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Archives of Toxicology (v.79, #9)
Effects of various man-made mineral fibers on cell apoptosis and viability by Hermine Dika Nguea; Bertrand Rihn; Delphine Mahon; Jean-Luc Bernard; Aymon De Reydellet; Alain Le Faou (pp. 487-492).
Evaluating the pathogenic potentials of man-made mineral fibers (MMMF) is an important task performed by the European Community. Noting that it has been proposed that the use of laboratory animals for scientific tests should be reduced or phased out, macrophages then become the cells of choice for conducting in vitro studies. We have evaluated the in vitro toxicity of six commercial stonewool fibers (A, B1, B2, C, D, and E) on U-937 cells. The physical interaction between U-937 cells and MMMF was observed using scanning electron microscopy, and the cytotoxicity was evaluated by studying cell viability using MTT assay and cell apoptosis with an ELISA detection kit. Scanning electron microscopy (SEM) analysis has shown that long fibers can be covered by several macrophages, and that a small fiber can be completely engulfed by one cell. With 50 μg/mL of MMMF, a decrease in cell viability appeared after seven days of incubation, whereas 200 μg/mL induced loss of viability and apoptosis after one day. Fiber D, comprising a high proportion of fibers >20 μm in length and a high concentration of MgO, induced the highest loss in viability and the highest rate of apoptosis compared to the other five fibers. Whether this toxic effect is related to either the physical characteristics of the fibers (such as length), or to the high concentration of magnesium is still to be determined. Because the results can be rapidly obtained, the proposed model is suitable for studying the toxicities of mineral components, even if the tested concentrations are far from the ones reached in the lung.
Keywords: Mineral fibers; U-937 cells; MTT assay; Apoptosis
Effects of STZ-induced diabetes and its treatment with vanadyl sulphate on cyclosporine A-induced nephrotoxicity in rats by Sherif Y. Saad; Tawfeeg A. O. Najjar (pp. 493-499).
The aim of this study was to analyze the effect of streptozotocin (STZ)-induced diabetic state and the insulin-like acting, vanadyl sulphate (VS) on cyclosporine A (CyA) related nephrotoxicity in rats. Male Wistar rats were divided into six groups, of 12 animals each: The control, diabetic rats and diabetic rats whose drinking VS in the drinking water in a concentration of 1 mg/ml. Another three similarly treated groups were injected intra-peritoneally (ip) with CyA in a dose of 25 mg/kg/day for ten doses, 10 days after diabetic induction by using a single dose of STZ of 65 mg/kg. Rats were sacrificed 48 h after the last CyA dose and serum as well as kidneys were isolated and analyzed. Treatment with CyA to control normoglycemic rats resulted in significant increases in kidney weight, serum creatinine, urea nitrogen, cholesterol and triglycerides (TG) levels. Also, the kidney tissue of CyA-treated control animals showed significant increases in total nitrate/nitrite (NOx) concentration and malondialdehyde (MDA) production level as well as depletion of glutathione (GSH) content and glutathione peroxidase (GSH-Px) activity level. Histopathologic evaluation of CyA-treated control rats revealed tubular atrophy, hyaline casts and focal tubular necrosis. However, treatment of diabetic rats with CyA showed significant reduction in serum creatinine and elevation in TG level as well as reductions in the kidney NOx concentration and MDA production level and increase in GSH concentration compared to CyA-treated control rats. Moreover, histopathology of the kidney of CyA-treated diabetics showed typical changes of the diabetic controls revealing glomerular hypertrophy and tubular dilation. On the other hand, treatment with CyA to those diabetic animals administered VS in the drinking water resulted in exacerbation of renal dysfunction, manifested by significant increases in serum indices of nephrotoxicity, cholesterol, TG and bilirubin levels. Also, VS administration to CyA-treated diabetics showed significant increase in kidney NOx concentration compared to those CyA-treated diabetics drinking plain tap water, and to a level significantly lower than those CyA-treated controls. Histopathologically, kidney of CyA/VS-treated diabetic showed marked CyA related changes. In conclusion, STZ-induced diabetes might provide partial protection against CyA-induced renal dysfunction. Also, treatment of hyperglycemia with VS might exacerbate CyA related nephrotoxicity.
Keywords: Cyclosporin A; Streptozotocin; Diabetes; Nephrotoxicity and vanadyl sulphate
Investigation on urinary proteins and renal mRNA expression in canine renal papillary necrosis induced by nefiracetam by Yoshimi Tsuchiya; Yuri Tominaga; Kyuichi Matsubayashi; Toshimasa Jindo; Kazuhisa Furuhama; Kazuo T. Suzuki (pp. 500-507).
