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Archives of Toxicology (v.81, #1)
Toxicity of tetrabromobisphenol A (TBBPA) in zebrafish (Danio rerio) in a partial life-cycle test by R. V. Kuiper; E. J. van den Brandhof; P. E. G. Leonards; L. T. M. van der Ven; P. W. Wester; J. G. Vos (pp. 1-9).
Toxicological effects of the widely used flame retardant, tetrabromobisphenol A (TBBPA) were assessed in a partial life-cycle test with zebrafish (Danio rerio). Exposure of adult fish during 30 days to water-borne TBBPA in nominal concentrations ranging from 0 (control) to 1.5 μM was followed by exposure of the offspring in early life stages up to 47 days posthatching (dph) to the same concentrations. Adults exposed to 3 and 6 μM showed severe disorientation and lethargy shortly after beginning of exposure and were euthanized. Because semistatic exposure resulted in fluctuating water concentrations, pooled fish samples were chemically analyzed for internal dose assessment. Egg production was decreased in fish exposed to TBBPA concentrations of 0.047 μM and higher, and a critical effect level of 7.2 μg/g lipid with a lower 5% confidence limit of 3.9 μg/g lipid for 50% decreased egg production was calculated. Histology of adult ovaries indicated a relative increase of premature oocytes in two surviving females exposed to 1.5 μM. Hatching of TBBPA-exposed larvae was decreased except in animals exposed to 0.375 μM. In the highest exposure concentration, early posthatching mortality was high (81%) in larvae and the surviving juveniles showed a significant predominance of the female phenotype. Exposure of eggs from control parents up to 6 μM TBBPA resulted in increasing malformation and pericardial fluid accumulation from 1.5 μM; at higher concentrations, all embryos failed to hatch. The presented results indicate decreased reproductive success in zebrafish at environmentally relevant TBBPA concentrations.
Keywords: Tetrabromobisphenol A; Zebrafish; Reproduction; Endocrine toxicity; Brominated flame retardants (BFRs)
The effects of low dose aluminum on hemorheological and hematological parameters in rats by Sebahat Turgut; Melek Bor-Kucukatay; Gülten Emmungil; Piray Atsak; Günfer Turgut (pp. 11-17).
Aluminum (Al) is a nonessential element and humans are constantly exposed to Al as a result of an increase in industrialization and improving technology practices. Al toxicity can induce several clinical disorders such as neurotoxicity, gastrointestinal toxicity, hepatotoxicity, bone diseases, and anemia. This study aimed at evaluating the possible effects of short term and low dose Al exposure on hemorheological and hematological parameters in rats. Fourteen young, male Wistar albino rats were divided into two groups: 1 mg/200 g body weight of aluminum sulfate (Al2(SO4)3 was injected intraperitoneally to the first group for two weeks, three times a week. The animals of the control group received only physiological saline solution during this period. At the end of the experimental period, anticoagulated blood samples were collected and hematological parameters were determined using an electronic hematology analyzer. Red blood cell (RBC) deformability and aggregation were measured using an ektacytometer (LORCA) and plasma and whole blood viscosities were determined with a Wells-Brookfield cone-plate rotational viscometer. Significant decreases in mean corpuscular volume (MCV), red blood cell (RBC) deformability at low shear stress levels, the aggregation half time (t1/2) and the amplitude (AMP) of aggregation and significant increments in whole blood viscosity (WBV) at native and 40% hematocrit (Hct) of Al-treated rats have been observed. In conclusion, low dose Al2(SO4)3 exposure for a short-time may be responsible for alterations in either rheological properties of blood or hemorheological properties through a remarkable effect on RBC membrane mechanical properties .These alterations may also play an important role in the development of anemia in the Al-treated animals.
Keywords: Aluminum; Red blood cell deformability; Erythrocyte aggregation; Blood viscosity; Plasma viscosity; Hemorheology
Increased CYP1A1 expression in human exfoliated urothelial cells of cigarette smokers compared to non-smokers by Angelika Dörrenhaus; Tina Müller; Peter H. Roos (pp. 19-25).
Polycyclic aromatic hydrocarbons, arylamines and nitrosamines, constituents of cigarette smoke, are known inducers of bladder cancer. The biochemical response of the target tissue, the bladder urothelium, following inhalation of cigarette smoke has not been studied so far. We used exfoliated transitional urothelial cells from human urine samples to analyze effects of smoking on induction of the cytochrome P450 enzyme CYP1A1. Samples of 40 subjects, including male and female smokers and non-smokers, were examined. A prerequisite for the immunofluorescence microscopic analysis of the cells was the enrichment of the urothelial cell population. This was achieved by a new method which is based on magnetic cell sorting exploiting specific binding of immobilized Griffonia simplicifolia lectin to the surface of urothelial cells. Immunostaining of the final cell preparation with a monoclonal antibody to CYP1A1 showed that about 6% of the urothelial cells of non-smokers stained positive for CYP1A1. However, this fraction of positive cells was more than 44% of the urothelial cells in samples from cigarette smokers. In spite of the individual variation, the difference was statistically significant. There were no gender-related differences in the portion of CYP1A1 expressing urothelial cells of smokers and non-smokers. In essence, we show for the first time that human urothelial cells respond to cigarette smoking by induction of CYP1A1. The approach opens new fields of mechanistic and biomarker research with respect to the pathogenetic processes of cancer development in the human bladder.
