxicity. The expression levels of key genes are also verified by quantitative PCR after cell treatment with different concentrations of WO3-x. This work fills the gap between the biocompatibility of nano WO3-x materials and molecular cytology and paves the way for investigating the mechanism and risks of oxygen vacancy in cancer therapy.

Ecotoxicological effects of tungsten on celery (Apium graveolens L) and pepper (Capsicum spp.).

Background: Tungsten (W) is an emerging heavy metal pollutant, yet research remains scarce on the biomonitor and sensitive biomarkers for W contamination. Methods: In this study, celery and pepper were chosen as study subjects and subjected to exposure cultivation in solutions with five different levels of W. The physiological and biochemical toxicities of W on these two plants were systematically analyzed. The feasibility of utilizing celery and pepper as biomonitor organisms for W contamination was explored and indicative biomarkers were screened. Results: The results indicated that W could inhibit plants' root length, shoot height, and fresh weight while concurrently promoting membrane lipid peroxidation. Additionally, W enhanced the activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and total antioxidant capacity (TAOC) to counteract oxidative damage. From a physiological perspective, pepper exhibited potential as a biomonitor for W contamination. Biochemical indicators suggested that SOD could serve as a sensitive biomarker for W in celery, while TAOC and POD were more suitable for the roots and leaves of pepper. In conclusion, our study investigated the toxic effects of W on celery and pepper, contributing to the understanding of W's environmental toxicity. Furthermore, it provided insights for selecting biomonitor organisms and sensitive biomarkers for W contamination.

Effects of tungsten and titanium oxide nanoparticles on the diazotrophic growth and metals acquisition by Azotobacter vinelandii under molybdenum limiting condition.

The acquisition of essential metals, such as the metal cofactors (molybdenum (Mo) and iron (Fe)) of the nitrogenase, the enzyme responsible for the reduction of dinitrogen (N(2)) to ammonium, is critical to N(2) fixing bacteria in soil. The release of metal nanoparticles (MNPs) to the environment could be detrimental to N(2) fixing bacteria by introducing a new source of toxic metals and by interfering with the acquisition of essential metals such as Mo. Since Mo has been reported to limit nonsymbiotic N(2) fixation in many ecosystems from tropical to cold temperate, this question is particularly acute in the context of Mo limitation. Using a combination of microbiology and analytical chemistry techniques, we have evaluated the effect of titanium (Ti) and tungsten (W) oxide nanoparticles on the diazotrophic growth and metals acquisition in pure culture of the ubiquitous N(2) fixing bacterium Azotobacter vinelandii under Mo replete and Mo limiting conditions. We report that under our conditions (≤10 mg·L(-1)) TiO(2) NPs have no effects on the diazotrophic growth of A. vinelandii while WO(3) NPs are highly detrimental to the growth especially under Mo limiting conditions. Our results show that the toxicity of WO(3) NPs to A. vinelandii is due to an interference with the catechol-metalophores assisted uptake of Mo.

Effect of ingested tungsten oxide (WOx) nanofibers on digestive gland tissue of Porcellio scaber (Isopoda, Crustacea): fourier transform infrared (FTIR) imaging.

Tungsten nanofibers are recognized as biologically potent. We study deviations in molecular composition between normal and digestive gland tissue of WOx nanofibers (nano-WOx) fed invertebrate Porcellio scaber (Iosopda, Crustacea) and revealed mechanisms of nano-WOx effect in vivo. Fourier Transform Infrared (FTIR) imaging performed on digestive gland epithelium was supplemented by toxicity and cytotoxicity analyses as well as scanning electron microscopy (SEM) of the surface of the epithelium. The difference in the spectra of the Nano-WOx treated and control cells showed up in the central region of the cells and were related to lipid peroxidation, and structural changes of nucleic acids. The conventional toxicity parameters failed to show toxic effects of nano-WOx, whereas the cytotoxicity biomarkers and SEM investigation of digestive gland epithelium indicated sporadic effects of nanofibers. Since toxicological and cytological measurements did not highlight severe effects, the biochemical alterations evidenced by FTIR imaging have been explained as the result of cell protection (acclimation) mechanisms to unfavorable conditions and indication of a nonhomeostatic state, which can lead to toxic effects.

