Search

Nutrient or energy deprivation, especially glucose restriction, is a promising anticancer therapeutic approach. However, establishing a precise and potent deprivation strategy remains a formidable task. The Golgi morphology is crucial in maintaining the function of transport proteins (such as GLUT1) driving glycolysis. Thus, in this study, we present a "Golgi-customized Trojan horse" based on tellurium loaded with apigenin (4',5,7-trihydroxyflavone) and human serum albumin, which was able to induce GLUT1 plasma membrane localization disturbance via Golgi dispersal leading to the inhibition of tumor glycolysis. Diamond-shaped delivery system can efficiently penetrate into cells as a gift like Trojan horse, which decomposes into tellurite induced by intrinsically high H 2 O 2 and GSH levels. Consequently, tellurite acts as released warriors causing up to 3.8-fold increase in Golgi apparatus area due to the down-regulation of GOLPH3. Further, this affects GLUT1 membrane localization and glucose transport disturbance. Simultaneously, apigenin hinders ongoing glycolysis and causes significant decrease in ATP level. Collectively, our "Golgi-customized Trojan horse" demonstrates a potent antitumor activity because of its capability to deprive energy resources of cancer cells. This study not only expands the applications of tellurium-based nanomaterials in the biomedicine but also provides insights into glycolysis restriction for anticancer therapy., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024. Published by Elsevier B.V.)

Cadmium toxicity occurs where there is absorption and accumulation of cadmium ions (Cd 2+ ) in tissues beyond tolerable levels. Significant differences in the release of Cd 2+ from cadmium compounds in biological fluids, like gastric fluid, may indicate differences in bioavailability and absorption. This means that direct read-across from high solubility cadmium compounds to lower solubility compounds may not accurately reflect potential hazards. Here, the relative bioaccessibility in gastric fluid of cadmium telluride and cadmium chloride was evaluated using in vitro bioelution tests whilst the toxicokinetic behavior of these two compounds were compared after dietary administration for 90 days in male and female Wistar Han rats following OECD TG 408. Cadmium chloride was highly bioaccessible, whilst cadmium telluride showed low solubility in simulated gastric fluid (90 % and 1.5 % bioaccessibility, respectively). This difference in bioaccessibility was also reflected by a difference in bioavailability as shown by the difference in the liver and kidney concentrations of cadmium after repeat oral exposure. Feeding at doses of 750 and 1500 ppm of cadmium telluride did not result in tissue cadmium levels above the lower limit of quantification (LLOQ). In contrast, feeding with a lower test substance concentration yet higher concentration of bioaccessible cadmium (30 ppm cadmium chloride) resulted in tissue accumulation of cadmium. Only slight, non-adverse changes in hematology and clinical chemistry parameters were seen at these doses, indicating an absence of significant cadmium mediated toxicity towards target organs (kidney and liver), reflected in minimal cadmium accumulation in these organs. This study demonstrates that bioelution tests can help determine the bioaccessibility of cadmium, which can be used to estimate the potential for target tissue toxicity based on known toxicokinetic profiles and threshold levels for cadmium toxicity, while reducing and refining animal testing., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The potential toxicity of cadmium-containing quantum dots (QDs) has received much attention because of increasing biomedical applications. However, little has been known about how cadmium telluride (CdTe) QDs influence the gut microbiota and lipid metabolism. In this study, mice were exposed orally to CdTe QDs (200 μL of 0.2, 2, 20 or 200 μm; twice per week) for 4 weeks. The oral experiments showed CdTe QD exposure led to a decrease of the Firmicutes/Bacteroidetes (F/B) ratio of gut microbiota, which highly negatively correlated with the low-density lipoprotein (LDL), triglyceride (TG) and total cholesterol (TC) levels in serum. In addition, the low-dose (0.2 and 2 μm) CdTe QDs significantly increased the diversity of gut microbiota, and did not elevate the LDL, TG and TC levels in serum. The medium dose (20 μm) of CdTe QDs caused the biggest decrease of the F/B ratio, so it significantly increased the LDL, TG and TC levels compared with the control. Furthermore, high-dose (200 μm) CdTe QDs caused various toxicities in the histopathology of liver and intestine, liver function and intestinal immunity, but did not significantly lead to changes of the LDL, TG and TC levels in serum. This study demonstrates that high-dose oral CdTe QDs mainly lead to tissue damage of the liver and intestine, while the medium and low doses of oral CdTe QDs induce shifts of gut microbiota structure, which are associated with blood lipid levels., (© 2020 John Wiley & Sons, Ltd.)

Quantum dots (QDs) are engineered nanoparticles (NPs) of semiconductor structure that possess unique optical and electronic properties and are widely used in biomedical applications; however, their risks are not entirely understood. This study investigated the tissue distribution and toxic effects of cadmium telluride quantum dots (CdTe-QDs) in male BALB/c mice for up to 1 week after single-dose intravenous injections. CdTe-QDs were detected in the blood, lung, heart, liver, spleen, kidney, testis and brain. Most CdTe-QDs accumulated in the liver, followed by the spleen and kidney. At high doses, exposure to CdTe-QDs resulted in mild dehydration, lethargy, ruffled fur, hunched posture, and body weight loss. Histological analysis of the tissues, upon highest dose exposures, revealed hepatic hemorrhage and necrotic areas in the spleen. The sera of mice treated with high doses of CdTe-QDs showed significant increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin levels, as well as a reduction in albumin. CdTe-QD exposure also led to a reduced number of platelets and elevated total white blood cell counts, including monocytes and neutrophils, serum amyloid A, and several pro-inflammatory cytokines. These results demonstrated that the liver is the main target of CdTe-QDs and that exposure to CdTe-QDs leads to hepatic and splenic injury, as well as systemic effects, in mice. By contrast, cadmium chloride (CdCl 2 ), at an equivalent concentration of cadmium, appeared to have a different pharmacokinetic pattern from that of CdTe-QDs, having minimal effects on the aforementioned parameters, suggesting that cadmium alone cannot fully explain the toxicity of CdTe-QDs.

In this study, the cytotoxicity of CdTe quantum dots (QDs) of various dimensions was examined using the electroporation method. The influence of the size of QDs on normal and tumour cell viability after 24 h of incubation with nanomaterials was examined. The three human cell lines were chosen for the tests: A549 (a tumour cell line derived from the lung), MRC-5 (normal fibroblasts from the lung) and HaCaT (normal keratinocytes from the skin). Accordingly, we modelled the effect of nanocrystals on various human tissues because nanoparticles can be introduced into an organism through different routes. We were also able to study which cells are more sensitive to nanoparticles: normal or tumour cells. The nanoparticles were introduced into cells through pores in the cell membranes that were generated by electrical pulses. The effectiveness of introducing nanocrystals into cells was determined as a function of the nanocrystal dimensions and accumulation locations. Moreover, the cytotoxicity of quantum dots was tested, and cell viability after electroporation was evaluated. We also investigated whether the introduced nanocrystals released cadmium ions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Pig skin is a widely acknowledged surrogate for human skin for in vitro/ex vivo skin penetration studies with application for small molecules and nanosystems. We have investigated the influence of biological factors such as age and anatomical site on the penetration and distribution of nanoparticles (2.1 nm hydrophilic CdTe/CdS quantum dots: QDs) in adult pig skin (APS), weanling pig skin (WPS) and newborn pig skin (NBPS) at two different anatomical sites (ear and abdomen)., Methods: QDs in saline were applied to 1 × 1 cm2 skin (62.5 pmol/cm2) with 2-min finger rubbing using a standardized protocol. After 6- or 24-h incubation on Franz diffusion cells, tape stripping (×10) followed by manual follicular casting was conducted. Cadmium in QDs was quantified using inductively coupled plasma mass spectrometry for all samples. The presence of QDs in similarly treated skin samples was also captured using multiphoton tomography., Results: QDs were mainly localized in hair follicles after 6 and 24 h of exposure with no cadmium detected in the Franz cell receptor compartment regardless of pig age or anatomical site. The amount of QDs deposited in the follicles was similar at 6 h but higher on APS and WPS ears compared to NBPS ears at 24 h. This is associated with the high follicle density and small follicle diameter of the NBPS compared to the smaller density of much larger follicles on the APS. NBPS showed consistent QD distribution for ear and abdomen up to 24 h., Conclusions: There is minimal penetration of QDs through pig skin. Density and diameter of follicles in association with age of pigs and application site influenced the amount of QDs deposited in follicles. The structure of the stratum corneum, follicle density and diameter of NBPS are similar to human skin suggesting that NBPS is an appropriate model for human skin in the evaluation of topical applications of a range of chemicals including nanosystems., (© 2019 S. Karger AG, Basel.)