Keywords: CYP1A1; Urothelial cells; Transitional cells; Cigarette smoking; Bladder; Magnetic cell sorting
Di-(2-ethylhexyl) phthalate suppresses tamoxifen-induced apoptosis in GH3 pituitary cells by H.-S. Kim; M. Ishizaka; A. Kazusaka; S. Fujita (pp. 27-33).
Tamoxifen, an estrogen receptor antagonist, has been clinically used as an antitumor drug and induces apoptosis in GH3 pituitary cells. Although di-(2-ethylhexyl) phthalate (DEHP) is a well-known environmental estrogen and the exposure to this chemical is well expected, reports are limited regarding effects of DEHP on tamoxifen-induced apoptosis in pituitary cells. In the cytotoxicity assay, the reduced cell viability in tamoxifen-treated GH3 cells was reversed by DEHP (250 μM) treatment for 4 days. To characterize cell death, cells were stained using Hoechst 33258. Apoptotic morphological change such as chromatin condensation induced by tamoxifen was suppressed by treatment with DEHP. Flow cytometric analysis revealed that the number of apoptotic cells induced by tamoxifen was significantly decreased by DEHP treatment. Enhanced poly (ADP-ribose) polymerase (PARP) cleavage by tamoxifen treatment was also inhibited by DEHP. These results suggest that DEHP suppresses tamoxifen-induced apoptosis in association with its estrogenic effect in GH3 cells and might counteract the therapeutic effect of tamoxifen.
Keywords: Di-(2-ethylhexyl) phthalate (DEHP); Tamoxifen; Apoptosis; Pituitary; GH3 cells
Irritative effects of fumes and aerosols of bitumen on the airways: results of a cross-shift study by Monika Raulf-Heimsoth; Beate Pesch; Klaus Schott; Martin Kappler; Ralf Preuss; Boleslaw Marczynski; Jürgen Angerer; Hans Peter Rihs; Jens Uwe Hahn; Rolf Merget; Thomas Brüning (pp. 35-44).
Possible health hazards of fumes and aerosols of bitumen are in discussion, and data on their adverse effects on human airways under current exposure conditions are limited. To assess the irritative effects of exposure to fumes and aerosols of bitumen on the airways, a cross-sectional cross-shift study was conducted including external and internal exposure measurements, spirometry and especially non-invasive methods like nasal lavage collection and induction of sputum in order to identify and evaluate more precisely inflammatory process in the upper and lower airways. The cross-shift study comprised 74 mastic asphalt workers who were exposed to fumes and aerosols of bitumen and 49 construction workers without this exposure as reference group. Questionnaire, spirometry, ambient monitoring and urinary analysis were performed. Humoral and cellular parameters were measured in nasal lavage fluid (NALF) and induced sputum. For data analysis, a mixed linear model was performed on the different outcomes with exposure group, time of measurement (pre-, post-shift), current smoking, German nationality and age as fixed factors and subjects as random factor. Based on personal exposure measurements during shift, mastic asphalt workers were classified into a low (≤10 mg/m3; n = 46) and a high (>10 mg/m3; n = 28) exposure group. High exposure was accompanied by significant higher urinary post-shift concentrations of 1-hydroxypyrene and the sum of hydroxyphenanthrenes. Acute respiratory symptoms were reported more frequently in the high exposure group after shift. Significant cross-shift declines in lung function parameters (forced expiratory volume in 1 s [FEV1 (% predicted)] and forced vital capacity [FVC (% predicted)]) were measured in mastic asphalt workers. Pre-shift FEV1 (% predicted) and FVC (% predicted) were higher in the low exposure group. In pre- and post-shift NALF samples, interleukin (IL)-1β-, IL-8- and total protein concentrations were lower in the low exposure group compared to the reference and the high exposure group. Pre- and post-shift neutrophil percentages in both nasal and sputum samples were also lower in the low exposure group. Significantly higher pre- and post-shift sputum concentrations of IL-8, IL-6, nitrogen oxide (NO) derivatives and total protein were detected especially in highly exposed workers. Irritative effects of exposure to fumes and aerosols of bitumen on the upper and lower airways were apparent, especially in mastic asphalt workers with exposure above 10 mg/m3.
Keywords: Bitumen; Irritative effects; Cross-shift design; Biomarkers; Non-invasive methods
Protection effect of piper betel leaf extract against carbon tetrachloride-induced liver fibrosis in rats by Shun-Chieh Young; Chau-Jong Wang; Jing-Jing Lin; Pei-Ling Peng; Jui-Ling Hsu; Fen-Pi Chou (pp. 45-55).
