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.84, #3)
Enhanced OECD TG 407 in detection of endocrine-mediated effects of 4,4′-(octahydro-4,7-methano-5H-inden-5-ylidene)bisphenol by Takaaki Umano; Katsumi Miyata; Yasushi Minobe; Kanji Yamasaki (pp. 175-182).
The purpose of this study was to investigate whether the estrogenic effects were detected in the enhanced TG 407 if the estrogenic property was not so strong in the uterotrophic assay. The estrogenic property of 4,4′-(octahydro-4,7-methano-5H-inden-5-ylidene)bisphenol in the uterotrophic assay was slightly stronger than that of genistein or nonylphenol, but weaker than that of ethinyl estradiol. We performed a 28-day repeated-dose toxicity study (enhanced OECD test guideline No. 407) on 4,4′-(octahydro-4,7-methano-5H-inden-5-ylidene)bisphenol based on the OECD draft protocol. The test chemical, administered orally at doses of 0, 10, 50, and 250 mg/kg per day for at least 28 days, caused such estrogenic effects as abnormal estrous cycle, increased ovarian follicles, increased uterine epithelial height, and vaginal mucification in the 50 and/or 250 mg/kg groups. Moreover, follicular epithelial cell hyperplasia of the thyroid was detected in all male rats given the test chemical and in female rats in the 250 mg/kg group. It was concluded that the estrogenic effects were detected in growing rats given 4,4′-(octahydro-4,7-methano-5H-inden-5-ylidene)bisphenol, and thyroid dysfunction was also observed as the endocrine-mediated effects.
Keywords: Endocrine effects; 4,4′-(Octahydro-4,7-methano-5H-inden-5-ylidene)bisphenol; Rat; Updated OECD test guideline 407
Biodistribution and toxicity of intravenously administered silica nanoparticles in mice by Guangping Xie; Jiao Sun; Gaoren Zhong; Liyi Shi; Dawei Zhang (pp. 183-190).
As the biosafety of nanotechnology becomes a growing concern, the in vivo nanotoxicity of NPs has drawn a lot of attention. Silica nanoparticles (SiNPs) have been widely developed for biomedical use, but their biodistribution and toxicology have not been investigated extensively in vivo. Although investigations of in vivo qualitative distribution of SiNPs have been reported, the time-dependent and quantitative informations about the distribution of SiNPs are still lacking. Here we investigated the long-term (30 days) quantitative tissue distribution, and subcellular distribution, as well as potential toxicity of two sizes of intravenously administered SiNPs in mice using radiolabeling, radioactive counting, transmission electron microscopy and histological analysis. The results indicated that SiNPs accumulate mainly in lungs, liver and spleen and are retained for over 30 days in the tissues because of the endocytosis by macrophages, and could potentially cause liver injury when intravenously injected.
Keywords: Tissue distribution; Nanotoxicity; Silica nanoparticles; Quantitative; Endocytosis
Gene expression profiling in the lung tissue of cynomolgus monkeys in response to repeated exposure to welding fumes by Jeong-Doo Heo; Jung-Hwa Oh; Kyuhong Lee; Choong Yong Kim; Chang-Woo Song; Seokjoo Yoon; Jin Soo Han; Il Je Yu (pp. 191-203).
Many in the welding industry suffer from bronchitis, lung function changes, metal fume fever, and diseases related to respiratory damage. These phenomena are associated with welding fumes; however, the mechanism behind these findings remains to be elucidated. In this study, the lungs of cynomolgus monkeys were exposed to MMA-SS welding fumes for 229 days and allowed to recover for 153 days. After the exposure and recovery period, gene expression profiles were investigated using the Affymetrix GeneChip® Human U133 plus 2.0. In total, it was confirmed that 1,116 genes were up-or down-regulated (over 2-fold changes, P < 0.01) for the T1 (31.4 ± 2.8 mg/m3) and T2 (62.5 ± 2.7 mg/m3) dose groups. Differentially expressed genes in the exposure and recovery groups were analyzed, based on hierarchical clustering, and were imported into Ingenuity Pathways Analysis to analyze the biological and toxicological functions. Functional analysis identified genes involved in immunological disease in both groups. Additionally, differentially expressed genes in common between monkeys and rats following welding fume exposure were compared using microarray data, and the gene expression of selected genes was verified by real-time PCR. Genes such as CHI3L1, RARRES1, and CTSB were up-regulated and genes such as CYP26B1, ID4, and NRGN were down-regulated in both monkeys and rats following welding fume exposure. This is the first comprehensive gene expression profiling conducted for welding fume exposure in monkeys, and these expressed genes are expected to be useful in helping to understand transcriptional changes in monkey lungs after welding fume exposure.