An increasing interest has been developed in the past 15 years in the relationship between trace elements and cell functioning. In the present work the possibility of transgenerational effects of Te was investigated in rats. F 1 generation exposed to K 2 TeO 3 (1.55nM) from day 1 of pregnancy until litters were 30 day old, these animals with no other treatment than tap water and food were let to reach 60-70 day old. At this age, female rats were mated with normal untreated male rats. The F 2 generation also without any Te treatment was allowed to grow until 30 days of age. At this age, behavioral tests measuring exploration induced by novelty, lateralized exploration, social interaction and survival behavior were applied. Results showed that head-dipping, rearing, lateralized exploration, social interaction, and survival behaviors, affected by Te treatment in F 1 generation, also were modified in the same manner in F 2 generation. These data show that Te effects on coping behavior in rats are preserved epigenetically in the next generation., (© 2019 Elsevier B.V. All rights reserved.)

Quantum dots (QDs) have widespread application in many fields such as medicine and electronics. The need for understanding the potentially harmful side effects of these materials becomes clear. In this study, the toxicity of cadmium telluride quantum dots (CdTe-QDs) and bulk Cd 2+ has been investigated and compared by applying metabolomics methods. The datasets were 1 H-NMR data from mice plasma which had been taken from four groups of mice in different time intervals. Then, the data were analyzed by applying chemometrics methods and the metabolites were found from Human Metabolome Database (HMDB). The results showed the significant change in the level of some metabolites especially estrogenic steroids in different groups with different amounts of received Cd. The findings also indicated that steroid hormone biosynthesis, lysine biosynthesis and taurine and hypotaurine metabolism are the most affected pathways by CdTe-QDs especially in estrogenic steroids. The over-representation analysis indicated that endoplasmic reticulum, gonads, and hepatocytes are most affected. Since the pattern of metabolite alteration of CdTe-QDs with equivalent Cd 2+ was similar to those of CdCl 2 , it was postulated that beside Cd 2+ effects, the toxicity of CdTe-QDs is associated with other factors.

Unfolded protein response (UPR) and endoplasmic reticulum (ER)-phagy are essential for cell homeostasis. Quantum dots (QDs), which have been widely used for biomedical applications, can accumulate in the kidney tissues and may cause renal dysfunction. However, the molecular mechanism of QDs-induced nephrotoxicity is still obscure. The present study was aimed to elucidate the role and mechanism of UPR and ER-phagy in QDs-induced nephrotoxicity. Herein, human embyronic kidney (HEK) cells were exposed to 15, 30, 45, and 60 nM cadmium telluride (CdTe)-QDs for 12 and 24 h. And CdTe-QDs (30-60 nM) inhibited the HEK cell viability. The clathrin-dependent endocytosis was determined as the main pathway of CdTe-QDs cellular uptake. Within cells, CdTe-QDs disrupted ER ultrastructure and induced UPR and FAM134B-dependent ER-phagy. Blocking UPR with inhibitors or siRNA rescued the FAM134B-dependent ER-phagy, which was triggered by CdTe-QDs. Moreover, suppression of UPR or FAM134B-dependent ER-phagy restored the cell vability. In vivo, mice were intravenously injected with 8 and 16 nmol/kg body weight CdTe-QDs for 24 h. Kidney was shown as one of highest distributed organs of CdTe-QDs, resulting in renal dysfunction, as well as UPR and FAM134B-dependent ER-phagy in it. Thus, for the first time, we demonstrated that ER-phagy can be triggered by nanomaterials both in vitro and in vivo. In addition, blocking of UPR and ER-phagy showed protective effects against CdTe-QDs-induced toxicity in kideny cells. Notably, a secreted alkaline phosphatase reporter gene system has been developed as a sensitive and rapid method for evaluating the ER quality under the exposure of nanomaterials.

The purpose of this study was to investigate if a novel parameter, the stress-to-rest ratio of the signal-to-noise ratio (RSNR) obtained with a cadmium zinc telluride (CZT) SPECT scanner, could be used to distinguish triple-vessel disease (TVD) patients. Methods . One hundred and two patients with suspected coronary artery disease were retrospectively involved. Each subject underwent a Tl-201 SPECT scan and subsequent coronary angiography. Subjects were separated into TVD ( n = 41) and control ( n = 61) groups based on coronary angiography results using 50% as the stenosis cutoff. The RSNR was calculated by dividing the stress signal-to-noise ratio (SNR) by the rest SNR. Summed scores were calculated using quantitative perfusion SPECT (QPS) for all subjects. Results . The RSNR in the TVD group was found to be significantly lower than that in the control group (0.83 ± 0.15 and 1.06 ± 0.17, resp.; P < 0.01). Receiver-operating characteristic (ROC) analysis showed that RSNR can detect TVD more accurately than the summed difference score with higher sensitivity (85% versus 68%), higher specificity (90% versus 72%), and higher accuracy (88% versus 71%). Conclusion . The RSNR may serve as a useful index to assist the diagnosis of TVD when a fully automatic quantification method is used in CZT-based SPECT studies.

