Forgot your password?
New user?
New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
CAS announces the release of SciFinder Scholar for Mac OS X
Press Releases
Press Releases
| Check out our New Publishers' Select for Free Articles |
Archives of Toxicology (v.81, #12)
Subacute oral toxicity study of bisphenol F based on the draft protocol for the “Enhanced OECD Test Guideline no. 407” by Nobuhiko Higashihara; Keiji Shiraishi; Katusi Miyata; Yutaka Oshima; Yasushi Minobe; Kanji Yamasaki (pp. 825-832).
Since bisphenol F (4,4’-dihydroxydiphenylmethane) has been reported to exhibit estrogen agonistic properties in the uterotrophic assay, we performed a 28-day repeated-dose toxicity study (enhanced OECD test guideline No. 407) on bisphenol F based on the OECD draft protocols to determine whether it has endocrine-mediated properties. Bisphenol F was orally administered at doses 0, 20, 100 and 500 mg/kg per day for at least 28 days, but no clear endocrine-mediated changes were detected, and it was concluded to have no endocrine-mediated effects in young adult rats. On the other hand, the main effect of bisphenol F was concluded to be liver toxicity based on clinical biochemical parameters and liver weight, but without histopathological changes. The no-observed-effect level for bisphenol F is concluded to be under 20 mg/kg per day since decreased body weight accompanied by decreased serum total cholesterol, glucose, and albumin values were observed in the female rats given 20 mg/kg per day or higher doses of bisphenol F.
Keywords: Bisphenol F; Enhanced Test Guideline 407; Rat; Endocrine effects
Discrepancies between different rat models for the assessment of percutaneous penetration of hazardous substances by Gintautas Korinth; Thomas Göen; Karl Heinz Schaller; Hans Drexler (pp. 833-840).
By regulatory authorities the rat is considered to be a suitable animal model to predict the percutaneous absorption of hazardous substances in humans. In our study, the percutaneous penetration of 2-butoxyethanol (BE) and toluene was compared in different rat models. Intradermal microdialysis and static diffusion cells were used in in vivo and in vitro experiments with haired Wistar and hairless Lewis rats. Microdialysis experiments showed a steady-state penetration for BE and a penetration maximum for toluene in both rat strains at ∼60 min after beginning of exposure. However, in diffusion cell experiments the penetration of the test compounds in both rat strains increased until the end of exposure (4 h). Additionally, in microdialysis experiments BE penetrated in hairless rats in a higher amount than in haired rats (factor: 1.4; P < 0.01), for toluene it was just the opposite (factor: 1.9; P < 0.001). In diffusion cell experiments, the penetrated amounts of both compounds were higher in hairless rats compared to haired rats. The fluxes for BE were in diffusion cell experiments at a factor of 14.5 (haired rat) and 18.1 (hairless rat) higher than in microdialysis experiments, the difference factor for toluene was 2.6 (haired rat) and 12.9 (hairless rat). The lag times indicate a significantly faster penetration in microdialysis experiments compared with diffusion cell experiments (P < 0.001). There are great differences in percutaneous penetration behaviour between the techniques and the rat strains. The diffusion cell method has difficulties to describe the percutaneous penetration kinetics, whereas microdialysis describes it more reliable. Due to these differences the reliability of a conversion factor for the transfer of percutaneous absorption data from rat to human skin, as proposed in the literature, is questionable.
Keywords: Percutaneous absorption; Microdialysis; Diffusion cell; Wistar rat; Hairless rat; 2-Butoxyethanol; Toluene
Tissue distribution and elimination of N-methyl-N-2,4,6-tetranitroaniline (tetryl) in rats by Steven R. Myers; Joseph A. Spinnato (pp. 841-848).