Keywords: MMA-SS welding fumes; Monkey; Gene expression profiling
Dectin-1 and inflammation-associated gene transcription and expression in mouse lungs by a toxic (1,3)-β-d glucan by Thomas. G. Rand; M. Sun; A. Gilyan; J. Downey; J. D. Miller (pp. 205-220).
The form of (1-3)-β-d glucan found in the cell walls of the anamorphic Trichocomaceae that grow on damp building materials is considered to have potent toxic and inflammatory effects on cells of the respiratory system. It is also considered to have a potential role in the development of non-allergenic respiratory health effects. While human studies involving experimental exposures all point to the inflammatory potential of pure curdlan, a linear (1-3)-β-d glucan in a triple helix configuration, animal experiments result in conflicting conclusions concerning the inflammatory potency of this glucan. However, because mice appear to be a better model than guinea pigs for exploring the respiratory effects of curdlan and because molecular mechanisms associated with this glucan remain largely unknown, we conducted further work to clarify the role of curdlan on the inflammatory response using our mouse model of lung disease. This study used in situ hybridization (ISH) to probe dectin-1 mRNA transcription with a digoxigenin-labeled cDNA probe, with reverse transcription (RT)-PCR based arrays used to measure inflammation gene and receptor transcriptional responses. Also, immunohistochemistry (IHC) was used to probe dectin-1 as well as anti-mouse Ccl3, Il1-alpha, and TNF-alpha expression to evaluate dose and time-course (4 and 12 h) postexposure (PE) response patterns in the lungs of intratracheally instilled mice exposed to a single 50 μl dose of curdlan at 10−7, 10−8, 10−9, and 10−10 M/animal (=4 μg to 4 ng curdlan/kg lung wt). Dectin-1 mRNA transcription and expression was observed in bronchiolar epithelium, alveolar macrophages (AMs), and alveolar type II cells (ATIIs) of lungs exposed to 4 μg to 40 ng curdlan/kg lung wt, at both time points. Compared to controls, array analysis revealed that 54 of 83 genes assayed were significantly modulated by curdlan. mRNA transcription patterns showed both dose and time dependency, with highest transcription levels in 10−7 and 10−8 M treatment animals, especially at 4-h PE. Nine gene mRNA transcripts (Ccl3, Ccl11, Ccl17, Ifng, Il1α, Il-20, TNF-α, Tnfrsf1b, and CD40lg) were significantly expressed at all doses suggesting they may have a central role in immunomodulating curdlan exposures. IHC revealed Ccl3, Il1-alpha, and TNF-alpha expression in bronchiolar epithelium, AMs and ATIIs illustrate the important immunomodulatory role that these cells have in the recognition of, and response to glucan. Collectively, these results confirm the inflammatory nature of curdlan and demonstrate the complex of inflammation-associated gene responses induced by (1-3)-β-d glucan in triple helical forms. These observations also provide a biological basis for the irritant and inflammatory response to curdlan observed in humans and animals in experimental studies.
Keywords: Trichocomaceae; Molds; Damp building materials; (1-3)-β-d glucan; Curdlan; Mouse lungs; Inflammation-associated genes; RT–PCR arrays; Dectin-1; In situ hybridization; Immunohistochemistry
Effects of moxifloxacin and clinafloxacin on murine limb buds cultured in regular and in magnesium-deficient medium by Kerstin Bode; Andrea Kunz; Irmela Baumann-Wilschke; Mehdi Shakibaei; Ralf Stahlmann (pp. 221-226).
Evaluation of the prenatal toxicity of a substance in rats or other animals according to the current guidelines is often hampered by the rapid metabolism of the test compound and/or by maternal toxicity. One example for such a compound is moxifloxacin. In vitro systems offer the possibility to study the direct effects of the test compound on embryonic tissues. The aim of this study was to evaluate the embryotoxic potential of moxifloxacin in vitro using the murine limb bud culture. Clinafloxacin, which was found to be teratogenic when tested in rats, was used for comparison. The effects of various concentrations of moxifloxacin (10, 30, 60 and 100 mg/L) and clinafloxacin (3, 10 and 30 mg/L) on growth and differentiation of 12–day-old murine limb buds were studied in a standard and in a magnesium-deficient medium. After termination of the culture, the respective front limb buds were examined by different methods. Clinafloxacin showed clear-cut effects at a concentration of 30 mg/L in both media. Effects were similarly pronounced as the effects observed with moxifloxacin at a concentration of 100 mg/L. Lower concentrations of moxifloxacin, which are achieved during therapy in humans, did not impair growth and differentiation of limb buds. Using electron microscopy, slight ultrastructural changes could be seen after exposure to 3 mg clinafloxacin/L medium. Ultrastructurally, clinafloxacin caused a concentration-dependent decrease of the extracellular matrix, swelling of cell organelles and at higher concentrations necrotic chondrocytes. These effects were significantly enhanced in a magnesium-deficient medium. In conclusion, the effects of moxifloxacin on murine limb buds in vitro were definitely less pronounced than those of clinafloxacin. Effects on growth and differentiation occurred with moxifloxacin only at concentrations that are higher than plasma concentrations observed during therapy. This result is of special interest, because due to rapid metabolism of moxifloxacin in rats results from a routinely performed segment II type study cannot be used for a risk assessment.
