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Archives of Toxicology (v.76, #8)

No Title by Rajagopalan Sivaprasad; Manickam Nagaraj; Palaninathan Varalakshmi (pp. 437-441).

The deleterious effect of lead has been attributed to lead-induced oxidative stress with the consequence of lipid peroxidation. The present study was designed to investigate the combined effect of DL-α-lipoic acid (LA) and meso-2,3-dimercaptosuccinic acid (DMSA) on lead-induced peroxidative damages in rat kidney. The increase in peroxidated lipids in lead-poisoned rats was accompanied by alterations in antioxidant defence systems. Lead acetate (Pb, 0.2%) was administered in drinking water for 5 weeks to induce lead toxicity. LA (25 mg/kg body weight per day i.p) and DMSA (20 mg/kg body weight per day i.p) were administered individually and also in combination during the sixth week. Nephrotoxic damage was evident from decreases in the activities of γ-glutamyl transferase and N-acetyl β-D-glucosaminidase, which were reversed upon combined treatment with LA and DMSA. Rats subjected to lead intoxication showed a decline in the thiol capacity of the cell, accompanied by high malondialdehyde levels along with lowered activities of catalase, superoxide dismutase, glutathione peroxidase and glutathione metabolizing enzymes (glutathione reductase, glucose-6-phosphate dehydrogenase, glutathione-S-transferase). Supplementation with LA as a sole agent showed considerable changes over oxidative stress parameters. The study has highlighted the combined effect of both drugs as being more effective in reversing oxidative damage by bringing about an improvement in the reductive status of the cell.

Keywords: Lead acetate DL-α-Lipoic acid, Meso-2,3-dimercaptosuccinic acid Lipid peroxidation Antioxidants

No Title by Pragya Sharma; Zahoor Shah; Sangeeta Shukla (pp. 442-448).

The efficacy of Tiron (4,5-dihydroxybenzene 1,3-disulfonic acid disodium salt) was examined in the treatment of beryllium-induced maternal and developmental toxicity in rats. Single administration of beryllium nitrate at a dose of 50 mg/kg (i.m.) on day 13 of gestation caused reductions in fetal and placental weights, the number of implantation sites and number of corpora lutea, as well as causing post-implantation loss, stunted growth, increase in the number of resorptions, and also a disturbed sex ratio. Maternal toxicity was demonstrated by reduction in body weight gain. Administration of beryllium also showed significant alteration in the hematological and biochemical indices of the mother as well as the fetus. Marked decreases were recorded in hemoglobin percentage, blood sugar levels, serum protein contents and serum alkaline phosphatase activity. By contrast, significant elevation was found in the activity of transaminases (aspartate aminotransferase and alanine aminotransferase). Tissue protein contents, glycogen contents, activities of alkaline phosphatase, adenosine triphosphatase and succinic dehydrogenase of kidney, lungs and uterus, and maternal and fetal liver all showed significantly decreased values after beryllium exposure, and remarkable elevation was observed in acid phosphatase, glucose-6-phosphatase and hepatic lipid peroxidation. These parameters were restored considerably with administration of 471 mg/kg i.m. Tiron from days 14 to 18 of gestation. Atomic absorption spectrophotometry also revealed a high concentration of beryllium in different organs of pregnant rats. Interestingly, a small amount of metal ion was also detected in the fetus and reduced accumulation of beryllium was noticed after Tiron treatment.

Keywords: Beryllium toxicity Developmental toxicity Tiron Chelating agents

No Title by Jan Dreßler; Katja Schulz; Matthias Klemm; R. Schüttig; Arnulf Beuthin; Dieter Felscher (pp. 449-451).

A case of a lethal manganese-cadmium (Mn-Cd) intoxication is reported. The postmortem examination revealed a noticeable reddish-violet discolouration of the serous cutes of all body cavities, but there was no indication of any corrosive burns of the mucous membranes of the gastrointestinal tract. An Mn concentration of 899 µg/l blood and a Cd concentration of 238 µg/l blood were found in the deceased woman. These concentrations are higher than normal levels by a factor of about 100. A subacute or chronic manganese-cadmium absorption must be assumed.

Keywords: Manganese Cadmium Lethal intoxication

No Title by Ali A. Abdel-Rahman; Gregory M. Blumenthal; Sherif A. Abou-Donia; Fouad A. Ali; A. Abdel-Monem; Mohamed B. Abou-Donia (pp. 452-459).