The occurrence of renal papillary necrosis (RPN), seen only in dogs after repeated oral administration of nefiracetam, a neurotransmission enhancer, at a relatively high dose, is because of inhibition of renal prostaglandin synthesis by the nefiracetam metabolite M-18. In this study, analyses of urinary proteins and renal mRNA expression were performed to investigate the possible existence of a specific protein expressing the characteristics of RPN evoked by nefiracetam. In the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS–PAGE) of urinary proteins from male dogs given nefiracetam at 300 mg kg−1 day−1 over weeks 5–11, a protein of approximately 40 kDa, which was not seen in control urine, and protein of approximately 30 kDa emerged as distinct bands. Subsequently, clusterin precursor was identified in the former band and tissue kallikrein precursor in the latter by LC–electrospray ionization tandem mass spectrometry (LC–ESI-MS–MS). By quantitative real-time RT-PCR analysis with renal morphological aspects, individual findings showed that renal clusterin mRNA was increased in dogs with severe renal injury, and renal tissue kallikrein also increased, presumably related to hemodynamics. These results demonstrate that changes in renal clusterin mRNA may reflect the progression or severity of RPN, whereas upregulation of tissue kallikrein mRNA may subsequently play a compensating role in the prevention of RPN.
Keywords: Nefiracetam; Renal papillary necrosis; Clusterin; Tissue kallikrein
Sensitivity of human cord blood cells to tetrachloroethylene: cellular and molecular endpoints by Cristina Diodovich; Daniele Ferrario; Barbara Casati; Ilaria Malerba; Erminio Marafante; Dominique Parent-Massin; Laura Gribaldo (pp. 508-514).
The International Agency for Research on Cancer (IARC) currently lists tetrachloroethylene [perchloroethylene (PCE)] as being carcinogenic in animals. PCE is listed as possibly carcinogenic to humans upon occupational exposure. Human exposure to PCE can produce oesophageal cancer, cervical cancer, non-Hodgkin’s lymphoma, urinary bladder cancer and leukemia. This work shows that PCE modulates the expression of some genes implicated in cancer induction, cell differentiation, cell-cycle progression, and the survival and clonogenic potential of human cord blood cells. After exposure to the compound, the modulated genes were involved in inflammatory responses as with the mitogen-activated protein kinase 14 (MPK 14), or in tumor and metastasis progression as with the matrix metalloproteinase 17 (MMP 17), in cell proliferation as with c-jun and c-fos, and moreover in the apoptotic process as with interferon alpha-inducible protein (IFI), BAX and BCL-2. Analysis of cord blood cells via flow cytometry showed that PCE treatment induced a statistically significant increase in necrosis after 24 h, while the clonogenicity of Human Colony-Forming Unit-Granulocyte/Macrophage (CFU-GM) and Burst-Forming Unit-Erythrocyte (BFU-E) progenitors did not change. In conclusion, our data showed that PCE affected various pathways involved in cancer induction, but its action on cell proliferation and differentiation is not yet clearly understood.
Keywords: Tetrachloroethylene; Human cord blood cells; Macroarray; Gene expression
High blood pressure is one of the symptoms of paraquat-induced toxicity in rats by M. V. B. Oliveira; J. A. Albuquerque; A. D. O. Paixão; L. S. Guedes; A. M. S. Cabral (pp. 515-518).
This study investigated whether paraquat (Pq)-induced lipidic peroxidation (LP) is accompanied by changes in blood pressure and heart rate (HR) in rats. Groups of adult male Wistar rats were studied 2 and 12 h after Pq (35 mg/kg, i.p.) administration. The LP was evaluated by monitoring thiobarbituric acid reactive substances (TBARS) in the kidneys, liver and lungs, and validated by including a group treated with an antioxidant, superoxide dismutase (CuZnSOD 50,000 IU/kg), in the study. The TBARS levels were significantly higher (p<0.05) in the kidneys of the rats studied 2 h after Pq than in their respective controls. Similarly, systolic and diastolic blood pressure (DBP) were higher (p<0.05), while HR was lower (p<0.05) than basal levels 2 and 12 h after Pq administration. In contrast, the group treated simultaneously with Pq and CuZnSOD exhibited lower levels of TBARS (p<0.05) in all studied organs compared to the control group, while the mean arterial pressure and HR did not differ from those seen in the control group. These findings indicate that acute Pq poisoning symptoms include high blood pressure.
Keywords: Paraquat; Blood pressure; Oxidative stress; Lipid peroxidation
Weakness in the mechanical properties of the femurs of growing female rats exposed to cadmium by Małgorzata M. Brzóska; Katarzyna Majewska; Janina Moniuszko-Jakoniuk (pp. 519-530).