The elimination of tetryl was studied using ring-labeled 14C-tetryl. Tetryl was given subcutaneously to male Sprague–Dawley rats at doses of 25, 100, and 300 mg kg−1, and urine and feces were collected 24 h post-injection. Percent urinary elimination was observed to be 10.02 ± 2.48, 11.2 ± 1.66, and 13.24 ± 5.79 (mean ± SEM) respectively. Percent fecal elimination was 15.68 ± 6.13, 9.41 ± 1.52, and 8.45 ± 1.81 respectively. At 24 h post-injection, tissues from male Sprague–Dawley rats were collected from animals that received 100 mg kg−1 14C-tetryl. Tetryl was found to be poorly absorbed with approximately 65% of the administered dose remaining at the site of subcutaneous injection. Blood was found to be the principal depot of radioactivity, followed by muscle, liver, and kidney. Analysis of the tissue to blood radioactivity ratio revealed that the liver had the highest ratio (1.2), followed by brain (0.45), kidney (0.38), and testes (0.35). All other tissues analyzed had ratios less than 0.30. Urine of animals receiving 14C-tetryl (100 mg kg−1) was analyzed using HPLC coupled with UV detection (200–600 nm; 1.2 nm resolution). During HPLC analysis, 1 min fractions were collected and radioactivity measured. Two major peaks of radioactivity were identified at approximately 5 and 14 min retention times, respectively. The 14 min peak had the same retention time and UV spectrum as picric acid and 5 min peak had the same retention time and UV profile as picramic acid. The data presented demonstrates that that there is little retention of tetryl in specific tissue depots and that tetryl is eliminated in roughly equal amounts in both urine and feces. The major urinary metabolites identified picric acid and picramic acid (a known urinary metabolite observed in rabbits). From microsomal fraction studies, a major metabolite, NMPA, was identified. The formation of this metabolite was found to be dependent on at least two enzymes. One enzyme is dependent on NAD+ for NMPA formation and is likely to be NADP(H):quinone oxidoreductase. The second metabolite is NADP+ dependent and is probably related to NADPH:cytochrome-P450 reductase.
Keywords: Tetryl; Pharmacodynamics; Pharmacokinetics; Nitroaromatics; Metabolism
Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans by Andreas Kampkötter; Christiane Gombitang Nkwonkam; Ruben Felix Zurawski; Claudia Timpel; Yvonni Chovolou; Wim Wätjen; Regine Kahl (pp. 849-858).
Flavonoids present in many herbal edibles possess a remarkable spectrum of biochemical and pharmacological actions and they are assumed to exert beneficial effects to human health. Although the precise biological mechanisms of their action has not been elucidated yet many of the protective properties of flavonoids are attributed to their antioxidative activity since oxidative stress is regarded as a main factor in the pathophysiology of various diseases and ageing. Oxidative stress results from excessive generation of reactive oxygen species (ROS) or diminished antioxidative defence and thus antioxidants are able to counteract such situations. We used the multicellular model organism Caenorhabditis elegans that is conserved in molecular and cellular pathways to mammals to examine the effects of the flavonoids kaempferol and fisetin with respect to their protective action in individual living worms. Both flavonoids increased the survival of C. elegans, reduced the intracellular ROS accumulation at lethal thermal stress, and diminished the extent of induced oxidative stress with kaempferol having a stronger impact. Kaempferol but not fisetin attenuated the accumulation of the ageing marker lipofuscin suggesting a life prolonging activity of this flavonoid. In addition to these effects that may be attributed to their antioxidative potential kaempferol and fisetin caused a translocation of the C. elegans FoxO transcription factor DAF-16 from the cytosol to the nucleus indicating a modulatory influence of both flavonoids on signalling cascade(s).
Keywords: Caenorhabditis elegans ; Kaempferol; Fisetin; Stress resistance; DAF-16; Lipofuscin accumulation
Cordycepin induced eryptosis in mouse erythrocytes through a Ca2+-dependent pathway without caspase-3 activation by Julian C. K. Lui; Judy W. Y. Wong; Y. K. Suen; T. T. Kwok; K. P. Fung; S. K. Kong (pp. 859-865).
Cordyceps sinensis is a prized traditional Chinese medicine and its major component cordycepin is found to have anti-leukemia activities. However, its cytotoxicity in erythrocytes was unclear. To examine the effect of cordycepin on the induction of eryptosis (an apoptosis-like process in enucleated erythrocytes), flow cytometric assays based on membrane integrity and asymmetry were employed. For comparison, analyses were performed in parallel with two other anti-leukemia agents, indirubin 3′-monoxime (IDM) and As2O3. We found that at the IC50 against leukemia HL-60, cordycepin elicited eryptosis while IDM and As2O3 showed no erythrotoxicity in mouse erythrocytes. Mechanistically, cordycepin increased the [Ca2+]i and activated μ-calpain protease in a dose-dependent manner. Yet, no caspase-3 activation was observed in the cordycepin-treated erythrocytes. When extracellular Ca2+ was depleted, both the cordycepin-induced eryptosis and μ-calpain cleavage were suppressed. Our study therefore demonstrated for the first time that cordycepin induces eryptosis through a calcium-dependent pathway in the absence of mitochondria and caspase-3 activation.