The pharmacokinetics and placental transfer of a single intravenous dose of 5.0 mg/kg (10 µCi/kg) ring-labeled [¹⁴C]chlorpyrifos were investigated in pregnant Sprague-Dawley rats at 11–13 days of gestation. Three rats were killed at 5, 15 or 30 min, or 1, 2, 4, 8, 12, 18, 24, 36, 48, 72 or 96 h after dosing. Radioactivity and 3,5,6-trichloropyridinol (TCP) were detected in all tissues 5 min after dosing. Chlorpyrifos was only found in maternal plasma and liver. Peak maternal plasma concentration of radioactivity (µg chlorpyrifos equivalents/ml) was 157 at 5 min, compared with 1.9 for fetal plasma at 15 min. The maximum concentrations of radioactivity (µg chlorpyrifos equivalents/g), detected in most tissues within 12 h of dosing, were, in descending order: liver (30), brain (29), placenta (21), and fetus (2). All peaks occurred at 5 min except for fetus and fetal plasma, which were at 15 min. TCP was detected by HPLC as the major compound identified in plasma and tissues. The maximum concentration detected was in plasma, at 12.4 µg/ml, and for the following tissues was: liver 4.3 ng/g fresh tissue, fetus 4 ng/g, placenta 2.97 ng/g, brain 1.68 ng/g, and fetal plasma 0.52 ng/g. All TCP peaks occurred at 5 min except for fetus at 30 min and fetal plasma at 15 min. Parent chlorpyrifos was detected in maternal plasma and liver at maximum concentrations of 5.1 µg/ml and 0.40 µg/g, respectively, at 5 min. Chlorpyrifos was detectable in maternal plasma up to 36 h after dosing, and in liver up to 24 h after dosing. Pharmacokinetic analysis best described radioactivity, chlorpyrifos, and TCP as disappearing biexponentially from plasma and tissues. The terminal elimination half-lives of radioactivity, chlorpyrifos and TCP from maternal plasma were 16, 18, and 16 h, respectively. The results indicate that (1) chlorpyrifos undergoes a rapid metabolism to its major metabolites (TCP); (2) chlorpyrifos and its metabolites are distributed to all maternal and fetal tissues and plasma; and (3) the elimination of chlorpyrifos and TCP is slow, with redistribution from lipid stores a likely determinant of elimination rates.

Keywords: Chlorpyrifos Maternal-fetal exchange Pharmacokinetics Tissue distribution Rats

No Title by Örjan Lindhe; Lizette Granberg; Ingvar Brandt (pp. 460-466).

7,12-Dimethylbenz[a]anthracene (DMBA) is an adrenocorticolytic agent that causes apoplexy (haemorrhage) and massive necrosis in the adrenal cortex in rat. Several explanations regarding the origin of toxicity have been proposed. Huggins and Morii (J Exp Med 114:741–60, 1961) suggested that the cells of the inner adrenal cortex are the primary target, whereas Horváth and Kovács (Pathol Eur 8:43–59, 1973) suggested the vascular endothelium as being the origin of toxicity. In the present study, cultured precision-cut tissue slices were used to localize target cells for irreversible [³H]DMBA binding in rat and mouse adrenal cortex. The sites of binding were confirmed by autoradiography in vivo. Irreversible [³H]DMBA binding was confined to zona fasciculata/reticularis cells in rat (but not in mouse) adrenal cortex. Pronounced binding was observed in clusters of cells (focal binding), localized predominantly in zona reticularis of rat. [³H]DMBA binding in zona fasciculata/reticularis cells was inhibited by the cytochrome P450 1A/B (CYP1A/B) inhibitors ellipticine, α-naphthoflavone, and 1-ethynylpyrene. The CYP11B1-inhibitor metyrapone did not reduce [³H]DMBA binding. In CYP1-induced (PCB 126-treated) rats and mice, intense irreversible [³H]DMBA binding was found also in endothelial cells of the adrenal cortex. The endothelial binding was abolished by the CYP1 inhibitors but remained unaffected by metyrapone. We conclude that the metabolic activation in adrenal parenchymal cells is presumably catalysed by CYP1B1, whereas CYP1A1 presumably catalyses the activation in endothelial cells. We suggest that the adrenocorticolytic effect of DMBA is the result of a dual mode of action, targeting both endothelial and parenchymal cells in the rat adrenal cortex.

