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Archives of Toxicology (v.77, #12)
Glutamate increases toxicity of inorganic lead in GT1-7 neurons: partial protection induced by flunarizine by Jarkko Loikkanen; Jonne Naarala; Kirsi H. Vähäkangas; Kai M. Savolainen (pp. 663-671).
Recent studies point to an interaction between the glutamatergic neurotransmitter system and inorganic lead (Pb) neurotoxicity. Pb (1–100 µM) evoked cytotoxicity over the period of 72 h in mouse hypothalamic GT1-7 neurons. Glutamate (0.1 or 1 mM) on its own did not have any effect on cell viability. However, 1 mM glutamate clearly increased Pb-induced cell death at 48 and 72 h. Although flunarizine (0.1–10 µM), an antagonist of L- and T-type voltage-sensitive calcium channels (VSCCs), partially protected from the cytotoxicity induced by co-exposure to Pb (10 or 100 µM) and glutamate (1 mM), it had no protective effect on cytotoxicity induced by Pb alone. The flunarizine-induced protection was dependent on time and observed only at 48 h. Neither verapamil, an antagonist of L-type VSCCs, nor DIDS, an inhibitor of anion exchange, at non-toxic concentrations (0.1–10 µM) had any effect on cytotoxicity induced by Pb alone or together with glutamate at any studied time point. Co-exposure to Pb and glutamate also resulted in more prominent production of reactive oxygen species (ROS) than either of the compounds alone. Interestingly, we observed an increase in intracellular glutathione (GSH) levels in cells exposed to micromolar concentrations of Pb. Glutamate decreased the levels of intracellular GSH and also partially reduced the Pb-induced increase in GSH levels. These results suggest that the interaction of glutamate and Pb results in increased neuronal cell death via mechanisms that involve an increase in ROS production, a decrease in intracellular GSH defense against oxidative stress and probably T-type VSCCs.
Keywords: Lead; Glutamate; Reactive oxygen species; Glutathione; Calcium channels; Neurons
Biomonitoring of aromatic amines VI: determination of hemoglobin adducts after feeding aniline hydrochloride in the diet of rats for 4 weeks by I. Zwirner-Baier; K. Deckart; R. Jäckh; H.-G. Neumann (pp. 672-677).
The assessment of the carcinogenic properties of aniline is still controversial. Aniline has, if at all, genotoxic properties but is also acutely toxic and it has been proposed that the hematotoxic effects are responsible for the formation of hemangiosarcomas and fibrosarcomas in the spleen of male rats. As part of a bigger project in which the pathology of male Fischer F344 rats was studied after feeding 10, 30, or 100 mg/kg body weight aniline hydrochloride for 1 and 4 weeks in the diet, the aniline–hemoglobin (Hb) adducts were determined as a biochemical effect marker during those periods. An improved method for the work-up procedure and the adduct analysis was developed for this purpose. The Hb adduct levels increased proportionately with dose after 1 week, which indicates that metabolic activation was not saturated. After 4 weeks of feeding, the adduct levels increased less than proportionately, which suggests that a saturation process is involved. Since it is unlikely that metabolic activation was saturated, the results could be explained by a more rapid clearance of stressed erythrocytes at the carcinogenic dose level. The latter interpretation is supported by other observations which indicate that erythrocytes are damaged dose dependently. A no-observed-effect level (NOEL) has not been reached but could be close to the low dose of 10 mg/kg body weight per day. The Hb adduct formation at the low dose, however, indicates that this should not be considered a no-effect level (NEL). The results support the conclusion that hemolytic anemia is an essential prerequisite for aniline toxicity and tumor development, but they do not fully explain the tissue specificity.
Keywords: Aniline; Hemoglobin adduct; Toxicity; Carcinogenicity; Dose dependence
Transcellular signalling pathways and TNF-α release involved in formation of reactive oxygen species in rat alveolar macrophages exposed to tert-butylcyclohexane by Berit Bjugan Aam; Oddvar Myhre; Frode Fonnum (pp. 678-684).