Keywords: Limb bud culture; Clinafloxacin; Moxifloxacin; Teratogenicity; Quinolones
Genotoxic effects of the antileishmanial drug glucantime® by Mayara Ingrid Sousa Lima; Viviane Oliveira Arruda; Eliza Vanessa Carneiro Alves; Ana Paula Silva de Azevedo; Silvio Gomes Monteiro; Silma Regina Ferreira Pereira (pp. 227-232).
Leishmaniasis is caused by species of the protozoan parasite Leishmania. It is the third most important vector-borne disease and is widely distributed throughout the world. The World Health Organization recommends pentavalent antimonials as drugs of first choice in its treatment. Although Glucantime® has traditionally been used to treat leishmaniasis, there are still many questions about its structure, mechanisms of action and ability to induce damage in DNA. In this study, the genotoxic activity of this drug was evaluated in vitro using human lymphocytes treated for 3 and 24 h (comet assay) and 48 h (apoptosis assay) with 3.25, 7.5 and 15 mg/ml of Glucantime®, respectively, corresponding to 1.06, 2.12 and 4.25 mg/ml of pentavalent antimony. In the in vivo tests, Swiss mice received acute treatment with three doses (212.5, 425 and 850 mg/kg) of pentavalent antimony. All the treatments were administered intraperitoneally in the volumes of 0.1 ml/10 g of body weight, adapting human exposure to murine conditions. The animals were treated for 3 h in the comet assay using resident peritoneal exudate macrophages, for 24 h in the comet assay using peripheral blood leukocytes and for 24 h in the bone marrow erythrocyte micronucleus test. While no genotoxic effect was observed in the in vitro tests, the in vivo tests showed that Glucantime® induces DNA damage. These findings indicate that Glucantime® is a pro-mutagenic compound that causes damage to DNA after reduction of pentavalent antimony (SbV) into the more toxic trivalent antimony (SbIII) in the antimonial drug meglumine antimoniate.
Keywords: Glucantime® ; Mutagenesis; Genotoxicity; Antileishmanial drug
A Mechanism for the induction of renal tumours in male Fischer 344 rats by short-chain chlorinated paraffins by Gayathri D. Warnasuriya; Barbara M. Elcombe; John R. Foster; Clifford R. Elcombe (pp. 233-243).
Short-chain chlorinated paraffins (SCCPs) cause kidney tumours in male rats, but not in female rats or mice of either sex. Male rat-specific tumours also occur in rats dosed with a range of compounds including 1,4-dichlorobenzene (DCB) and d-limonene (DL). These compounds bind to a male rat-specific hepatic protein, alpha-2-urinary globulin (α2u), and form degradation-resistant complexes in the kidney. The resulting accumulation of α2u causes cell death and sustained regenerative cell proliferation, which in turn leads to the formation of renal tumours. To investigate whether the SCCP, Chlorowax 500C (C500C), causes tumours via the accumulation of α2u male rats were orally dosed with either C500C (625 mg/kg of body weight), DCB (300 mg/kg of body weight), or DL (150 mg/kg of body weight) for 28 consecutive days. An increase in renal α2u and cell proliferation was observed in DCB- and DL-treated rats but not in C500C-treated rats. C500C caused peroxisome proliferation and a down-regulation of α2u synthesis in male rat liver. This down-regulation occurred at the transcriptional level. Since less α2u was produced in C500C-treated rats, there was less available for accumulation in the kidney hence a typical α2u nephropathy did not appear. However, the administration of a radiolabelled SCCP, [14C]polychlorotridecane (PCTD), to male rats demonstrated its binding to renal α2u. Thus, it is possible that SCCPs bind to α2u and cause a slow accumulation of the protein in the kidney followed by delayed onset of α2u nephropathy. As a consequence of these findings in the current experiments, while evidence exists implicating α2u-globulin in the molecular mechanism of action of the C500C, the classic profile of a α2u-globulin nephropathy seen with other chemicals such as DCB and DL was not reproduced during this experimental protocol.
Keywords: Short-chain chlorinated paraffins; Chlorowax 500C; Alpha-2-urinary globulin nephropathy; 1,4-Dichlorobenzene; d-Limonene
Stem cells in chemical carcinogenesis
by Cornelia Dietrich; Carsten Weiss; Ernesto Bockamp; Cathrin Brisken; Tania Roskams; Rebecca Morris; Barbara Oesch-Bartlomowicz; Franz Oesch (pp. 245-251).