The study assessed the effect of cadmium (Cd) intoxication on the risk of deformities and fractures of the growing bones of female rats, in order to model human exposure to this metal. For this purpose, bone mineral density and mechanical properties of the proximal and distal ends and diaphysis of the femur were investigated in female Wistar rats exposed to 1, 5 and 50 mg Cd/l in drinking water for 3, 6, 9 and 12 months after the onset of weaning. Daily Cd doses received from drinking water during the treatment period were in the following ranges: 0.059–0.219, 0.236–1.005 and 2.247–9.649 mg/kg body weight at 1, 5 and 50 mg Cd/l, respectively. Biomechanical properties of the femoral proximal and distal ends were evaluated in a compression test, and those of the femoral diaphysis in a cutting test, with loading perpendicular to the longitudinal axis of the bone in all tests. The mineralization and mechanical properties of the bone tissue at various locations on the femur were affected by exposure to Cd in a dose- and duration-dependent manner. Exposure to 1 mg Cd/l (corresponding to low human exposure) during skeletal development weakened the fracture strength of the femoral neck and the trabecular bone at the level of the distal end of the femur and affected the elastic properties of the cortical bone at the femoral diaphysis. At higher levels of Cd exposure, adverse effects were generally observed after a shorter exposure period than for 1 mg Cd/l, and were more advanced. The cadmium-induced weakening of the biomechanical properties of bone at particular sites on the femur correlated with the decreased bone mineralization. The results indicate that even a low exposure to Cd may affect the mineralization and biomechanical properties of growing bone, thus enhancing the risk of fracture.
Keywords: Cadmium; Bone mineral density; Biomechanical testing; Femur; Rats
Chemoprevention of acrylamide toxicity by antioxidative agents in rats—effective suppression of testicular toxicity by phenylethyl isothiocyanate by Kyoung-Youl Lee; Makoto Shibutani; Keiko Kuroiwa; Hironori Takagi; Kaoru Inoue; Hiroshi Nishikawa; Tokutaro Miki; Masao Hirose (pp. 531-541).
The efficacies of N-acetylcysteine (NAC), phenylethyl isothiocyanate (PEITC), and 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ) at preventing the neurotoxicity and testicular toxicity of acrylamide (ACR) were investigated in rats. To this end, Sprague–Dawley males were given 0.02% ACR in drinking water, with or without 1% NAC, 0.5% PEITC or 0.1% HTHQ in the diet for four weeks. A group of untreated controls was also included in the study. All ACR-treated animals exhibited progressive neurotoxicity as judged by gait scores, and among the chemicals co-administered, only HTHQ caused any suppression by the end of the experiment, and this was slight. The severity of the neurotoxicity, as judged by axonal degeneration in the spinal gracile fasciculus and sciatic nerve (distal portion) and aberrant dot-like synaptophysin immunoreactivity, reflecting nerve terminal degeneration in the cerebellar molecular layer, was not clearly reduced by co-administration of HTHQ, NAC or PEITC either. ACR-induced sciatic nerve axon atrophy was marginally and non-significantly reduced by HTHQ. In contrast, in terms of ACR-induced testicular toxicity, exfoliation of spermatids into seminiferous lumen was clearly reduced by co-administered PEITC and was marginally reduced by co-administered HTHQ. These antioxidative agents may therefore reduce/prevent ACR-induced toxicity, at least in the testes.
Keywords: Acrylamide toxicity; Chemoprevention; Phenylethyl isothiocyanate (PEITC)N-acetylcysteine (NAC); 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ); Rat
Effect of sulfite on red blood cell deformability ex vivo and in normal and sulfite oxidase-deficient rats in vivo by Melek Bor-Kucukatay; Vural Kucukatay; Aysel Agar; Oguz Kerim Baskurt (pp. 542-546).
The effect of sulfite, a widely used food additive, on red blood cell deformability ex vivo and in vivo was investigated. Ex vivo experiments were conducted in human blood exposed to sulfite (5, 10 and 20 mM). In vivo experiments were carried out in sulfite oxidase-competent (SOXC) and sulfite oxidase-deficient (SOXD) rats. In the in vivo experiments, sulfite was administered in the form of sodium metabisulfite (Na2S2O5, 25 mg/kg/day) via drinking water. Vitamin E dissolved in olive oil at a dose of 50 mg/kg was administered by gastric gavages. Red blood cell (RBC) deformability was determined at various fluid shear stresses using an ektacytometer. Ex vivo sulfite exposure to RBC did not affect RBC deformability. In the in vivo experiments, although RBC deformability was not affected by sulfite treatment in SOXD rats, it was found to be significantly increased in SOXC rats. Vitamin E treatment in combination with sulfite caused impairment in RBC deformability in both SOXC and SOXD rats. We suggest that sulfite needs to be oxidized in order to improve RBC deformability.
Keywords: Food additives; Sulfite; Sulfite oxidase; Erythrocyte deformability