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Archives of Toxicology (v.68, #9)
Erythroid progenitor cells that survive benzene exposure exhibit greater resistance to the toxic benzene metabolites benzoquinone and hydroquinone by David J. Neun; Arthur Penn; Carroll A. Snyder (pp. 535-540).
Benzene is a well known hematotoxicant which induces hematopoietic dyscrasias of varying intensities in different individuals and even in different strains of the same experimental animal species. Although there is ample evidence that diverse responses to benzene are related to differences in benzene metabolism, we have recently provided evidence implicating differences in host target cell susceptibility to these diverse responses to benzene. The present study extends our previous work and concerns strain-specific differences in marrow progenitor cells that survive benzene exposure. Two mouse strains (Swiss-Webster and C57B1/6J) which respond to benzene exposure with different intensities of bone marrow cytotoxicity were used. Bone marrow cells from benzene-exposed and untreated mice were cultured with one of five benzene metabolites: 1,4-benzoquinone (BQ), catechol (C), hydroquinone (HQ), muconic acid (MA) or phenol (P) and the abilities of these cells to produce erythroid (CFU-e) or granulocyte/macrophage colonies (GM-CFU-c) were assessed. In both strains, marrow cells isolated from benzene-exposed mice showed a higher percentage of plated CFU-e surviving culture with BQ, HQ or MA than marrow cells isolated from control mice. In contrast, both strains of benzene-exposed mice displayed decreased percentages of plated CFU-e surviving culture with catechol than cells isolated from control mice. Only one condition (the culturing of cells with HQ under GM-CFU-c forming conditions) showed any strain-specific difference in plating efficiency. In all, 20 possible combinations of benzene metabolites and cell types were examined (5 metabolites × 2 progenitor cell types × 2 strains). With seven of these combinations, the colony-forming efficiencies were higher for plated cells isolated from benzene-exposed mice than from untreated mice. With three combinations, the colony-forming efficiencies were lower for cells from benzene-exposed mice, and for ten combinations, there were no changes in plating efficiencies. Possible mechanisms for an acquired resistance to the toxicities of benzene metabolites were explored by measuring the concentrations of hepatic and bone marrow sulfhydryl (SH) groups in cells isolated from benzene-exposed and untreated mice. In both strains, benzene exposure induced no changes in hepatic SH concentrations, but the SH content of bone marrow was more than doubled after benzene exposure in both strains. These results suggest that a fraction of hematopoietic progenitor cells are able to survive severe benzene exposure and produce progeny because of a marked increase in marrow SH groups which react with electrophilic benzene metabolites. Moreover, this protective mechanism occurs in two mouse strains with differing susceptibilities to benzene.
Keywords: Benzene; Haematopoiesis; Mice
Aluminum effects on blood chemistry and long bone development in the chick embryo by Conrad E. Firling; Arlen R. Severson; Theresa A. Hill (pp. 541-547).
Body growth, blood chemistry, and long bone development of 10- to 16-day chick embryos (Gallus gallus) treated with aluminum (Al) citrate, sodium (Na) citrate, or sodium chloride (NaCl) were investigated. Two administration protocols were used. Acutely-treated embryos received 6.0 μmol Al citrate or Na citrate on day 8 of incubation. Chronically-treated embryos received a daily dose of 1.5 μmol Al citrate or Na citrate beginning on day 8 of incubation. For both protocols, Al citrate and Na citrate had no significant influence on viability or body weight. Al citrate-treated embryos had: (a) significantly shorter mean tibia lengths by day 16 of incubation, (b) a consistently lower ratio of tibia length: body weight on all days investigated, and (c) a persistent mid-diaphyseal malformation (angulation) of the femur and tibia. Spatially correlated with the malformation was a calcification defect detected by alizarin red S staining of intact tibias and the accumulation of aluminum as demonstrated by acid solochrome azurine staining of histological sections. Aluminum was localized at the mineralization front of the osteogenic collar surrounding the cartilage core of the tibia. Aluminum citrate or Na citrate had no significant effect on serum total calcium, inorganic phosphorus, total alkaline phosphatase activity, or creatinine, except for a transitory hypercalcemia (day 10) and phosphatemia (days 10 and 12) in Al citrate-treated embryos. The concomitant localization of Al and the early calcification defect in the region of tibial malformation implicate aluminum in the pathogenesis of the skeletal abnormality.
Keywords: Aluminum toxicity; Chick embryo; Bone mineralization; Bone development; Citrate
Pulmonary clearance and inflammatory potency of intratracheally instilled or acutely inhaled nickel sulfate in rats by Seishiro Hirano; Tomomi Shimada; Junko Osugi; Naomi Kodama; Kazuo T. Suzuki (pp. 548-554).