In the present work, the effects of aliphatic (n-nonane and n-decane), alicyclic (1,2,4-trimethylcyclohexane and tert-butylcyclohexane, t-BCH) and aromatic (trimethylbenzene and tert-butylbenzene) hydrocarbon solvents on formation of reactive oxygen species (ROS) and the proinflammatory cytokine TNF-α in rat alveolar macrophages (AM) have been investigated. Formation of ROS was assessed by monitoring oxidation of 2′,7′-dichlorofluorescin to 2′,7′-dichlorofluorescein (DCF), and the proinflammatory cytokine tumour necrosis factor α (TNF-α) was detected using an enzyme-linked immunosorbent assay. DCF fluorescence was elevated in a concentration-dependent manner by the alicyclic hydrocarbons. The involvement of transcellular signalling pathways in the production of ROS by t-BCH, the most active compound, was elucidated by use of specific inhibitors. Preincubation of the AM with the mitogen-activated protein kinase (ERK 1/2) inhibitor U0126, the protein kinase C inhibitor bisindolylmaleimide, the superoxide dismutase inhibitor diethyldithiocarbamate, and the iron ion chelating agent deferoxamine reduced the DCF fluorescence significantly. t-BCH gave an increase in TNF-α release. Further, nitric oxide production measured by a modified Griess method, and intracellular calcium concentration measured by fura-2, were increased in the rat AM after exposure to t-BCH.
Keywords: Hydrocarbon solvents; Reactive oxygen species; Alveolar macrophages; Intracellular pathways
Apoptosis and oxidative stress induced by ochratoxin A in rat kidney by József Petrik; Tihana Žanić-Grubišić; Karmela Barišić; Stjepan Pepeljnjak; Božica Radić; Željko Ferenčić; Ivana Čepelak (pp. 685-693).
Ochratoxin A (OTA) is a widespread mycotoxin produced by several species of fungi. OTA induces a tubular-interstitial nephropathy in humans and in animals. It has been implicated as one of the aetiological agents involved in the development of endemic nephropathy. OTA-induced oxidative stress and apoptosis may play key roles in the development of chronic tubulointerstitial nephritis connected to the long-term exposure to this food contaminant. We studied the effects of low doses of OTA on kidney cells. Wistar rats were treated with 120 μg OTA/kg bodyweight daily, for 10, 30 or 60 days. Toxin concentration in kidney was proportional to the time of exposure, and amounted to 547.2, 752.5 and 930.3 ng OTA/g kidney tissue after 10, 30 and 60 days, respectively. OTA treatment caused an increased number of cells undergoing apoptosis in both proximal and distal epithelial kidney cells. The apoptotic cells were visualised using the TUNEL assay and staining with haematoxylin and eosin in situ. The number of apoptotic cells in rats treated for 10, 30 and 60 days increased by 5-, 6.4- and 12.7-fold, respectively, compared with the control cells. However, DNA electrophoresis did not show characteristic fragmentation (DNA laddering). The oxidative stress was evident via increased malondialdehyde formation. The concentration of lipid peroxides showed an increase (36%), but the activity of superoxide dismutase decreased (26%) in 60-day treated rats. In spite of the observed biochemical and morphological changes in the kidney cells, renal functional status was preserved to the end of experiment. This study demonstrates that a combination of morphologic and biochemical markers can be used to monitor early cell death in OTA-induced renal injury. We have shown that the exposure to the relatively low OTA concentrations has activated apoptotic processes and oxidative damage in kidney cells.
Keywords: Ochratoxin A; Apoptosis; Oxidative stress; Proximal tubule cells; Rat kidney
Time-course of cadmium-induced acute hepatotoxicity in the rat liver: the role of apoptosis by Konstantinos N. Tzirogiannis; Georgios I. Panoutsopoulos; Maria D. Demonakou; Rosa I. Hereti; Katerina N. Alexandropoulou; Aristidis C. Basayannis; Michael G. Mykoniatis (pp. 694-701).
Exposure to toxic metals and pollutants is a major environmental problem. Cadmium is a metal causing acute hepatic injury but the mechanism of this phenomenon is poorly understood. In the present study, we investigated the mechanism and time-course of cadmium-induced liver injury in rats, with emphasis being placed on apoptosis in parenchymal and nonparenchymal liver cells. Cadmium (3.5 mg/kg body weight) was injected intraperitoneally and the rats were killed 0, 9, 12, 16, 24, 48 and 60 h later. The extent of liver injury was evaluated for necrosis, apoptosis, peliosis, mitoses and inflammatory infiltration in hematoxylin–eosin-stained liver sections, and by assaying serum enzyme activities. The number of cells that died via apoptosis was quantified by TUNEL assay. The identification of nonparenchymal liver cells and activated Kupffer cells was performed histochemically. Liver regeneration was evaluated by assaying the activity of liver thymidine kinase and by the rate of 3H-thymidine incorporation into DNA. Both cadmium-induced necrotic cell death and parenchymal cell apoptosis showed a biphasic elevation at 12 and 48 h and peaked at 48 and 12 h, respectively. Nonparenchymal cell apoptosis peaked at 48 h. Peliosis hepatis, another characteristic form of liver injury, was first observed at 16 h and, at all time points, closely correlated with the apoptotic index of nonparenchymal liver cells, where the lesion was also maximial at 48 h. Kupffer cell activation and neutrophil infiltration were minimal for all time points examined. Based on thymidine kinase activity, liver regeneration was found to discern a classic biphasic peak pattern at 12 and 48 h. It was very interesting to observe that cadmium-induced liver injury did not involve inflammation at any time point. Apoptosis seems to be a major mechanism for the removal of damaged cells, and constitutes the major type of cell death in nonparenchymal liver cells. Apoptosis of nonparenchymal cells is the basis of the pathogenesis of peliosis hepatis. The first peaks of necrosis and parenchymal cell apoptosis seem to evolve as a result of direct cadmium effects whereas the latter ones result from ischemia.
