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Archives of Toxicology (v.77, #2)
Arsenic species excretion after dimercaptopropanesulfonic acid (DMPS) treatment of an acute arsenic trioxide poisoning by R. Heinrich-Ramm; K. Schaller; J. Horn; J. Angerer (pp. 63-68).
We studied the urinary excretion of the different arsenic species in urine samples from a young man who tried to commit suicide by ingesting about 0.6 g arsenic trioxide. He received immediate therapy with dimercaptopropanesulfonic acid (DMPS) after his delivery into the hospital. We assessed urinary arsenite (inorganic trivalent arsenic), arsenate (inorganic pentavalent arsenic), pentavalent dimethylarsinic acid (DMA) and pentavalent monomethylarsonic acid (MMA) in urine with ion-exchange chromatography and on-line hydride-technique atomic absorption spectrometry. The predominant amount of the excreted arsenic was unchanged trivalent inorganic arsenic (37.4%), followed by pentavalent inorganic arsenic (2.6%), MMA (2.1%), DMA (0.2%) and one unidentified arsenic species (0.7%, if calculated as DMA). In the first urine voiding in the clinic, the total arsenic concentration was 215 mg/l, which fell 1000-fold after 8 days of DMPS therapy. A most striking finding was the almost complete inhibition of the second methylation step in arsenic metabolism. As mechanisms for the reduced methylation efficiency, the saturation of the enzymatic process of arsenic methylation, the high dosage of antidote DMPS, which might inhibit the activity of the methyl transferases, and analytical reasons are discussed. The high dosage of DMPS is the most likely explanation. The patient left the hospital after a 12-day treatment with antidote.
Keywords: Arsenic intoxication Urinary arsenic species Antidote therapy Dimercaptopropanesulfonic acid (DMPS)
Cadmium-induced ectopic apoptosis in zebrafish embryos by Po Chan; Shuk Cheng (pp. 69-79).
In this study, we tested the hypothesis that cadmium-induced developmental toxicity was mediated via ectopic occurrence of apoptosis during embryonic development. We employed confocal microscopy to acquire images of whole-mount staining of apoptotic cells in zebrafish embryo exposed to 100 µM cadmium from 5 hours post fertilisation (hpf) to 28 hpf. Three-dimensional reconstruction of the images was performed and the spatial and temporal distributions of apoptotic cells in the embryos were compared. In cadmium-treated embryos with varying degrees of gross developmental malformations, significantly higher numbers of apoptotic cells were detected with this method. In order to detect the precise locations of apoptotic cells, we performed terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay in sectioned embryos. In the degenerating neural tube of cadmium-treated embryos apoptotic cells were detected, while in the healthy neural tube of the untreated controls no apoptotic cells were found. We then employed flow cytometry to investigate whether cadmium exposure would affect the dynamics of apoptosis or induce any abnormalities in cell-cycle progression. It appeared that cadmium did not induce cell-cycle arrest. The percentages of apoptotic cells did not differ in the two groups at 13, 16 or 19 hpf. At 28 hpf, however, a significantly higher percentage of apoptotic cells were found in the cadmium-treated group. Exposure to cadmium, therefore, induced ectopic apoptosis at 28 hpf without affecting the dynamics of apoptosis at earlier developmental stages.
Keywords: Cadmium Apoptosis Zebrafish embryos Confocal microscopy TUNEL assay Flow cytometry
New approaches to the metabolism of xylenes: verification of the formation of phenylmercapturic acid metabolites of xylenes by Luis Gonzalez-Reche; Thomas Schettgen; Jürgen Angerer (pp. 80-85).
It was the aim of this study to ascertain whether xylenes form phenylmercapturic acids via aromatic epoxides in the human metabolism. Aromatic epoxides are suspected to exert mutagenic properties. Therefore we developed an LC/MS/MS procedure for the determination of these mercapturic acids. Using this method we were able to detect dimethylphenylmercapturic acid (DPMA) in urine samples of persons occupationally exposed to xylenes. The unequivocal LC/MS/MS detection of phenylmercapturic acid metabolites of xylene thanks to authentic standards was verified with an independent GC/MS method. Xylene concentrations in the air of the workplaces ranged between 0.7 and 58.1 ppm (median 12.6 ppm). The excretion of methylhippuric acid in the urine samples of the workers (n=27) ranges from 19.8 to 2332.5 mg/l (median 450.9 mg/l). DPMA was detected in only 9 samples of 27 exposed persons. According to a rough calculation DPMA is only formed in a ratio of 0.0003% respective to the xylene main metabolite MHA. That means that even under occupationally relevant xylene exposure potential mutagenic potencies should be negligible. DPMA in urine is not sensitive enough for general biomonitoring purposes due to the low ratio of excretion. MHA should therefore be used for biomonitoring from now on. Furthermore, our results show that irrespective of the structure of xylene isomers there is no preferences in metabolism.