Powder characteristics and biocidal activity of the MnOx-WO3-TiO2 system synthesized by a sol-gel method for antifouling agents.

The TiO2-system powders were investigated with respect to the crystallinity and the microstructure. The biocidal activity increased from TiO2 to binary MnOx-TiO2 to ternary MnOx-WO3-TiO2 against Vibrio fischeri as a model of Gram-negative bacteria. Anatase and rutile TiO2 were not toxic even at 200 mg/L, but anatase has been observed in bacterial growth inhibition due to the different electronic band (lattice) structure. All materials containing manganese oxides were toxic: the toxicity correlation (EC50) of MnOx-WO3 and MnOx-WO3-TiO2 was 7.0, 1.8 ppm, respectively. The high antifouling activity of MnOx-WO3-TiO2 was attributed to its redox potential and soluble metal ions originating from tungsten oxides according to the improvements in the powder characteristics.

Comparative pulmonary toxicity assessment of tungsten trioxide and tungsten trioxide hydrate nanoparticles.

Tungsten trioxide (WO3)-based nanoparticles (NPs) are gaining popularity because of their exciting potential for photocatalytic applications; however, the toxic potential of WO3-based NPs remains a concern. In this study, we evaluated the toxic risk of WO3 NPs and hydrated WO3 NPs (WO3·H2O NPs) using lung cells and explored the underlying mechanism. WO3 NPs and WO3·H2O NPs significantly decreased the number of viable cells (59.5 %-85.8 % of control) and promoted apoptosis in human alveolar basal epithelial A549 cells after a 24-h exposure. Both WO3 NPs and WO3·H2O NPs reduced the expression of heme oxygenase-1 (0.15-0.33 folds of control) and superoxide dismutase 2 (0.31-0.66 folds of control) and increased reactive oxygen species production (1.4-2.6 folds of control) and 8-hydroxy-2'-deoxyguanosine accumulation (1.22-1.43 folds of control). The results showed that WO3 NPs have higher cytotoxicity and oxidative potential than WO3·H2O NPs. In addition, the WO3 NP cellular uptake rate was significantly higher than the WO3·H2O NPs uptake rate in pulmonary cells. The greater extent of oxidative adverse effects induced by WO3-based NPs appears to be related to the enhanced particle uptake. WO3 NPs and WO3·H2O NPs exposure led to the secretion of inflammatory factor interleukin 6 (1.63-3.42 folds of control). Decreases in serpin family A member 1 gene expression (0.28-0.58 folds of control) and increases in the oxidation of neutrophil elastase inhibitor (1.34-1.62 folds of control) in pulmonary cells also suggest that exposure to WO3 NPs and WO3·H2O NPs raises the risk of developing chronic obstructive pulmonary disease. Taken together, our findings indicate that the toxic risk of WO3 NPs and WO3·H2O NPs must be considered when manufacturing and applying WO3-based NPs.

Acute inhalation of tungsten particles results in early signs of cardiac injury.