Keywords: Adrenal Tissue-slice culture Irreversible binding 7,12-Dimethylbenz[a]anthracene Cytochrome P450 1A1/1B1

No Title by Ahmad Sadewa; Yuri Miyabe; Hisahide Nishio; Chiyo Hayashi; Retno Sutomo; Myeong Lee; Hitoshi Ayaki; Naoko Koizumi; Kimiaki Sumino (pp. 467-469).

Itai-itai (ouch-ouch) disease is a syndrome accompanied by bone mineral disorders that may be related to oral cadmium exposure. Itai-itai predominantly affects postmenopausal women with a history of multiple childbirth. In a previous study we have examined the genotype distributions of PvuII and XbaI restriction fragment length polymorphisms of the estrogen receptor α (ERα) gene in patients with itai-itai disease and compared them with those of controls. However, no significant differences were shown between the genotype distributions of the patients and controls. In the present study, we determined the TA repeat polymorphisms of the patients and controls. The distributions of the patients were: HH 25.0%, HL 50.0%, and LL 25.0%; where HH includes two alleles with a high number of TA repeats (TA≥16), HL includes one high number allele and one low number allele (TA≤15), and LL includes two alleles with a low number of TA repeats. These patients' distributions were not significantly different from those of the controls. Although our sample number was limited, we concluded that a polymorphism variant of the ERα gene is not a predisposing factor for itai-itai disease.

Keywords: Itai-itai disease Estrogen receptor TA repeat polymorphisms Restriction fragment length polymorphism

No Title by Irfan Altuntas; Namik Delibas; Mustafa Demirci; Ibrahim Kilinc; Numan Tamer (pp. 470-473).

Methidathion (MD) [O,O-dimethyl S-(2,3-dihydro-5-methoxy-2-oxo-1,3,4-thiadiazol-3-ylmethyl) phosphorodithioate] is one of the most widely used organophosphate insecticides (OPIs) in agriculture and public health programmes. We have, therefore, examined the in vivo and in vitro effects of MD on the serum activities of cholinesterase (ChE), enzymes concerning liver damage and lipid peroxidation (LPO; only in vivo), and have evaluated the ameliorating effects of a combination of vitamins E and C against MD toxicity. The in vivo experimental groups were: control group, MD-treated group (MD), and a group treated with MD plus vitamin E plus vitamin C (MD+Vit). The MD and MD+Vit groups were treated orally with a single dose of 8 mg MD/kg body weight at 0 h. Vitamin E and vitamin C were injected at doses of 150 mg/kg body weight i.m. and 200 mg/kg body weight i.p., respectively, 30 min after the treatment with MD in the MD+Vit group. Blood samples were taken 24 h after the MD administration. For in vitro study, venous blood samples were obtained from volunteers, and serum recovered. The activities of serum enzymes were determined in each sample and these served as 0 h values. Each sample was divided into four portions, each of which served as one of the experimental groups, as follows: control group, vitamin E plus vitamin C group (Vit), MD-treated group (MD) and MD plus vitamin E plus vitamin C group (MD+Vit). Vitamin E and vitamin C were added at doses of 7.5 and 10 µg/ml, respectively, into the Vit and MD+Vit groups. MD was added at doses of 0.4 mg/ml into the MD and MD+Vit groups. The activities of serum enzymes were determined in each sample at 24 h. The results of the in vivo experiment demonstrated that thiobarbituric acid reactive substances were increased in the MD group compared with the control group, and decreased in the MD+Vit group compared with MD group. ChE activity was decreased in both MD and MD+Vit groups compared with controls and increased in the MD+Vit group compared with the MD group. The activities of aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT) and lactate dehydrogenase (LDH) were increased in both the MD and MD+Vit groups compared with the control group. AST activity was decreased in MD+Vit group compared with the MD group. Alanine aminotransferase (ALT) activity was decreased in both the MD and MD+Vit groups compared with control group. The results of in vitro experiment showed that all enzyme activities remained unchanged in both the control and Vit groups compared with values at 0 h. The activities of ChE, ALT and LDH were decreased in both the MD and MD+Vit groups compared with 0 h values. There was no significant difference between the MD and MD+Vit groups. The activities of AST, ALP and GGT remained unchanged in all groups. From these results, it can be concluded that MD caused liver damage, and LPO may be one of the molecular mechanisms involved in MD-induced toxicity. Single-dose treatment with a combination of vitamins E and C after the administration of MD can reduce LPO caused by MD.