Keywords: Eryptosis; Apoptosis; Erythrocytes; Cordycepin
Effects of SO2 derivatives on expressions of MUC5AC and IL-13 in human bronchial epithelial cells by Ruijin Li; Ziqiang Meng (pp. 867-874).
Sulfur dioxide (SO2) is a common air pollutant, and inhaled SO2 in airway epithelium easily forms its soluble derivatives in vivo (bisulfite and sulfite), which are toxic to the respiratory system and related to the exacerbation of asthma. To investigate the effects of SO2 derivatives on the expressions of asthma related genes (MUC5AC and IL-13), the mRNA and protein levels of the two genes in cultured human bronchial epithelial (BEP2D) cells were analyzed using real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) assay, immunocytochemistry method and enzyme-linked immunosorbent assay (ELISA), respectively. The results showed that the mRNA expressions of MUC5AC and IL-13 were significantly increased at different concentrations of SO2 derivatives (0.0001, 0.001, 0.01, 0.1 and 1.0 mM), and the maximum appeared at 0.01 mM for MUC5AC (3.9-fold) or at 0.001 mM for IL-13 (4.7-fold). Meanwhile, SO2 derivatives significantly increased the mRNA levels at 0, 0.5, 1, 4 and 24 h post-exposure with the maximum at 4 h post-exposure (25-fold for MUC5AC and 41-fold for IL-13). Furthermore, the protein levels of MUC5AC and IL-13 in BEP2D cells were significantly increased at different concentrations and different time courses exposed to SO2 derivatives, along with the maximum at 4 h post-exposure. These results lead to a conclusion that SO2 derivatives can increase the expressions of MUC5AC and IL-13 genes on the transcription and translation levels, and it suggests that SO2 derivatives can induce mucus over-production and inflammation responses in human bronchial epithelial cells and may have relations with asthma diseases. This might be one of the possible mechanisms that SO2 aggravates asthma disease.
Keywords: Sulfur dioxide derivatives; Asthma; MUC5AC; IL-13; BEP2D
Testicular toxicity of profenofos in matured male rats by Gihan Gamal Moustafa; Zein Shaban Ibrahim; Yoshiharu Hashimoto; Alkelch M. Alkelch; Kentaro Q. Sakamoto; Mayumi Ishizuka; Shoichi Fujita (pp. 875-881).
To investigate the effect of the phosphorothoate insecticide profenofos on male specific gene expression on rat testis, 16-week-old Wistar rats were orally administered at dose of 17.8 mg/kg twice weekly for 65 days. Gene expression in the testes was monitored by DNA microarray analysis and real-time RT-PCR, which revealed that genes related to steroidogenesis including cytochrome P450 17A1 (CYP17A1), steroidogenic acute regulatory protein (StAR) and CYP11A1 were significantly increased. Besides the testes were histopathologicaly examined, which revealed testicular destruction and degeneration represented by a layer of columnar epithelium, oedematous changes surrounding the seminiferous tubules besides vacuolated spermatogonial cells and more elongated Leydig cells. These data suggest that profenofos considered as one of the male reproductive toxicants. Furthermore, we propose that the above three steroidogenic-related genes and the gene of acrosomal reaction as potential biomarkers of testicular toxicity.
Keywords: Profenofos; Cytochrome P450; Testosterone; Testis
Carcinogenic susceptibility of rasH2 mice to troglitazone by Meilan Jin; Miwa Takahashi; Mitsuyoshi Moto; Masako Muguruma; Kazumi Ito; Kyoko Watanabe; Yusuke Kenmochi; Taichi Kono; Keiji Hasumi; Kunitoshi Mitsumori (pp. 883-894).
To evaluate the carcinogenicity of troglitazone in rasH2 mice, 7-week-old male and female rasH2 mice were fed a diet containing 0, 3,000 or 6,000 ppm troglitazone for 26 weeks. An increased tendency in the incidence of vascular tumors was observed in females of the 6,000 ppm group. The preliminary analysis using a high-density oligonucleotide microarray on a splenic hemangiosarcoma of a high dose female that could be obtained as a fresh sample showed that several genes related to the ras/MAPK pathway activation, angiogenesis, cell cycle and cell multiplication were up-regulated. In addition, most of the genes up-regulated were confirmed by the reverse transcriptase-polymerase chain reaction (RT-PCR). These results may suggest that the carcinogenic susceptibility of rasH2 mice to troglitazone is relatively low and up-regulations of the ras/MAPK pathway and angiogenesis-related genes are probably involved in the production of splenic hemangiosarcomas in rasH2 mice given troglitazone.
Keywords: Troglitazone; PPAR agonist; rasH2 mice