Although quantum dot (QD)-induced toxicity occurs due to free radicals, generation of oxidative stress mediated by reactive oxygen species (ROS) formation is considered an important mechanism. However, free radical mechanisms are essentially difficult to elucidate at the molecular level because most biologically relevant free radicals are highly reactive and short-lived, making them difficult to directly detect, especially in vivo. Antioxidants play an important role in preventing or, in most cases, limiting the damage caused by ROS. Healthy people and animals possess many endogenous antioxidative substances that scavenge free radicals in vivo to maintain the redox balance and genome integrity. The antioxidant capacity of an organism is highly important but seldom studied. In this study, the dose and time effects of CdTe QDs on the antioxidant capacities of the liver and kidneys were investigated in mice using the electron paramagnetic resonance (EPR) spin-trapping technique. We found that the liver and kidneys of healthy mice contain specific antioxidant capacities that scavenge ·OH and ·O 2 - . Furthermore, oxidative stress markers (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx], glutathione [GSH] and malondialdehyde [MDA]) were examined. In dose course studies, the free radical scavenging efficiencies of the liver and kidneys were found to gradually decrease with increasing concentration of CdTe QD exposure. The activities and levels of SOD, CAT, GPx and MDA were observed to increase in treated groups, whereas those of GSH were reduced. The time course studies revealed that the QD-induced antioxidant efficiency reduction was time dependent with GSH decrease and could recover after a period of time. These experimental results offer new information on QD toxicity in vivo. Specifically, CdTe QDs can deplete GSH to reduce the elimination ability of the liver and kidneys for ·OH and ·O 2 - , thus inducing oxidative damage to tissues., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Introduction: We aimed to evaluate whether the hyperemic myocardial blood flow (MBF) can be estimated using cadmium zinc telluride (CZT)-based single-photon emission computed tomography (SPECT) cameras with a single, rapid rest/stress dynamic scan. Dynamic contrast-enhanced (DCE) cardiac magnetic resonance imaging (MRI) was used as a reference modality for flow measurement., Materials and Methods: The proposed protocol included both the rest and stress acquisitions within a 24-min scan. Patients were first injected with 99mTc-Sestamibi at the resting state. Sixty minutes after the first injection, the subject was positioned via scintigraphy, after which the list-mode data acquisition was initiated and continued for 24 minutes. Five minutes after data acquisition was initiated, a stressed state was induced via dipyridamole infusion, after which a second dose of 99mTc-Sestamibi was injected. Dynamic SPECT images were reconstructed for all subjects, who also underwent T1-weighted cardiac DCE-MRI performed on days other than those of the SPECT studies. MBF values were estimated for the rest and stress MRI studies, and for the stress portion of the SPECT study. The SPECT-measured hyperemic MBF was compared with the MR-measured hyperemic MBF and coronary flow reserve (CFR), based on the regions of interest., Results: A total of 30 subjects were included in this study. The hyperemic MBF estimated from SPECT showed a strong correlation with the MR-measured hyperemic MBF (r2 = 0.76) and a modest correlation with the MR-measured CFR (r2 = 0.56). Using MR-measured CFR <1.3 as a cutoff for coronary stenosis, we found that the SPECT-measured hyperemic MBF served as a useful clinical index with 94% sensitivity, 90% specificity, and 93% accuracy., Conclusions: Hyperemic MBF can be measured with a rapid, single-scan rest/stress study with CZT-based SPECT cameras.

Plastic and reconstructive surgeons increasingly apply adipose tissue grafting in a clinical setting, although the anticipation of graft survival is insecure. There are only few tools for tracking transplanted fat grafts in vivo.Murine adipose tissue clusters were incubated with negatively charged, mercaptoproprionic acid-coated cadmium telluride quantum dots (QDs) emitting in the dark red or near infrared. The intracellular localization of QDs was studied by confocal laser scanning microscopy.As a result, the adipose tissue clusters showed a proportional increase in fluorescence with increasing concentrations (1, 10, 16, 30, 50 nM) of cadmium telluride QDs. Laser scanning microscopy demonstrated a membrane bound localization of QDs. Vacuoles and cell nuclei of adipocytes were spared by QDs. We conclude that QDs were for the first time proven intracellular in adult adipocytes and demonstrate a strong fluorescence signal. Therefore, they may play an essential role for in vivo tracking of fat grafts.

Hypermethylated cancer populations are hard to treat due to their enhanced chemo-resistance, characterized by aberrant methylated DNA subunits. Herein, we report on invoking response from such a cancer lineage to chemotherapy utilizing multifunctional copper telluride (Cu 2-X Te) nanocubes (NCs) as photothermal and photodynamic agents, leading to significant anticancer activity. The NCs additionally possessed photoacoustic and X-ray contrast imaging abilities that could serve in image-guided therapeutic studies.

High efficiency cadmium-zinc-telluride (CZT) cameras provide an opportunity to lower the injected activities of radiopharmaceuticals for single photon emission tomography (SPECT) myocardial perfusion imaging (MPI). The limits for reducing activities of thallium have not been determined, particularly in obese patients. After an injection of 0.7 megabecquerel (MBq) of thallium/kg, we collected an average 1.5 million counts for the 10-min acquisition in a pilot cohort of ten patients. After extrapolation, we reduced the administered activity to 0.5 MBq/kg to obtain the expected 1 million counts. We studied the image quality in 124 patients (86 men, 43 obese with body mass index over 30 kg/m 2 ) referred for MPI. The quality of images was assessed by a number of recorded counts and visually by a four-grade scale (one-poor quality, four-excellent quality). In non-obese and obese patients, the average number of recorded counts was 1.1 vs. 1.07 million counts for the 10-min stress acquisition, 1.04 vs. 1.06 million counts for the 13-min rest acquisition, and the average quality score was 3.97 vs. 3.90, respectively (p = NS).The mean administered activity was 39.2 ± 7 MBq for non-obese and 48.7 ± 6 for obese patients (p < 0.0001), and the calculated effective dose was 4.0 ± 0.7 and 4.9 ± 0.6 mSv respectively (p < 0.0001). The ultra-low-dose thallium stress-redistribution protocol, including post-stress prone imaging, provides good quality of images with a low radiation burden, even in obese patients.

Tellurium (Te) is a semiconductor and is frequently doped with copper, tin, gold or silver. It is also used to color glass and ceramics and is one of the primary ingredients in blasting caps. Little is known about Te biological activity but it is well known for toxicity to human and animals. It has inhibited the lipids profiles and oxidative stress in the brain of mice. Sodium tellurite 4.15, 8.3 and 16.6 mg/kg (1/20, 1/10 and 1/5 of LD50, respectively) was given to male Wistar rats orally in saline for a period of 15 days. On day 16, the blood was collected and the livers were dissected out for biochemical assays. The hepatotoxicity biomarkers [bilirubin, aspartate aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP)] were elevated significantly and dose dependently in the serum of Te treated groups as compared to control group. The content of thiobarbituric reactive substances in Te treated groups was increased significantly and dose-dependently as compared to control group. Conversely, the content of glutathione and activities of antioxidant enzymes (glutathione peroxidase, glutathione reductase, glutathione-S-transferase, superoxide dismutase and catalase) were decreased significantly in Te treated groups as compared to control group. No data of inorganic Te compounds on the liver toxicity of rats are available. The aim of the present study was to evaluate the hepatotoxicity of inorganic Te compound. In conclusion, Te accelerated hepatotoxicity and oxidative stress in liver tissue of rats.