Epidemiological studies have established that exposure to tungsten increases the risk of developing cardiovascular diseases. However, no studies have investigated how tungsten affects cardiac function or the development of cardiovascular disease. Inhalation of tungsten particulates is relevant in occupational settings, and inhalation of particulate matter has a known causative role in driving cardiovascular disease. This study examined if acute inhalation to tungsten particulates affects cardiac function and leads to heart tissue alterations. Female BALB/c mice were exposed to Filtered Air or 1.5 ± 0.23 mg/m3 tungsten particles, using a whole-body inhalation chamber, 4 times over the course of two weeks. Inhalation exposure resulted in mild pulmonary inflammation characterized by an increased percentage and number of macrophages and metabolomic changes in the lungs. Cardiac output was significantly decreased in the tungsten-exposed group. Additionally, A', an indicator of the amount of work required by the atria to fill the heart was elevated. Cardiac gene expression analysis revealed, tungsten exposure increased expression of pro-inflammatory cytokines, markers of remodeling and fibrosis, and oxidative stress genes. These data strongly suggest exposure to tungsten results in cardiac injury characterized by early signs of diastolic dysfunction. Functional findings are in parallel, demonstrating cardiac oxidative stress, inflammation, and early fibrotic changes. Tungsten accumulation data would suggest these cardiac changes are driven by systemic consequences of pulmonary damage.

In vivo toxicity evaluation of a polyoxotungstate nanocluster as a promising contrast agent for computed tomography.

In this study, we demonstrate for the first time, that a discrete metal-oxo cluster α-/ß-K6P2W18O62 (WD-POM) exhibits superior performance as a computed tomography (CT) contrast agent, in comparison to the standard contrast agent iohexol. A toxicity evaluation of WD-POM was performed according to standard toxicological protocols using Wistar albino rats. The maximum tolerable dose (MTD) of 2000 mg/kg was initially determined after oral WD-POM application. The acute intravenous toxicity of single WD-POM doses (1/3, 1/5, and 1/10 MTD), which are at least fifty times higher than the typically used dose (0.015 mmol W kg-1) of tungsten-based contrast agents, was evaluated for 14 days. The results of arterial blood gas analysis, CO-oximetry status, electrolyte and lactate levels for 1/10 MTD group (80% survival rate) indicated the mixed respiratory and metabolic acidosis. The highest deposition of WD-POM (0.6 ppm tungsten) was found in the kidney, followed by liver (0.15 ppm tungsten), for which the histological analysis revealed morphological irregularities, although the renal function parameters (creatinine and BUN levels) were within the physiological range. This study is the first and important step in evaluating side effects of polyoxometalate nanoclusters, which in recent years have shown a large potential as therapeutics and contrast agents.

In vivo corrosion, tumor outcome, and microarray gene expression for two types of muscle-implanted tungsten alloys.

Tungsten alloys are composed of tungsten microparticles embedded in a solid matrix of transition metals such as nickel, cobalt, or iron. To understand the toxicology of these alloys, male F344 rats were intramuscularly implanted with pellets of tungsten/nickel/cobalt, tungsten/nickel/iron, or pure tungsten, with tantalum pellets as a negative control. Between 6 and 12 months, aggressive rhabdomyosarcomas formed around tungsten/nickel/cobalt pellets, while those of tungsten/nickel/iron or pure tungsten did not cause cancers. Electron microscopy showed a progressive corrosion of the matrix phase of tungsten/nickel/cobalt pellets over 6 months, accompanied by high urinary concentrations of nickel and cobalt. In contrast, non-carcinogenic tungsten/nickel/iron pellets were minimally corroded and urinary metals were low; these pellets having developed a surface oxide layer in vivo that may have restricted the mobilization of carcinogenic nickel. Microarray analysis of tumors revealed large changes in gene expression compared with normal muscle, with biological processes involving the cell cycle significantly up-regulated and those involved with muscle development and differentiation significantly down-regulated. Top KEGG pathways disrupted were adherens junction, p53 signaling, and the cell cycle. Chromosomal enrichment analysis of genes showed a highly significant impact at cytoband 7q22 (chromosome 7) which included mouse double minute (MDM2) and cyclin-dependant kinase (CDK4) as well as other genes associated with human sarcomas. In conclusion, the tumorigenic potential of implanted tungsten alloys is related to mobilization of carcinogenic metals nickel and cobalt from corroding pellets, while gene expression changes in the consequent tumors are similar to radiation induced animal sarcomas as well as sporadic human sarcomas.