Rats were exposed to nickel sulfate (NiSO4) either by intratracheal (IT) instillation or by acute aerosol inhalation, and pulmonary clearance of Ni and pulmonary inflammatory responses were studied. The half-time of Ni in the lung (initial lung burden = 50 μg Ni/rat) was about 32 h in both the IT instillation and inhalation groups. Ni retention in the lung tissue following IT instillation of NiSO4 was saturable with reference to dose, suggesting that clearance rate of Ni from the rat lung depends on lung burden of Ni. Lung inflammatory responses were evaluated by biochemical, elemental and cytological indicators in bronchoalveolar lavage fluid (BALF) following IT instillation of NiSO4. Activities of lactate dehydrogenase and β-glucuronidase, contents of lysozyme, protein, sulfur and calcium, and the number of polymorphonuclear leukocytes were increased with a peak at 2–3 days post-instillation, while BALF alkaline phosphatase (ALP) activity was significantly decreased after IT instillation of NiSO4. Lung tissue ALP activity was also decreased by NiSO4. Because Ni does not inhibit ALP directly, the decrease in ALP activity is probably due to functional changes of type II cells (a major source of BALF ALP). Thiobarbituric acid reacting substances in the lung tissue were not changed by NiSO4, suggesting that lipid peroxidation plays a minimal, if any role, in the Ni-induced inflammation in the rat lung.
Keywords: Nickel sulfate; Intratracheal instillation; Inhalation; Pulmonary clearance; Inflammatory response
Effect of cadmium (CdCl2) on cell proliferation and production of EDRF (endothelium-derived relaxing factor) by cultured human umbilical arterial endothelial cells by Takuji Kishimoto; Tetsuhisa Oguri; Mika Ohno; Kazuo Matsubara; Kazuhiko Yamamoto; Manabu Tada (pp. 555-559).
The effect of cadmium chloride (CdCl2) on cell proliferation and EDRF (endothelium-derived relaxing factor) production by cultured human umbilical arterial endothelial cells (HUAECs) was investigated. The viability of HUAECs decreased dose-dependently after the addition of Cd (cadmium chloride). Morphologic examination by phase contrast microscopy revealed severe damaging effects of Cd at higher concentrations. The cytotoxic effect of Cd on DNA synthesis was also concentration-dependent. The effect of Cd on EDRF production by indomethacin-treated HUAECs was assessed by its anti-platelet aggeragory effect. Platelet aggregation studies were carried out in cuvettes lined with HUAECs using an aggregometer. The anti-platelet aggregatory effect was decreased dose-dependently by pretreatment with Cd. These findings suggest that HUAECs are susceptible to concentration-dependent Cd cytotoxicity, and that Cd can inhibit the production of EDRF by HUAECs.
Keywords: Cadmium; Cell proliferation; Endothelium-derived relaxing factor; Human umbilical arterial endothelial cells
Alteration of glycosaminoglycans induced by cadmium in cultured vascular smooth muscle cells by Toshiyuki Kaji; Susumu Ohkawara; Miho Inada; Chika Yamamoto; Michiko Sakamoto; Hiroshi Kozuka (pp. 560-565).
Alteration of glycosaminoglycans (GAGs) in cultured bovine aortic smooth muscle cells after exposure to cadmium was investigated. It was revealed that cadmium increased the accumulation of GAGs metabolically labeled with [3H]glucosamine but decreased that with [35S]sulfate in the cell fraction, the cell surface fraction and the medium fraction. This suggested that cadmium stimulated the biosynthesis of GAGs but inhibited their sulfation in the cells. A similar alteration was observed in cadmium-treated human aortic smooth muscle cell layer. Of tested cations including cadmium, bismuth, cobalt, copper, lead, manganese, nickel and zinc, only cadmium stimulated [3H]glucosamine incorporation, with a strong inhibition of the [35S]sulfate incorporation in the bovine cells. Characterization of bovine smooth muscle GAGs showed that the cadmium-induced increase in the [3H]glucosamine incorporation was mainly observed in heparan sulfate; the inhibition of the [35S]sulfate incorporation occurred non-selectively. Cadmium accumulated in bovine vascular smooth muscle cells in a dose-dependent manner with an increase in the leakage of lactate dehydrogenase into the medium. The present data suggest that vascular smooth muscle cells respond to the cytotoxicity of cadmium and promote the GAG synthesis with a reduction of their sulfation. It is postulated that this response may be a defensive one to the damage of the vascular tissue caused by cadmium but would be a component of the metal-induced atherosclerosis.
Keywords: Cadmium; Glycosaminoglycans; Heparan sulfate; Vascular smooth muscle cells; Vascular
Dopaminergic system activity and cellular defense mechanisms in the striatum and striatal synaptosomes of the rat subchronically exposed to manganese by M. S. Desole; M. Miele; G. Esposito; R. Migheli; L. Fresu; G. De Natale; E. Miele (pp. 566-570).