In this study, we report the design and delivery of tumor-targeted, quantum dot (QD) and doxorubicin (DOX)-encapsulated PEG-PLGA nanopolymersomes (NPs) for the imaging and chemotherapy of breast cancer. To achieve active cancer targeting, QD and DOX-encapsulated NPs were conjugated with folate for folate-binding protein receptor-guided delivery, which overexpressed in many cancer cells. Hydrophobic DOX and hydrophilic MSA-capped QD were encapsulated in the bilayer and core of the PEG-PLGA nanopolymersomes, respectively. The data show that the formulated NPs sustained DOX release for a period of 12 days. Fluorescence microscopy and MTT assay demonstrated that the developed folate-targeted DOX-QD NPs had higher cytotoxicity than non-targeted NPs and the free form of the drug; moreover, they preferentially accumulated in 4T1 and MCF-7 cells in vitro. In vivo experiments including whole organ tissue-homogenate analysis and organ fluorescence microscopy imaging of BALB/c mice bearing 4T1 breast adenocarcinoma showed that the folate receptor-targeted QD encapsulated NPs accumulate at tumor sites 6h following intravenous injection. Acute toxicity studies of the prepared targeted QD-loaded NPs showed no evidence of long-term harmful histopathological and physiological effects on the treated animals. The in vivo tumor inhibitory effect of folic acid (FA)-QD-DOX NPs demonstrated an augmented therapeutic efficacy of targeted formulation over the non-targeted and free drug. The data obtained illustrate a high potential of the prepared targeted theranostic nanoplatform in the treatment and imaging of breast cancer. This study may open new directions for preparation of QD-based theranostic polymersomes for clinical application., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Multimodal imaging has made great contribution for diagnosis and therapy of disease since it can provide more effective and complementary information in comparison to any single imaging modality. The design and fabrication of fluorescent-magnetic nanoparticles for multimodal imaging has rapidly developed over the years. Herein, we demonstrate the facile synthesis of GdS coated CdTe nanoparticles (CdTe@GdS NPs) as multimodal agents for fluorescence (FL) and T1-weighted magnetic resonance (MR) imaging. These nanoparticles obtain both prominent fluorescent and paramagnetic properties by coating the GdS shell on the surface of CdTe core via a simple room-temperature route in aqueous solution directly. It is shown that the as-prepared CdTe@GdS NPs have high quantum yield (QY) value of 12% and outstanding longitudinal relaxation rate (r1) of 11.25 mM s(-1), which allow them to be employed as FL/MR dual-modal imaging contrast agents. They also exhibit small particle size of 5 nm, excellent colloidal stability and low cellular toxicity for concentrations up to 750 μg mL(-1). In addition, with the conjugation of folic acid, the nanoparticles were successfully used for tumor-targeted FL/MR dual-modal imaging in vitro and in vivo., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Although it has been reported that fluorescent quantum dots (QDs) have obvious acute toxic effects in vitro, their toxic effects at low doses or threshold doses are still unknown. Therefore, we evaluated the biological histocompatibility and in vitro toxicity of three types of QDs at threshold doses. Also, we compared the toxic effects of QDs with different raw chemical compositions and sizes. The results showed that low concentrations of QDs (≤7 μg/mL) had no obvious effect on cell viability and cell membrane damage, oxidative damage, cell apoptosis or DNA damage. However, QD exposure led to a significant cytotoxicity at higher doses (≥14 μg/mL) and induced abnormal cellular morphology. In addition, when comparing the three types of QDs, 2.2 nm CdTe QDs exposure showed a significantly increased proportion of apoptotic cells and significant DNA damage, suggesting that size and composition contribute to the toxic effects of QDs. Based on these discussions, it was concluded that the concentration (7 μg/mL) may serve as a threshold level for these three types of QDs only in L929 fibroblasts, whereas high concentrations (above 14 μg/mL) may be toxic, resulting in inhibition of proliferation, induction of apoptosis and DNA damage in L929 fibroblasts.

Background: Nanotechnology-based near-infrared quantum dots (NIR QDs) have many excellent optical properties, such as high fluorescence intensity, good fluorescence stability, and strong tissue-penetrating ability. Integrin αvβ3 is highly and specifically expressed in tumor angiogenic vessel endothelial cells of almost all carcinomas. Recent studies have shown that NIR QDs linked to peptides containing the arginine-glycine-aspartic acid (RGD) sequence (NIR QDs-RGD) can specifically target integrin αvβ3 expressed in endothelial cells of tumor angiogenic vessels in vivo, and they offer great potential for early cancer diagnosis, in vivo tumor imaging, and tumor individualized therapy. However, the toxicity profile of NIR QDs-RGD has not been reported. This study was conducted to investigate the toxicity of NIR QDs-RGD when intravenously administered to mice singly and repeatedly at the dose required for successful tumor imaging in vivo., Materials and Methods: A NIR QDs-RGD probe was prepared by linking NIR QDs with the maximum emission wavelength of 800 nm (QD800) to the RGD peptide (QD800-RGD). QD800-RGD was intravenously injected to BALB/C mice once or twice (200 pmol equivalent of QD800 for each injection). Phosphate-buffered saline solution was used as control. Fourteen days postinjection, toxicity tests were performed, including complete blood count (white blood cell, red blood cell, hemoglobin, platelets, lymphocytes, and neutrophils) and serum biochemical analysis (total protein, albumin, albumin/globulin, aspartate aminotransferase, alanine aminotransferase, and blood urea nitrogen). The coefficients of liver, spleen, kidney, and lung weight to body weight were measured, as well as their oxidation and antioxidation indicators, including superoxide dismutase, glutathione, and malondialdehyde. The organs were also examined histopathologically., Results: After one or two intravenous injections of QD800-RGD, as compared with control, no significant differences were observed in the complete blood count; biochemical indicators of blood serum, organ coefficient, and oxidation and antioxidation indicators; and no cell necrosis or inflammation were seen in the liver, spleen, kidney, or lung through histopathological examination., Conclusion: Our data demonstrate that the single and repeated intravenous injection of QD800-RGD at a dose needed for successful tumor imaging in vivo is not toxic to mice. Our work lays a solid foundation for further biomedical applications of NIR QDs-RGD.

Redox-modulating compounds derived from natural sources, such as redox active secondary metabolites, are currently of considerable interest in the field of chemoprevention, drug and phytoprotectant development. Unfortunately, the exact and occasionally even selective activity of such products, and the underlying (bio-)chemical causes thereof, are often only poorly understood. A combination of the nematode- and yeast-based assays provides a powerful platform to investigate a possible biological activity of a new compound and also to explore the "redox link" which may exist between its activity on the one side and its chemistry on the other. Here, we will demonstrate the usefulness of this platform for screening several selenium and tellurium compounds for their activity and action. We will also show how the nematode-based assay can be used to obtain information on compound uptake and distribution inside a multicellular organism, whilst the yeast-based system can be employed to explore possible intracellular mechanisms via chemogenetic screening and intracellular diagnostics. Whilst none of these simple and easy-to-use assays can ultimately substitute for in-depth studies in human cells and animals, these methods nonetheless provide a first glimpse on the possible biological activities of new compounds and offer direction for more complicated future investigations. They may also uncover some rather unpleasant biochemical actions of certain compounds, such as the ability of the trace element supplement selenite to induce DNA strand breaks.

Background: Quantum dots (QDs) have been used as novel fluorescent nanoprobes for various bioapplications. The degradation of QDs, and consequent release of free cadmium ions, have been suggested to be the causes of their overall toxicity. However, in contrast to sufficient investigations regarding the biological fate of QDs, a paucity of studies have reported their chemical fate in vivo. Therefore, the overall aim of our study was to understand the chemical fate of QDs in vivo and explore analytical techniques or methods that could be used to define the chemical fate of QDs in vivo., Methods: Male ICR mice were administered a single intravenous dose (0.2 μmol/kg) of aqueous synthesized CdTe/ZnS aqQDs. Inductively coupled plasma-mass spectrometry (ICP-MS) was used to simultaneously measure the concentrations of cadmium (Cd) and tellurium (Te) in the blood and tissues over the course of a 28 day period. We compared the blood kinetic parameters and biodistributions of Cd and Te, and used the molar ratio of Cd:Te as a marker for QDs degradation., Results: Cd and Te display different blood kinetics and biodistribution profiles. The Cd:Te ratio in the blood did not vary significantly within the first hour compared with intact CdTe/ZnS aqQDs. The Cd:Te ratio decreased gradually over time from the 6 h time point on. Cd accumulated in the liver, kidneys, and spleen. Te was distributed primarily to the kidneys. Sharp time-dependent increases in the Cd:Te ratio were found in liver tissues., Conclusions: QDs can undergo degradation in vivo. In vitro, QDs are chemically stable and do not elicit the same biological responses or consequences as they do in vivo. Our methods might provide valuable information regarding the degradation of QDs in vivo and may enable the design and development of QDs for biological and biomedical applications.