Piper betel leaves (PBL) are used in Chinese folk medicine for the treatment of various disorders. PBL has the biological capabilities of detoxication, antioxidation, and antimutation. In this study, we evaluated the antihepatotoxic effect of PBL extract on the carbon tetrachloride (CCl4)-induced liver injury in a rat model. Fibrosis and hepatic damage, as reveled by histology and the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were induced in rats by an administration of CCl4 (8%, 1 ml/kg body weight) thrice a week for 4 weeks. PBL extract significantly inhibited the elevated AST and ALT activities caused by CCl4 intoxication. It also attenuated total glutathione S-transferase (GST) activity and GST α isoform activity, and on the other hand, enhanced superoxide dismutase (SOD) and catalase (CAT) activities. The histological examination showed the PBL extract protected liver from the damage induced by CCl4 by decreasing α-smooth muscle actin (α-sma) expression, inducing active matrix metalloproteinase-2 (MMP2) expression though Ras/Erk pathway, and inhibiting TIMP2 level that consequently attenuated the fibrosis of liver. The data of this study support a chemopreventive potential of PBL against liver fibrosis.
Keywords: Piper betel leaf; Liver fibrosis; Glutathione S-transferase; α-smooth muscle actin; Matrix metalloproteinase-2
Di-(2-ethylhexyl)-phthalate affects lipid profiling in fetal rat brain upon maternal exposure by Yan Xu; Shruti Agrawal; Thomas J. Cook; Gregory T. Knipp (pp. 57-62).
Lipids, especially essential fatty acids (EFAs), play critical roles in guiding proper fetal development. Exposure to xenobiotics that may alter the fetal supply of EFAs/lipids could potentially lead to fetotoxicity. In this study, we investigated the effects of the peroxisome proliferator chemical, di-(2-ethylhexyl)-phthalate (DEHP), on the lipid metabolomic profile of the rat fetal brain upon maternal exposure during gestation. Female Sprague–Dawley rats were orally gavaged with a control vehicle or DEHP (1,500 mg/kg) from gestational day (GD) 0 to GD 19 and fetal brain tissue was isolated at GD 20. The concentrations of 11 lipid classes [free fatty acid, free cholesterol (FC), cholesterol ester (CE), diacylglycerol (DAG), triacylglyceride, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine (PS), lysophosphatidylcholine (LYPC), cardiolipin, and sphingomyelin (SM)] were determined, as well as the differences in the composition of individual fatty acids. The total lipid concentration decreased with DEHP exposure, particularly for FC and SM, by 33 and 54%, respectively. The same trend was observed in the fatty acid compositions, particularly the unsaturated fatty acids, where a greater decrease was observed with longer fatty acid chain length. The compositions of docosahexaenoic acid decreased significantly in five lipid classes (P < 0.05), including CE (43%), DAG (60%), PS (33%), LYPC (35%), and SM (40%). In contrast, the most remarkable reduction of arachidonic acid presented in two lipid classes, CE and LYPC, with a decrease of up to 33%. These results suggest that in utero exposure to DEHP alters the lipid metabolome in the fetal brain, which may lead to aberrant neurodevelopment.
Keywords: DEHP; Rat; Placenta; Lipomics; Metabolome
Lack of in vivo mutagenicity and oxidative DNA damage by flumequine in the livers of gpt delta mice by Yuichi Kuroiwa; Takashi Umemura; Akiyoshi Nishikawa; Keita Kanki; Yuji Ishii; Yukio Kodama; Ken-ichi Masumura; Takehiko Nohmi; Masao Hirose (pp. 63-69).
Flumequine (FLU), an anti-bacterial quinolone agent, has been recognized as a non-genotoxic carcinogen for the mouse liver, but recent reports have suggested that some genotoxic mechanism involving oxidative DNA damage may be responsible for its hepatocarcinogenesis. In the present study, we investigated this possibility in the mouse liver using male and female B6C3F1 gpt delta mice fed diet containing 0.4% FLU, a carcinogenic dose, for 13 weeks. Measurements of 8-hydroxydeoxyguanosine levels in liver DNA, and gpt point and deletion mutations revealed no significant increases in any of these parameters in either sex. Histopathologically, centrilobular swelling of hepatocytes with vacuolation was apparent, however, together with significant increase in bromodeoxyuridine-labeling indices in the treated males and females. These results suggest that genotoxicity, including oxidative DNA damage, is not involved in mouse hepatocarcinogenesis by FLU, which might rather solely exert tumor-promoting effects in the liver.
Keywords: Flumequine; In vivo mutagenicity; Oxidative DNA damage; Cell proliferation; gpt delta mouse
Weakness in the mechanical properties of the femur of growing female rats exposed to cadmium
by Małgorzata M. Brzóska; Katarzyna Majewska; Janina Moniuszko-Jakoniuk (pp. 71-71).
International course on Laboratory Animal Science, Utrecht, The Netherlands, July 9–20, 2007
by Stephan van Meulebrouck MA (pp. 73-73).