In 6-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), uric acid and glutathione (GSH) were determined by HPLC in the striatum and striatal synaptosomes after subchronic oral exposure to MnCl2 50–100–150 mg/kg. Mn significantly decreased levels of DA and GSH and increased levels of DHAA and uric acid both in the striatum and synaptosomes. In synaptosomes, individual total Mn doses/rat were directly correlated with individual DOPAC/DA ratio values (r=+0.647), uric acid (r=+0.532) and DHAA levels (r=+0.889) and inversely correlated with DA (r=−0.757) and GSH levels (r=−0.608). In turn, GSH levels were inversely correlated with uric acid (r=−0.451) and DHAA levels (r=−0.460). In conclusion, the response of striatal cellular defense mechanisms (increase in AA oxidation, decrease in GSH levels) correlated well with changes in markers of dopaminergic system activity and increase in uric acid levels. The latter provides evidence of an Mn-induced oxidative stress mediated by xanthine oxidase.
Keywords: Manganese neurotoxicity; Oxidative stress; GSH; Ascorbic acid; Uric acid; Striatum
Cardiotoxicity of adrenochrome in isolated rabbit hearts assessed by epicardial NADH fluorescence by Alexis F. E. Rump; Wolfgang Klaus (pp. 571-575).
Noradrenaline in a micromolar concentration has recently been shown to contribute to ischemic tissue injury by direct cardiotoxic effects independent of functional alterations. Oxygen free radicals, generated during the auto-oxidation of catecholamines, are important mediators of catecholamine cardiotoxicity. However, the role of the oxidative products (aminochromes) is still unclear. We examined the effects of adrenochrome on functional parameters and on regional myocardial ischemia (MI) in isolated electrically-driven rabbit hearts with depleted catecholamine stores (reserpine 7.0 mg/kg i.p. 16–24 h before preparation, Langendorff, constant pressure: 70 cm H2O, Tyrode solution, Ca++ 1.8 mmol/l, 37°C). Repetitive MI, separated by a reperfusion period of 50 min, was induced by coronary artery branch ligature, and MI was quantitated from epicardial NADH fluorescence photography. Adrenochrome-treatment (10−6 M or 10−4 M) was started after a reperfusion period of 20 min. The left ventricular pressure (LVP) was significantly enhanced by adrenochrome (p<0.05), but it fell thereafter to below its initial value in hearts treated with adrenochrome 10−4 M. The global coronary flow (CF) was not affected by adrenochrome 10−6 M (P>0.05), but it was significantly decreased by adrenochrome 10−4 M (P<0.05). The relative CF (=CF/LVP×heart-rate) was numerically decreased by adrenochrome 10−6 M (p>0.05) and more markedly by adrenochrome 10−4 M (p<0.05). Whereas epicardial NADH fluorescence was similar after repetitive coronary artery occlusions in controls and in hearts treated with adrenochrome 10−6 M (p>0.05), it was significantly enhanced by adrenochrome 10−4 M (p<0.05). In isolated rabbit hearts, adrenochrome possesses deleterious effects on MI only at a very high concentration but not in a micromolar concentration. Therefore, it seems that aminochromes may be less cardiotoxic than catecholamines.
Keywords: NADH fluorescence; Cardiotoxicity; Myocardial ischemia; Adrenochrome; Aminochromes
Ganglioside content of rat liver after administration of ethanol and pentazocine or sucrose supplemented diets by M. J. Ruano; V. S. Martínez-Zorzano; J. A. Cabezas; P. Hueso (pp. 576-581).
In a previous paper, we determined the effect of either ethanol or pentazocine administered separately on the ganglioside content of rat liver. In the present paper we have investigated the effect of pentazocine injection on the liver ganglioside contents of chronic alcoholic rats. The effect of high carbohydrate ingestion was also studied. Thirty male Wistar rats were divided into three experimental groups that received ethanol and pentazocine, a carbohydrate supplemented diet or a laboratory diet and water. Liver ganglioside contents were slightly increased in the ethanol plus pentazocine group as compared to the control and high carbohydrate diet groups. No differences were found between the two latter groups. The percentage distribution of individual gangliosides (ganglioside pattern) was also modified. A decrease in gangliosides belonging to the b-series (GD3, GD1b, GT1b and GQ1b) in parallel with an increase in that of the a-series (GM2, GM1 and GD1a) were found for both the ethanol plus pentazocine and the highcarbohydrate fed rats. The results suggest that ethanol or high carbohydrate ingestion diminishes the activity of GD3 synthase, a key enzyme in the metabolism of gangliosides, which determines the proportion of gangliosides, belonging to the a- and b-series.
Keywords: Liver; Chronic ethanol; Pentazocine; Gangliosides; Sialic acids
Oxidation pathways for the intracellular probe 2′,7′-dichlorofluorescin by Huan Zhu; Gerard L. Bannenberg; Peter Moldéus; Howard G. Shertzer (pp. 582-587).