Nanoconjugates composed of drug molecules encapsulated in quantum dots (QDs) attract enormous attention due to their promising bioimaging and biomedical applications. Here, the anticancer efficiency of potential pharmacophore agents (o-carborane (Cb), o-carborane-C-carboxylic acid (Cbac1), and o-carborane-C(1)C(2)-dicarboxylic acid (Cbac2) coupling with cadmium telluride QDs capped with cysteamine (CA-CdTe QDs)) have been explored. Compared with free CA-CdTe QDs, the composites consisting of Cbac1/Cbac2 and safe-dosage QDs can greatly improve the inhibition efficiency toward SMMC-7721 hepatocellular carcinoma cells with the aid of our real-time cell bioelectronic sensing system and the MTT assay. The enhanced cytotoxicity correlates with increased intracellular reactive oxygen species generation and cell apoptosis. Confocal laser scanning fluorescent microscopy shows improved cellular uptake and drug distribution of the Cbac1/Cbac2-CdTe QDs nanoconjugates. This work raises the possibility that the carborane pharmacophore in combination with QDs or other anticancer drugs may be viable for efficient cancer diagnosis and chemotherapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

BACKGROUND AND OBJECTIVE. Nanotechnology works with substances at a nanometer scale, and it offers many solutions for biomedicine. Nanoparticles (NPs) have been shown as effective agents for imaging, drug delivery, pathogen detection, etc. However, to date, NP toxicity is poorly known. The aim of our study was to investigate the embryotoxicity and teratogenicity of quantum dots (QDs) at the different stages of rat embryogenesis. MATERIALS AND METHODS. Wistar rats were injected with CdSe/ZnS or CdTe QDs on the 6th, 13th, and 18th days of embryogenesis. Cyclophosphamide was chosen as a positive control of embryotoxicity. On the 21st day, the number of resorptions, weight, length, and external malformations of the embryos were estimated. Fluorescence spectroscopy and microscopy analysis were used to determine the accumulation of QDs in the tissues. RESULTS. Exposure to cyclophosphamide during the pregnancy decreased the embryonic weight and length when compared with the control group and produced numerous malformations. The effects depended on the stage of embryogenesis. Meanwhile, QDs did not cause any embryotoxic or teratogenic effects. However, CdTe QDs induced necrosis in the tissues of the peritoneal cavity. The necrotic tissues contained QDs with altered spectroscopic properties. Spectroscopic and microscopic tissue examination revealed that QDs accumulated in the placenta, but no penetration to the embryonic tissues was observed. CONCLUSIONS. QDs did not cause any direct embryotoxic or teratogenic effects, but they had adverse effects on the maternal organism. The observed QD effects and the long-term accumulation of QDs in the maternal organism may increase the risk of adverse effects on embryo development.

Aim: To investigate the metalloestrogenic effects of cadmium telluride quantum dots (QDs) in both human breast cancer cells and in vivo in mice., Materials & Methods: Human breast cancer cells (MCF-7 cells) were utilized to study QDs, cadmium and 17β-estradiol induced estrogen-related genomic and nongenomic signaling. Female prepubescent and ovariectomized adult mice were treated with CdTe QDs to assess whether QD-induced estrogenicity would lead to uterine changes., Results & Discussion: Our findings demonstrate that in vitro cadmium-containing QDs induce cellular proliferation, estrogen receptor α activation, and biphasic phosphorylation of AKT and ERK1/2, comparable with 17β-estradiol. Green QDs elicited a more robust estrogenic response than orange QDs. Addition of the selective estrogen receptor antagonist, ICI 182780, completely abolished all QD-induced estrogenic effects, suggesting that QD-induced estrogenic signaling is mediated via the estrogen receptor. In vivo, chronic treatment of mice with QDs led to a two- to three-fold increase in uterine weight, comparable or greater than 17β-estradiol., Conclusion: These findings suggest that certain cadmium-containing nanocrystals are endocrine disruptors, whose effects can exceed those induced by ionic cadmium or 17β-estradiol.

Background: In novel treatment approaches, therapeutics should be designed to target cancer stem cells (CSCs). Quantum dots (QDs) are a promising new tool in fighting against cancer. However, little is known about accumulation and cytotoxicity of QDs in CSCs., Methods: Accumulation and cytotoxicity of CdTe-MPA (mercaptopropionic acid) QDs in CSCs were assessed using flow cytometry and fluorescence-activated cell sorting techniques as well as a colorimetric cell viability assay., Results: We investigated the expression of two cell surface-associated glycoproteins, CD44 and CD133, in four different cancer cell lines (glioblastoma, melanoma, pancreatic, and prostate adenocarcinoma). Only the melanoma cells were positive to both markers of CD44 and CD133, whereas the other cells were only CD44-positive. The QDs accumulated to a similar extent in all subpopulations of the melanoma cells. The phenotypical response after QD treatment was compared with the response after ionizing radiation treatment. The percentage of the CD44(high-)CD133(high) subpopulation decreased from 72% to 55%-58% for both treatments. The stem-like subpopulation CD44(high)CD133(low/-) increased from 26%-28% in the untreated melanoma cells to 36%-40% for both treatments., Conclusion: Treatment of melanoma cells with QDs results in an increase of stem-like cell subpopulations. The changes in phenotype distribution of the melanoma cells after the treatment with QDs are comparable with the changes after ionizing radiation.

A population-based case-control study of thyroid cancer was carried out in contaminated regions of Belarus and Russia among persons who were exposed during childhood and adolescence to fallout from the Chernobyl accident. For each study subject, individual thyroid doses were reconstructed for the following pathways of exposure: (1) intake of 131I via inhalation and ingestion; (2) intake of short-lived radioiodines (132I, 133I, and 135I) and radiotelluriums (131mTe, 132Te) via inhalation and ingestion; (3) external dose from radionuclides deposited on the ground; and (4) ingestion of 134Cs and 137Cs. A series of intercomparison exercises validated the models used for reconstruction of average doses to populations of specific age groups as well as of individual doses. Median thyroid doses from all factors for study subjects were estimated to be 0.37 and 0.034 Gy in Belarus and Russia, respectively. The highest individual thyroid doses among the subjects were 10.2 Gy in Belarus and 5.3 Gy in Russia. Iodine-131 intake was the main pathway for thyroid exposure. Estimated doses from short-lived radioiodines and radiotelluriums ranged up to 0.53 Gy. Reconstructed individual thyroid doses from external exposure ranged up to 0.1 Gy, while those from internal exposure due to ingested cesium did not exceed 0.05 Gy. The uncertainty of the reconstructed individual thyroid doses, characterized by the geometric standard deviation, varies from 1.7 to 4.0 with a median of 2.2.