Keywords: Mercapturic acids Alkylbenzenes Biological monitoring HPLC/MS/MS Human urine
In vitro activation of dibromoacetonitrile to cyanide: role of xanthine oxidase by Ahmed M. Mohamadin; Ashraf B. Abdel-Naim (pp. 86-93).
Dibromoacetonitrile (DBAN) is a disinfection byproduct of chlorination of drinking water. Epidemiological studies indicate that it might present a potential hazard to human health. The present work provides evidence for DBAN activation to cyanide (CN–) by the hypoxanthine (HX)/xanthine oxidase (XO)/iron (Fe) system in vitro. Optimum conditions for the oxidation of DBAN to CN–were characterized. Addition of the sulfhydryl compounds glutathione, N-acetyl-L-cysteine or dithiothreitol significantly enhanced the rate of CN–release. A high positive correlation existed between hydroxyl free radical (•OH) generation and CN– formation. Addition of the •OH scavengers mannitol or dimethylthiourea to the reaction mixtures resulted in a significant decrease in the rate of DBAN oxidation. Addition of the antioxidant enzymes catalase or superoxide dismutase resulted in a significant decrease in the rate of DBAN oxidation. The iron chelator desferrioxamine significantly decreased CN– formation. The maximum velocity (V max) and Michaelis-Menten constant (K m) of the reaction were assessed. Allopurinol competitively inhibited the reaction, while folic acid uncompetitively inhibited the reaction. In conclusion, •OH generated by the HX/XO/Fe system are implicated in DBAN oxidation. The present results represent a novel pathway for DBAN activation and might be important in explaining DBAN-induced toxicity.
Keywords: Dibromoacetonitrile Cyanide Xanthine oxidase
Comparative effect of benzanthrone and 3-bromobenzanthrone on hepatic xenobiotic metabolism and anti-oxidative defense system in guinea pigs by Ravindra P. Singh; Raj Khanna; Jawahar L. Kaw; Subhash K. Khanna; Mukul Das (pp. 94-99).
Benzanthrone (BA) and 3-bromobenzanthrone (3-BBA) are important dye intermediates used in the manufacture of various vat and disperse dyes. BA has been implicated as a cause of hepatic malfunctions and dermal lesions in workers. However, not much information on halogenated BAs, especially 3-BBA, is available. Experiments were designed to undertake a comparative safety assessment of both BA and 3-BBA, given orally at a dose of 50 mg/kg body weight for 10 days to guinea pigs. There was a significant decrease (25%) in body weight with 3-BBA, whereas BA treatment did not cause any change. Serum glutamate oxaloacetate transaminase and glutamate pyruvate transminase were found to be significantly (P<0.05) increased in 3-BBA- as well as in BA-treated animals. 3-BBA and BA led to substantial depletion of ascorbic acid in both liver and adrenal glands. However, depletion of ascorbic acid was more pronounced with 3-BBA (19.2–28.3%) than with BA (13.5–16.6%). 3-BBA and BA treatments caused 80% and 24% depletion of hepatic free sulfydryl content, while lipid peroxidation showed a significant enhancement of 73% and 47%, respectively. BA and 3-BBA caused decreases in cytochrome P-450 content and phase I enzymes particularly ethoxyresorufin-O-deethylase and aryl hydrocarbon hydroxylase, whereas phase II enzymes (quinone reductase and glutathione-S-transferase) were substantially increased. Activities of bio-antioxidant enzymes, viz., glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase, were significantly increased by 153, 104, 20 and 67% in the 3-BBA-treated group, whereas the degree of increase in these parameters was relatively less in BA-treated group. The data indicate that both BA and 3-BBA can disturb membrane integrity by decreasing endogenous glutathione and ascorbic acid levels with a concomitant increase in lipid peroxidative damage. This may in turn lead to impairment of hepatic P-450-dependent monooxygenase, while the changes in antioxidant enzymes reveal oxidative stress. 3-BBA treatment caused dilation of portal triad with thickening of arterial wall, hyperplasia of Kupffer cells and influx of inflammatory cells between hepatic cords, which could be due to formation of Br• radical or due to formation of semiquinone type of intermediate following oxidation. The results may be interpreted to mean that industrial workers exposed to 3-BBA are at higher risk than those exposed to BA, and necessary precautions should be taken to safeguard their exposure risks.