Keywords: Methidathion Liver Lipid peroxidation Vitamin E Vitamin C

No Title by Carina Carlsson; Fariba Bahrami; Anders Fredriksson; Ingvar Brandt (pp. 474-483).

Methylsulphonyl-2,6-dichlorobenzene [2,6-(diCl-MeSO₂-B)], and its 2,5-chlorinated isomer [2,5-(diCl-MeSO₂-B)] bind firmly in the olfactory mucosa of mice. Both isomers are also selectively localised in the olfactory bulb. Persistent olfactory mucosal metaplasia is induced by 2,6-(diCl-MeSO₂-B) whereas 2,5-(diCl-MeSO₂-B) has no effects. Furthermore, a strong induction of glial fibrillary acidic protein (GFAP) restricted to the olfactory bulb has been reported in 2,6-(diCl-MeSO₂-B)-treated mice. To explore whether these lesions give rise to early or long-lasting changes in behaviour, spontaneous motor activity and radial arm maze (RAM) learning were examined at 1, 2, 4 and 12 weeks following an intraperitoneal injection of a single low (32 mg/kg) or high (65 mg/kg) dose of 2,6-(diCl-MeSO₂-B). 2,5-(DiCl-MeSO₂-B) (65 mg/kg) was used as a negative control. Hyperactivity was observed in all treatment groups while deficits in the RAM performance was only seen in the 2,6-(diCl-MeSO₂-B)-treated groups. Alterations in motor activity and impaired performance in the RAM-test induced by 2,6-(diCl-MeSO₂-B) persisted up to 2 weeks in the low-dose group and 12 weeks in the high-dose group. The low-dose group consistently showed a less pronounced effect than the high-dose group. The 2,5-(diCl-MeSO₂-B)-induced changes in motor activity declined rapidly and did not remain after 2 weeks. As determined by immunohistochemistry, 2,6-(diCl-MeSO₂-B)-induced GFAP immunoreactivity was mainly confined to the glomerular layer of the olfactory bulb. We propose that the behavioural deficits caused by 2,6-(diCl-MeSO₂-B) result from a primary loss of sensory neurons in the olfactory mucosa with consequent astrocyte proliferation in the glomerular layer of the olfactory bulb. A targeted uptake of metabolites into the olfactory bulb could also contribute to the GFAP induction and/or behaviour response.

Keywords: Locomotion Radial arm maze Olfactory toxicity Aryl methyl sulphone Neurotoxicity

No Title by Yuan-Soon Ho; Hung-Bin Liou; Jen-Kun Lin; Jiiang-Huei Jeng; Min-Hsiung Pan; Yu-Ping Lin; How-Ran Guo; Sheng-Yow Ho; Ching-Chang Lee; Ying-Jan Wang (pp. 484-493).

Nitric oxide (NO) is an environmental pollutant found in smog and cigarette smoke. Recently, NO has been discovered to act as a molecular messenger, mediating various physiological functions. However, when an excess of NO is present, cytotoxic and mutagenic effects can also be induced. The reaction of NO with superoxide results in the formation of peroxynitrite (ONOO^–), which decomposes into the hydroxyl radical and nitrogen dioxide. Both of them are potent oxidant species that may initiate and propagate lipid peroxidation. In the present study, we examined the effects of NO and ONOO^– on the induction of lipid peroxidation and cell death mechanisms in rats and in A549 pulmonary epithelial cells. The results showed that ONOO^– is able to induce lipid peroxidation in pulmonary epithelial cells in a dose-dependent manner. 8-Epi-prostaglandin F₂ _α can serve as a good biomarker of lipid peroxidation both in vitro and in vivo. Postmitotic apoptosis was found in A549 cells exposed to NO, whereas ONOO^– induced cell death more characteristic of necrosis than apoptosis. Apoptosis that occurred in cells may be related to the dysfunction of mitochondria, the release of cytochrome c into cytosol, and the activation of caspase-9. The relationship between caspase activation and the cleavage of other death substrates during postmitotic apoptosis in A549 cells needs further investigation.

Keywords: Peroxynitrite Nitric oxide Lipid peroxidation Apoptosis

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Archives of Toxicology (v.76, #8)

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Archives of Toxicology (v.76, #8)