This study investigated the hemolytic and genotoxic effect of different organoselenium and organotellurium compounds in human blood cells, as simple tests for screening the toxicity of organochalcogenides. For osmotic fragility (OF) test, samples of total blood were incubated with the organochalcogens at 4, 8, 50, 75 and 100 microM or vehicle (DMSO) for 90 min at 37 degrees C. The EC(50) values for hemolysis were significantly increased in erythrocytes exposed to diphenyl selenide (II), diphenyl diselenide (III), diphenyl telluride (IV), diphenyl ditelluride (V), (S)-2-amino-1-diselenide-3-methylpropanyl (IX), butyl(styryl)telluride (XIII) and 2-(butyltellurium)furan (XIV) at higher concentrations tested. The exposure of erythrocytes to organochalcogens diphenyl diselenide (II) and butyl(styryl)telluride (XIII), which had greater hemolytic effect, did not modify catalase activity, reactive oxygen species (ROS) production and -SH content. On the other hand, Na(+)/K(+) ATPase activity of erythrocyte ghosts was significantly inhibited by the compounds diphenyl diselenide (II) and butyl(styryl)telluride (XIII) (P<0.05) in a concentration-dependent manner. The inhibition of Na(+)/K(+) ATPase activity was completely reversed by dithiothreitol (DTT); indicating reaction of these organochalcogens with thiol groups of the enzyme. The thiol oxidase activity of the compounds II and XIII was supported by the fact that the rate of DTT oxidation was increased significantly by both chalcogens. In the higher concentrations, the compounds (II) and (XIII) were strongly genotoxic and cytotoxic to human leukocytes cells, as verified by the DNA damage and cell viability evaluation. Our results suggest that at relatively high concentration organochalcogenides exhibit hemolytic and genotoxic action in human blood cells, which are probably linked to their thiol oxidase activity and preferential interaction with sulfhydryl groups critical to enzymes.

Cadmium telluride (CdTe) nanoparticles exhibit strong and stable fluorescence that is attractive for many applications such as biological probing and solid state lighting. The evaluation of nanoparticle toxicity is important for realizing these practical applications. However, no systematic studies of CdTe nanoparticle toxicity have been reported. We investigated and compared the size- and concentration-dependent cytotoxicity of CdTe nanoparticles in human hepatoma HepG2 cells using the MTT assay. CdTe nanoparticles elicited cytotoxicity in a concentration- and size-dependent manner, with smaller-sized particles exhibiting somewhat higher potency. Lesser cytotoxicity of partially purified CdTe-Red particles (following methanol precipitation and resuspension) suggested that free cadmium ions may contribute to cytotoxicity. We also evaluated the acute toxicity of CdTe-Red particles following intravenous exposure in male rats (2 micromol/kg). Few signs of functional toxicity or clinical (urinary or blood) changes were noted. Interestingly, motor activity was transiently reduced (2 hours after treatment) and then significantly increased at a later timepoint (24 hours after dosing). These studies provide a framework for further characterizing the in vitro and in vivo toxic potential of different types of CdTe nanoparticles and suggest that the nervous system may be targeted by these nanoparticles under some conditions.

The effect of various doses of sodium tellurite (0.4, 0.8, and 2.0 mg/kg body weight, orally) on the activity of antioxidant enzymes (glutathione peroxidase, glutathione reductase, glutathione-S-transferase, and catalase) and content of glutathione and thiobarbituric acid reactive substances (TBARSs) in the cerebrum, cerebellum, and brainstem of male albino mice was studied after 15 d of treatment. All of the doses of tellurium (0.4, 0.8, and 2.0 mg/kg body weight, orally) have depleted the activity of antioxidant enzymes and the content of glutathione dose dependently in the cerebrum, cerebellum, and brainstem and it was significant with the dose of 2.0 mg/kg. On the other hand, the 2.0-mg/kg dose of tellurium has significantly elevated the content of TBARSs in the cerebrum and cerebellum. The 0.8-mg/kg dose of tellurium has significantly depleted the activities of glutathione peroxidase in the cerebrum and brainstem, glutathione-Stransferase in the cerebrum and cerebellum, catalase in the brainstem, and the content of glutathione in the cerebrum and cerebellum. In contrast, this dose has significantly elevated the content of TBARSs in the cerebrum and cerebellum. However, the depletion in the activity of glutathione reductase with various doses of sodium tellurite was not significant in any brain part of mice. The result suggests that sodium tellurite differentially affects the antioxidant status within various parts of the mice brain.

The effect of various doses of sodium tellurite (1/50 LD50=0.4 mg/kg, 1/25 LD50=0.8 mg/kg, and 1/10 LD50=2.0 mg/kg body weight orally) on the lipid levels (cholesterol, triglycerides, phospholipids, esterified fatty acids, gangliosides, and total lipids) in the cerebrum, cerebellum, and brainstem of male albino mice was studied after 7 and 15 d of treatment. Sodium tellurite (2.0 mg/kg body weight) for 7 d has an apparent effect on the depletion of cholesterol, triglycerides, phospholipids, esterified fatty acids, and total lipids. The cholesterol content was decreased significantly in the cerebrum, cerebellum, and brainstem after 7 d of treatment with a 2.0-mg/kg dose compared to the control. On the other hand, treatment for 15 d with doses of 0.4, 0.8, and 2.0 mg/kg body weight resulted in a significant and dose-dependent increment in cholesterol level in the cerebrum, cerebellum, and brainstem. The triglycerides content was decreased significantly in the cerebrum, cerebellum, and brainstem with the 2.0-mg/kg dose after 7 d of treatment. The doses of 0.4, 0.8, and 2.0 mg/kg orally for 15 d resulted in a significant and dose-dependent depletion of triglycerides in the cerebrum, cerebellum, and brainstem. All the doses of tellurium (0.4, 0.8, and 2.0 mg/kg) both for 7 and 15 d have depleted the level of phospholipids in varying degrees of significance in the cerebrum, cerebellum, and brainstem. However, the level of esterified fatty acids was decreased significantly with the 2.0-mg/kg dose of tellurium for 7 d but increased with the 0.4-mg/kg dose for 15 d in the cerebrum and cerebellum. The level of gangliosides was depleted in the cerebrum but elevated in the cerebellum and brainstem after receiving a 2.0-mg/kg dose of sodium tellurite for 7 d. The content of gangliosides was increased with doses of 0.4 and 0.8 mg/kg but decreased with 2.0 mg/kg for 15 d in the cerebrum, cerebellum, and brainstem. The total lipids content was depleted significantly and dose dependently after 7 and 15 d of treatment in the cerebrum, cerebellum, and brainstem. These results suggest that sodium tellurite affects the lipids content differentially in various parts of the mice brain.

Radiotellurium is present in the environment primarily due to its release during nuclear reactor accidents. Little is known of tellurium metabolism in juveniles, although the element is relatively abundant and has a number of industrial uses. A biokinetic study of radiotellurium in rats was performed using gamma-ray counting. Wistar strain rats were used to determine the uptake of H2(123m)TeO3 by the whole-body retention of juvenile rats and the conceptus in relation to its gestational stages, by measurements in the placenta, fetal membranes, fetal fluid and fetus. The whole-body retention of 123mTe in juvenile rats was higher than that of adult rats. The relative concentration in the placenta and fetal membranes was higher than in the fetus. No activity was observed in the fetal fluid. These results indicate that the placenta and fetal membranes play significant roles as barriers to the transfer of 123mTe into the fetus. The ratio, relative concentration in fetus/relative concentration in mother (C(F)/C(M)), was calculated. The C(F)/C(M) ratio was dependent on the stage of gestation and ranged from 0.2 to 0.5. A little 123mTe was transferred to the suckling rats through the mother's milk when the isotope was administered intravenously to the mother.