Keywords: Apoptosis; Cadmium; Hepatic regeneration; Necrosis; Peliosis; Rat liver; Toxicity
Toxicity and carcinogenicity of Elmiron in F344/N rats and B6C3F1 mice following 2 years of gavage administration by Kamal M. Abdo; Jerry D. Johnson; Abraham Nyska (pp. 702-711).
Elmiron (sodium pentosan polysulfate) is used for the relief of urinary bladder pain associated with interstitial cystitis. The National Toxicology Program (NTP) tested this compound because of its orphan drug status and lack of information about its chronic toxicity and carcinogenicity. Groups of 50 male and 50 female F344/N rats were given Elmiron in de-ionized water by gavage at doses of 0, 14, 42, or 126 mg/kg to males and 0, 28, 84, or 252 mg/kg to females once daily, 5 days per week, for up to 2 years. The same numbers of male and female B6C3F1 mice were dosed similarly with 0, 56, 168, or 504 mg/kg. Elmiron administration produced no effect on the body weight of rats, male mice, or low- and mid-dose groups of female mice. The body weights of the high-dose female mice were significantly decreased relative to those of controls. Pairwise comparison showed that survival of all dosed groups of rats and mice was similar to that of the controls. Elmiron was not carcinogenic in F344/N rats. An increased incidence of liver hemangiosarcoma provided evidence of some carcinogenic activity for Elmiron in male B6C3F1 mice. Increased incidences of liver hemangiosarcoma, hepatocellular neoplasms (predominantly adenomas), and malignant lymphomas revealed carcinogenic activity of Elmiron in female B6C3F1 mice. Elmiron administration produced elevated occurrences of nonneoplastic lesions, such as vacuolated histiocytes in the rectum, lung, spleen (males only), and mesenteric lymph node in rats and liver, rectum, mesenteric lymph node, and spleen in mice. Myxomatous change, chronic inflammation, and squamous metaplasia (mice only) were observed in the large intestine, and lymphohistiocytic hyperplasia was found to be increased in the spleen of rats of both sexes treated with the highest dose. In the latter lesion, the histiocytes contained pale, finely granular cytoplasm and were not considered to represent the same change as the vacuolated histiocytes seen in the mesenteric lymph node and rectum. Under the conditions of these 2-year studies, Elmiron was carcinogenic to mice but not rats.
Keywords: Elmiron; Sodium pentosan polysulfate; Rodents; Toxicity; Carcinogenicity
Genotoxicity of benomyl and its residues in somatic and germ cells of mice fed on treated stored wheat grains by Soheir M. Amer; Souria M. Donya; Fawzia A. E. Aly (pp. 712-721).
Swiss mice were fed for 2, 4 and 8 weeks wheat grains treated with 1, 2, and 4 g benomyl/kg and stored for 6 and 12 weeks. The maximum effect of benomyl on the induction of chromosomal aberrations was observed after feeding mice for 8 weeks with wheat grains treated with 4 g benomyl/kg and stored for 12 weeks. Its proportion differed significantly in bone marrow and spermatocyte cells, 15±0.51% vs. 13.4±0.66%, respectively, from that in nontreated mice (background level), 4.4±0.24% and 3.8±0.20%, respectively. Lengthening the storage period of treated wheat grains caused a dose-dependent increase in the frequency of sister chromatid exchanges: 8.61±0.34 vs. 4.16±0.06/cell. The proportion of sperm-head abnormalities increased by lengthening the period of storage and feeding: 7.7±0.41% vs. 3.25±0.12%. In another experiment mice were orally treated by gavage with benomyl at 50, 100, 150, 200 mg/kg; a significant and dose-dependent increase in sperm-head abnormalities was observed. These findings demonstrate that benomyl (a 50% wettable powder formulation) and its residues in wheat grains are genotoxic in mice.
Keywords: Stored wheat grains; Benomyl; Chromosome aberrations (mouse); Sister chromatid exchanges; Sperm-head abnormalities