Keywords: Ascorbic acid Glutathione Lipid peroxidation 3-Bromobenzanthrone Benzanthrone Bio-antioxidant enzymes
Humic acid mediates iron release from ferritin and promotes lipid peroxidation in vitro: a possible mechanism for humic acid-induced cytotoxicity by Kuo-Jang Ho; Tsung-Kwei Liu; Tien-Shang Huang; Fung-Jou Lu (pp. 100-109).
Humic acid (HA) has been shown to be a toxic factor for many mammalian cells, however the specific mechanism of the cytotoxicity induced by HA remains unclear. From the assessment of its redox properties, HA has been shown to be capable of reducing iron(III) to iron(II) in aqueous conditions over a broad range of pH values (from 4.0 to 9.0). By using thiobarbituric acid-reactive substances as an index, the presence of HA was noted to increase the extent of lipid peroxidation both for linoleic acids and within rat liver microsomes. In addition, the increase in HA-induced lipid peroxidation is partially inhibited by sodium azide (a singlet oxygen scavenger) or disodium 4,5-dihydroxy-1,3-benzene-disulfonic acid (a superoxide scavenger), reflecting the involvement of singlet oxygen and superoxide in the process of lipid peroxidation. The addition of HA into a reaction system has been shown to generate superoxide in a dose-dependent manner by the superoxide dismutase-inhibitable cytochrome c reduction assay. In addition, HA is able to reduce and release iron from ferritin, but this process is partially inhibited by superoxide scavengers. Subsequently, the iron released from ferritin was shown to accelerate the HA-induced lipid peroxidation. From our results we conclude that HA has the ability to reduce and release iron from ferritin storage as well as to promote lipid peroxidation. Therefore, HA coupled with released iron can disturb the redox balance and elicit oxidative stress within a biological system. This may be one of the most important mechanisms for HA-induced cytotoxicity.
Keywords: Humic acid Lipid peroxidation Superoxide Iron Ferritin
Changes in expression and immunolocalization of protein associated with toxic bile salts-induced apoptosis in rat hepatocytes by Seon-Hee Oh; Ki-Jung Yun; Ji-Xing Nan; Dong-Hwan Sohn; Byung-Hoon Lee (pp. 110-115).
Cholestatic liver injury results from the accumulation of toxic bile salts within the liver. The aim of the present study was to examine the temporal changes in expression and immunolocalization of protein associated with apoptosis in cholestatic rat liver. Rats were anesthetized and cholestasis was induced by double ligation of the common bile duct and sectioning between the ligatures. The animals were euthanized at day 3 and at weeks 1, 2, 4, and 6 after bile duct ligation (BDL). Apoptotic cell death was increased fivefold after 3 days of BDL, decreased over 2 weeks, and remained constant thereafter as has been demonstrated by TUNEL staining. Western blot analysis for Bax, Bcl-2, cytochrome c, and p53 were performed. Results show that total cellular Bax protein was increased 3 days after BDL and decreased over time thereafter. We observed the translocation of Bax to mitochondria and subsequent release of cytochrome c. According to our immunohistochemical data, nuclear p53 increased 3 days after BDL, but cytoplasmic sequestration of p53 was observed after 1 week. The expression of c-Myc was inhibited by 3 days, but increased at later stages following BDL. Bcl-2 was increased over time in BDL rats. Our data suggest toxic bile salts-induced hepatocellular apoptosis is related to differential expression of Bcl-2 family member protein and release of cytochrome c. Cellular localization of p53 plays an important role in apoptotic death of hepatocytes in BDL rats.
Keywords: Cholestasis Apoptosis Bax Bcl-2 Cytoplasmic sequestration of p53
Reproductive impairment in Japanese quail (Coturnix japonica) after in ovo exposure to o,p'-DDT by Krister Halldin; Lena Holm; Yvonne Ridderstråle; Björn Brunström (pp. 116-122).
We have previously described various effects in adult Japanese quail consequent on treatment with oestrogenic compounds in ovo. In the present study, the environmental contaminant o,p'-DDT [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2,2-trichloroethane] was administered to quail eggs to further evaluate test endpoints for oestrogenic effects related to reproduction in the Japanese quail. Exposure to 2 mg o,p'-DDT/egg (150 µg/g egg) resulted in impaired sexual behaviour, reduced cloacal gland area and lowered plasma testosterone concentration in males. Females displayed oviductal abnormalities, including retained right oviduct, decreased length of left oviduct, alterations in shell gland morphology and disrupted distribution of carbonic anhydrase in the shell gland. Egg laying was severely impaired. Consequently, a number of endpoints in adult quail may be useful for demonstrating an oestrogen-like mode of action by environmental contaminants during embryonic development.
Keywords: Endocrine disruption Sexual behaviour Reproductive organs Japanese quail o,p'-DDT