Exposure of developing rats to a diet containing elemental tellurium systemically inhibits cholesterol synthesis at the level of squalene epoxidase. At high tellurium exposure levels (> 0.1% in the diet), there is an associated segmental demyelination of the PNS. Low levels of dietary tellurium (0.0001%) led to in vivo inhibition of squalene epoxidase activity in sciatic nerve, and inhibition increased with increasing exposure levels. With increasing dose and increasing exposure times, there was an increasing degree of demyelination and increasing down-regulation of mRNA levels for myelin P0 protein, ceramide galactosyltransferase (rate-limiting enzyme in cerebroside synthesis), and HMG-CoA reductase (rate-limiting enzyme in cholesterol synthesis). Because these were all down-regulated in parallel, we conclude there is coordinate regulation of the entire program for myelin synthesis in Schwann cells. An anomaly was that at early time points and low tellurium levels, mRNA levels for HMG-CoA reductase were slightly elevated, presumably in response to tellurium-induced sterol deficits. We suggest the eventual down-regulation relates to a separate mechanism by which Schwann cells regulate cholesterol synthesis, related to the need for coordinate synthesis of myelin components. Levels of mRNA for the low-affinity nerve growth factor receptor (indicator of alterations in axon-Schwann cell interactions) and for lysozyme (marker for phagocytic macrophages) were both up-regulated in a dose- and time-dependent manner which correlated with the presence of segmental demyelination. Levels of mRNA coding for myelin-related proteins were down-regulated at low tellurium exposure levels, without demyelination or up-regulation of nerve growth factor receptor. This suggests the down-regulation is related to the tellurium-induced cholesterol deficit, and not to the loss of axonal contact associated with early stages of demyelination or to the entry of activated macrophages.

Tellurium (Te) demonstrates properties similar to those of elements known to be toxic to humans, and has applications in industrial processes, which are rapidly growing in importance and scale. It is relevant, therefore, to consider the tellurium physiology, toxicity, and methods for monitoring the element in biological and environmental specimens. Animal studies suggest that up to 25% of orally administered tellurium is absorbed in the gut. There is a biphasic elimination from the circulation with loss of about 50% within a short period, t1/2 = 0.81 d, and slower elimination of the residual Te, t1/2 = 12.9 d. Following a single ip, injection the largest proportion is in the kidney and bone, but with repeated oral administration, Te is found in the heart > > kidney, spleen, bone, and lung. Formation of dimethyl telluride is a characteristic feature of exposure, and gives a pungent garlic-like odor to breath, excreta, and the viscera. The main target sites for Te toxicity are the kidney, nervous system, skin, and the fetus (hydrocephalus). Te can be reliable measured in different specimens by several analytical techniques. Recent work has employed hydride generation atomic absorption spectrometry. Topics for further investigation are proposed.

The combination of analytical techniques such as PNA and SIMS with a compartmental approach enables the study of the metabolism and biokinetics in humans of several elements by using stable isotopes as tracers. The techniques developed for Te require the administration of greater masses than those used for similar studies performed with radioactive tracers, therefore a test was carried out in rabbits in order to assess the possible influence of the administered amounts on the determination of the biokinetic parameters. The behaviour of the tracers was found to be similar for Te administration of up to 70 micrograms/kg of body weight. An inter-individual variability in the size of the transfer compartment was observed and has to be taken into account.

Acute toxicity studies were conducted on copper gallium diselenide (CGS), copper indium diselenide (CIS), and cadmium telluride (CT), three novel compounds used in the photovoltaic and semiconductor industries. Female Sprague-Dawley rats (six rats/dose) were administered 0, 12, 25, 50, or 100 mg/kg body wt of CGS, CIS, or CT by intratracheal instillation. At 72 hr after treatment, body weight gain was significantly decreased in the 100 mg/kg CIS group and in all CT dose groups. Lung weights were increased in most chemical-treated rats, with CT causing the greatest increase. Total numbers of cells in bronchoalveolar lavage fluid (BALF) were significantly increased in treated rats and were greatest in the 100 mg/kg CIS group. Differential cell counts of BALF demonstrated a marked decrease in the percentage of alveolar macrophages and an increase in the percentage of polymorphonuclear leukocytes in all dose groups of all three chemicals. Slight to moderate increases in lactate dehydrogenase activity were observed in BALF from CGS- and CIS-treated rats; marked increases were observed in CT-treated rats. BALF protein was significantly increased in rats treated with CIS and CT. Microscopic examination revealed lymphoid hyperplasia in lungs of rats treated with all three chemicals. CT caused necrosis of the terminal bronchiolar epithelium and epithelium of the alveolar duct region with inflammation, prominent fibrin exudates, and type II cell hyperplasia. CGS and CIS also caused intraalveolar inflammation and type II cell hyperplasia, but did not cause the necrosis and fibrin exudate observed in lungs of CT-treated rats. Based on changes in lung weight, BALF indices, and histopathology, CT was the most toxic for the lung; CIS had intermediate toxicity and CGS was the least toxic. The solubilities of CGS and CIS were relatively low and similar at both pH levels and do not readily explain the observed differences in pulmonary toxicity. The solubility of CdTe was considerably greater than that of CGS and CIS and likely contributed to the greater toxicity of this compound.

AS101 [ammonium-trichloro (0,0' dioxyethylene)tellurate] is a new immunomodulator shown previously to stimulate the production of various cytokines in vitro and in vivo, and to have minimal toxicity. In the present study we explore the possibility of oral administration of AS101 to mice via cannulation in lieu of interperitoneal or intravenous administration reported to date. Our studies show that oral administration of AS101 at a dose ranging between 50 and 100 micrograms/mouse promotes hemopoietic regeneration after treatment with sublethal doses of cyclophosphamide (CYP) and protects mice from the lethal effects of this compound. In addition, AS101 administered orally confers a strong radioprotective effect upon mice when given before irradiation.

Inclusion of 1.1% elemental tellurium in the diet of postweanling rats produces a peripheral neuropathy due to a highly synchronous primary demyelination of sciatic nerve; this demyelination is followed closely by remyelination. Sciatic nerves from animals fed tellurium for various times were removed and incubated ex vivo for 1 h with [14C]acetate, and radioactivity incorporated into individual lipid classes was determined. In nerves from rats exposed to tellurium, there was a profound and selective block in the conversion of radioactive acetate to cholesterol. Another radioactive precursor, [3H]water, gave similar results. We suggest that tellurium feeding inhibits squalene epoxidase activity and that the consequent lack of cholesterol destabilizes myelin, thereby causing destruction of the larger internodes. Ex vivo incubation experiments were also carried out with liver slices. As with nerve, tellurium feeding caused accumulation in squalene of label from radioactive acetate, whereas labeling of cholesterol was greatly inhibited. Unexpectedly, however, incorporation of label from [3H]water into both squalene and cholesterol was increased. Relevant is the demonstration that liver was the primary site of bulk accumulation of squalene, which accounted for 10% of liver dry weight at 5 days. Thus, accumulation of squalene (and other mechanisms, possibly including up-regulation of cholesterol biosynthetic pathways) drives squalene epoxidase activity at normal levels in liver even in the presence of inhibitors of this enzyme. This is reflected by continuing incorporation of [3H]water into cholesterol; incorporation of this precursor takes place at many of the postsqualene biosynthetic steps for sterol formation. [14C]Acetate entering the sterol pathway before squalene in liver is greatly diluted in specific activity when it reaches the large squalene pool, and thus increased squalene epoxidase activity does not transfer significant 14C label to sterols. In contrast to the situation with liver, synthesis of sterols is markedly depressed in sciatic nerve, and squalene does not accumulate to high levels.