The oxidation of 2′,7′-dichlorofluorescin (DCFH) to a fluorescent product is currently used to evaluate oxidant stress in cells. However, there is considerable uncertainty as to the enzymatic and nonenzymatic pathways that may result in DCFH oxidation. Iron/hydrogen peroxide-induced DCFH oxidation was inhibited by catalase or by the hydroxyl radical scavenger dimethylsulfoxide; however, superoxide dismutase (SOD) had no effect on DCFH oxidation. The formation of hydroxyl radical (indicated by the oxidation of salicylic acid to 2,3-dihydroxybenzoic acid) was proportional to DCFH oxidation, suggesting that the hydroxyl radical is responsible for the iron/peroxide-mediated oxidation of DCFH. Utilizing a superoxide generating system consisting of hypoxanthine/xanthine oxidase, oxidation of DCFH was unaffected by SOD, catalase or desferoxamine, and stimulated by removing hypoxanthine from the reaction mixture. In contrast, SOD or elimination of hypoxanthine abolished superoxide formation. In addition, potassium superoxide did not support the oxidation of DCFH. Thus, superoxide is not involved in DCFH oxidation. Boiling xanthine oxidase eliminated its concentration-dependent oxidation of 1 μM DCFH, indicating that xanthine oxidase ian enzymatically utilize DCFH as a high affinity substrate. Kinetic studies of the oxidation of DCFH by xanthine oxidase indicated a K m(app) of 0.62μM. Hypoxanthine competed with DCFH with a K i(app) of 1.03 mM. These studies suggest that DCFH oxidation may be a useful indicator of oxidative stress. However, other types of cellular damage may produce DCFH oxidation. For example, conditions or chemicals that damage intracellular membranes may release to the cytoplasm oxidases or peroxidases that might use DCFH as a substrate, similar to xanthine oxidase
Keywords: Dichlorofluorescein; Iron; Hydrogen peroxide; Hydroxyl radical; Oxidative stress; Superoxide anion; Xanthine oxidase
Inhalation toxicokinetics of butoxyethanol and its metabolite butoxyacetic acid in the male Sprague-Dawley rat by Gunnar Johanson (pp. 588-594).
A total of 16 male Sprague-Dawley rats were continuously exposed to 20 ppm or 100 ppm butoxyethanol (BE) vapor for 1, 2, 3, 4, 6, 8, 10, or 12 days. Urine was collected in 24-h intervals and stored at −70°C. At the end of the exposure the animals were euthanized by decapitation and tissue samples of blood, muscle, liver and were rapidly collected and frozen to −70°C. The samples were later derivatized and analyzed for BE and its major metabolite butoxyacetic acid (BAA) by electron capture gas chromatography. BE and BAA were rapidly distributed to the tissues examined. The concentration of BE in blood was slightly higher, and that of BAA markedly higher than in other tissues, indicating weak (BE) and pronounced (BAA) blood protein binding, respectively. BE was efficiently metabolized and the blood clearance averaged 2.6 l/h per kg, corresponding to a hepatic extraction ratio of about 0.75. The renal clearance of BAA (average 0.53 l/h per kg) corresponded to approximately 15% of the renal blood flow. The kinetics of BE and BAA were linear up to 100 ppm. There were no clear indications of changes in the toxicokinetics, such as metabolic induction or inhibition of metabolism or excretion, during the course of the exposure. The recovery of BAA in urine was 64% of the calculated inhaled amount of BE, on an equimolar basis.
Keywords: Analysis; Butoxyacetic acid; Butoxyethanol; Gas chromatography; Glycol ethers; Metabolism; Rat
Porphyrin studies in TCDD-exposed workers by Detlev Jung; Johannes Konietzko; Gertraud Reill-Konietzko; Axel Muttray; Herbert -Josef Zimmermann-Hölz; Manfred Doss; Hans Beck; Lutz Edler; Annette Kopp-Schneider (pp. 595-598).
2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin (TCDD) has been shown to inhibit uroporphyrinogen decarboxylase activity resulting in chronic hepatic porphyria. From a cross-sectional study of 170 workers in chemical industry 68 showed elevated coproporphyrin levels, interpreted as secondary coproporphyrinuria. Three persons suffered from chronic hepatic porphyria in subclinical stages. None of the workers showed an overt porphyria cutanea tarda. A lowgrade zinc protoporphyrinemia was observed in three persons. Forty-three of the 170 workers were evaluable for investigating the effect of TCDD on porphyrin levels. No significant correlation was found between TCDD concentration in adipose tissue and the level of uroporphyrin and coproporphyrin. The influence of a chloracne history is described.
Keywords: Dioxins; Epidemiology; Porphyrins; Tetrachlorodibenzodioxins