As tellurium ranks among the rare non-essential trace elements there is only little known of its intestinal absorption and its metabolic behaviour in humans. Data for risk evaluations needed for occupational medicine are based on animal experiments only. In order to investigate the metabolic behaviour of tellurium in man, tellurium in different forms was administered perorally to healthy male human volunteers. It was given as sodium tellurate, sodium tellurite, metallic colloid and intrinsically bound in cress. For the latter, cress was cultivated with tellurium-containing water in order to provide tellurium for ingestion in a form which is more equivalent to foodstuffs. After the administration the urinary excretion of tellurium was determined. Tellurium concentrations were measured in urine samples by means of graphite furnace atomic absorption spectroscopy (GFAAS) after wet ashing and a preconcentration of tellurium by solvent extraction with isobutyl methyl ketone (IBMK). From the cumulative tellurium excretion in the first four days after the administration, a percentage intestinal absorption of 25% +/- 10% for soluble tellurium salts can be calculated. The renal tellurium excretion is faster after administration of hexavalent tellurium than after ingestion of the tetravalent form. This can explain the higher toxicity of the tetravalent tellurium compounds found in animal experiments. The introduction of tellurium to cress lowered the intestinal absorption to approximately 15%. For metallic tellurium the fractional intestinal absorption was found to be about 10%.

A triple nuclide scintigraphic technique is presented for the precise and lasting intragastric monitoring in man of two concurrently ingested hydrophilic matrix pharmaceutical forms. After in vitro testing of various labels, ion exchange resin-coupled 201T1- and 111In-oxinate were selected for their release characteristics. 99mTc-pertechnetate oral solution was used to selectively delineate the stomach. This technique was validated on healthy volunteers. It allowed measurement of the effects on gastric residence time of galenic parameters (size, density of matrices), as well as of physiological parameters such as subject posture.

Exposure of weanling rats to a diet containing elemental tellurium results in a peripheral neuropathy characterized by segmental demyelination and minimal axonal degeneration. One of the earliest ultrastructural abnormalities in tellurium neuropathy is an increased number of cytoplasmic lipid droplets in myelinating Schwann cells. The pathogenesis of these lipid droplets was investigated using light and electron microscopic autoradiography. Nerve lipids were either "prelabeled" with [3H]acetate via in vivo intraneural injection 3 days before a 2-day exposure to tellurium, or "postlabeled" via in vivo intraneural injection or in vitro incubation with [3H]acetate following a 2-day exposure to tellurium. In the prelabeled nerves, myelin became heavily labeled, but the tellurium-induced cytoplasmic lipid droplets were rarely labeled. In the postlabeled nerves, the tellurium-induced cytoplasmic lipid droplets were the most heavily labeled structures within the nerve. These data indicate that the tellurium-induced lipid droplets in Schwann cells are derived from newly synthesized lipid rather than from the early breakdown and internalization of myelin lipids. The earliest biochemical abnormality observed in tellurium neuropathy is an inhibition of cholesterol synthesis at the squalene epoxidase step. This leads to an accumulation of squalene within the nerve. We conclude that the cytoplasmic lipid droplets in Schwann cells contain this accumulated lipid.

Seventy newly hatched ducklings were fed a commercial ration with 500 mg of added Te (as tetrachloride)/kg of feed for up to 28 days. Ducklings were euthanatized at day 14, 21, and 28, the hearts were studied by gross, microscopic, and ultrastructural examination. Cardiac damage was apparent grossly as hydropericardium and myocardial hemorrhage. Histopathologically, the ventricular myocardium had areas of acute hemorrhagic necrosis (often with mineralization), edema, and congestion. Resolving areas of necrosis appeared cellular with macrophages, heterophils, fibroblasts, and pale vacuolated cells with large vesicular nuclei that were identified as dedifferentiated myocytes. Ultrastructurally, necrotic fibers had disrupted contractile material and mineralized mitochondria. In resolving lesions, macrophages were numerous in the interstitium and within necrotic fibers. Also, a population of sublethally injured myocytes was present and appeared as dedifferentiated cardiac muscle cells with few myofibrils, scattered free filaments, prominent sarcoplasmic reticulum, abundant glycogen, and large nuclei with prominent nucleoli. These dedifferentiated myocytes represented a reparative phase of the Te-induced myocardial injury which has been termed "reactive hyperplasia" and "rejuvenating reorganization" in previous models of myocardial damage.

Mortality and myopathy of selenium-vitamin E (Se-E) deficiency was produced, in a concentration-dependent pattern, during a 4-week study of 750 ducklings fed a commercial duck starter mash that contained adequate amounts of Se and E, and supplemented with multiple amounts of Ag (50 to 3,000 mg/kg of feed, as acetate), Zn (3,000 to 6,000 mg/kg, as sulfate), Cd (10 to 500 mg/kg, as sulfate), Te (25-500 mg/kg, as tetrachloride), Co (100 to 1,000 mg/kg, as chloride), Cu (500 to 1,500 mg/kg, as sulfate), Hg (200 to 400 mg/kg, as chloride), and Sn (1,000 mg/kg, as chloride). Also, feeding supplements of Pb (500 mg/kg, as acetate), As (600 mg/kg, as sodium arsenilate), Fe (5,000 mg/kg, as sulfate), and S (5,000 mg/kg, as sodium sulfite) produced a low-to-medium frequency of lesions of Se-E deficiency. In ducklings with muscle lesions, the gizzard was most often affected (84.2%), followed in decreasing order by skeletal muscles (69.7%), intestine (34.9%), and heart (23.0%). The frequency of skeletal muscle lesions was high in birds fed Ag, and myocardial necrosis was frequent in ducklings fed Te and Hg. Ducklings affected with myopathy were reluctant to stand. Subcutaneous edema, with or without hemorrhages, and pale areas of myonecrosis in gizzard, skeletal muscles, intestine, and heart were seen at necropsy. Birds fed Te and Hg often had hydropericardium and hemorrhagic myocardial necrosis. Seemingly, addition of many elements to a Se-E adequate commercial diet will increase the requirement for Se-E. In our duckling model, minimal amounts shown to induce Se-E deficiency were 50 mg of Ag/kg, 3,000 mg of Zn/kg, 10 mg of Cd/kg, 25 mg of Te/kg, 1200 mg of Co/kg, 500 mg of Cu/kg, 200 mg of Hg/kg, 1,000 mg of Sn/kg, 500 mg of Pb/kg, 600 mg of As/kg, 5,000 mg of Fe/kg, and 5,000 mg of S/kg.

Single endotracheal injections of tellurium and tellurium dioxide, at dosage levels sufficient to cause observable stress in rats, did not result in a progressive fibrotic tissue response after 180 days. The observation period of 180 days is insufficient to assess the lack of tumorigenic potential of these compounds and, therefore, no conclusions on this point are to be inferred.