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Archives of Toxicology (v.71, #12)

Influence of particle surface area on the toxicity of insoluble manganese dioxide dusts by Dominique Lison; Cécile Lardot; François Huaux; Giovanna Zanetti; Bice Fubini (pp. 725-729).

The objective of this study was to examine the influence of specific surface area on the biological activity of insoluble manganese dioxide (MnO₂) particles. The biological responses to various MnO₂ dusts with different specific surface area (0.16, 0.5, 17 and 62 m²/g) were compared in vitro and in vivo. A mouse peritoneal macrophage model was used to evaluate the in vitro cytotoxic potential of the particles via lactate dehydrogenase (LDH) release. In vivo, the lung inflammatory response was assessed by analysis of bronchoalveolar lavage after intratracheal instillation in mice (LDH activity, protein concentration and cellular recruitment). In both systems, the results show that the amplitude of the response is dependent on the total surface area which is in contact with the biological system, indicating that surface chemistry phenomena are involved in the biological reactivity. Freshly ground particles with a specific surface area of 5 m²/g were also examined in vitro. These particles exhibited an enhanced cytotoxic activity, which was almost equivalent to that of 62 m²/g particles, indicating that undefined reactive sites produced at the particle surface by mechanical cleavage may also contribute to the toxicity of insoluble particles. We conclude that, when conducting studies to elucidate the effect of particles on the lung, it is important for insoluble particles such as manganese dioxide to consider the administered dose in terms of surface area (e.g. m²/kg) rather than in gravimetric terms (e.g. mg/kg).

Keywords: Key words Manganese dioxide; Specific surface area; Lung toxicity

Arsenic compound-induced increases in glutathione levels in cultured Chinese hamster V79 cells and mechanisms associated with changes in γ-glutamylcysteine synthetase activity, cystine uptake and utilization of cysteine by Takafumi Ochi (pp. 730-740).

Increases in the glutathione (GSH) level in cultured Chinese hamster V79 cells incubated with arsenic compounds were investigated in terms of changes in the activity of γ-glutamylcysteine synthetase (γ-GCS), rate of cystine uptake, and utilization of cysteine. Arsenite at subtoxic concentrations caused a marked increase of the GSH level at 8 h after addition and then declined. Increase in the GSH level caused by arsenite was associated with an increase in the rate of cystine uptake, but not in γ-GCS activity. Increase in the rate of uptake of cystine was attributed mainly to an increase in the utilization of cysteine in the synthesis of GSH. Dimethylarsinic acid (DMAA) also caused an increase in the GSH level in a time- and concentration-dependent manner. Increase in the GSH level was accompanied by increases in γ-GCS activity and in the uptake of cystine. DMAA caused a reduction in the rate of utilization of cysteine for protein synthesis while enhancing the rate of cysteine utilization for GSH synthesis. Cycloheximide inhibited increases in γ-GCS activity caused by DMAA and in the rate of cystine uptake caused by arsenite and DMAA. The cystine transport system is suggested to be induced by arsenite and DMAA with γ-GCS induced in cells incubated with DMAA. Among the arsenic compounds, methylarsonic acid (MAA) was not effective in causing an increase in the GSH level. Accordingly, increases in the GSH level caused by arsenite and DMAA may be specific phenomena in which the cells responded to the arsenicals by increasing the GSH level.

Keywords: Key words Arsenic compounds; Glutathione; γ-glutamylcysteine synthetase; Cystine uptake

Glutathione consumption and inactivation of glutathione-related enzymes in liver, erythrocytes and serum of rats after methanol intoxication by Elzbieta Skrzydlewska; Ryszard Farbiszewski (pp. 741-745).

The primary metabolic fate of methanol is oxidation to formaldehyde and then to formate. These processes are accompanied by formation of superoxide anion and further hydrogen peroxide. Glutathione plays a unique role in the cellular defence system against xenobiotics. The glutathione (GSH) content and glutathione peroxidase (GSH-Px) and glutathione reductase (GSSG-R) activities were measured in liver, erythrocytes and serum of rats. Rats were intoxicated with 3.0 and 6.0 g methanol/kg body wt. and measurements taken after 6, 12 and 24 h and 2, 5 and 7 days of intoxication. The decrease in GSH content and in GSH-related enzyme activity was observed during the whole time-course of the intoxication. The most significant changes were observed in the erythrocytes. The results obtained show that the protection against oxidative damage due to methanol intoxication in rats seems to be less efficient than in control rats.

Keywords: Key words Methanol intoxication; Glutathione; Glutathione reductase; Glutathione peroxidase

Ethoxyresorufin-O-deethylase (EROD) inducing potencies of planar chlorinated aromatic hydrocarbons in primary cultures of hepatocytes from different developmental stages of the chicken by Albertus T. C. Bosveld; Sean W. Kennedy; Willem Seinen; Martin van den Berg (pp. 746-750).

In vitro induction of ethoxyresorufin O-deethylase (EROD) activity in cell cultures is an extensively validated tool for measuring overall potencies of mixtures of halogenated aromatic hydrocarbons (HAHs) in samples from the abiotic or biotic environment. For risk assessment with special attention to effects in wild birds, an assay was developed that makes use of chicken embryo hepatocytes. However, it was questioned whether compound-specific responses are consistent at the various developmental stages. The results of our present study show that there are considerable differences between early and late embryonal and post-hatching stages. The induction of EROD was measured in primary chicken hepatocyte cultures. The cells were isolated at day 14 and day 19 of embryonal development and at day 1 post hatching. Hepatocytes were exposed in vitro to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126, IUPAC nomenclature) and 2,3′,4,4′,5-pentachlorobiphenyl (PCB 118). The respective compounds were chosen as representives for dioxins, furans, non-ortho PCBs, and mono-ortho PCBs. These groups of chemicals have been identified as environmental contaminants with major dioxin-like effects that are mediated by a common receptor, the arylhydrocarbon (Ah) receptor. At all developmental stages, TCDF was more potent than TCDD. Relative potencies (RP = EC50tcdd/EC50hah) decreased in the order TCDF50) and the maximum EROD activity (Y _max) of all compounds were lower in hepatocyte cultures from 14-day-old embryos than those from 19-day-old embryos or 1-day-old hatchlings. RPs were comparable in 19-day-old embryos and in hatchlings, but significantly different in 14-day-old embryos.

Keywords: Key words 2; 3; 7; 8-Tetrachlorodibenzo-p-dioxin; TCDD; 2; 3; 7; 8-Tetrachlorodibenzofuran; TCDF; 3; 3′; 4; 4′; 5-Pentachlorobiphenyl; 2; 3; 4; 4′; 5-Pentachlorobiphenyl; PCB; In vitro; Relative potency

l-2-Chloropropionic acid-induced cerebellar granule cell necrosis is potentiated by L-type calcium channel antagonists by P. S. Widdowson; A. Gyte; R. Upton; J. C. E. Smith; M. Pitts; R. Moores; I. Wyatt (pp. 751-755).

We have used the model of l-2-chloropropionic acid (L-CPA)-induced selective cerebellar granule necrosis to study excitatory amino acid-induced necrotic cell death in vivo produced by the activation of N-methyl-d-aspartate (NMDA) receptors. However, the mechanism for the NMDA receptor activation and the biochemical events which dictate the anatomical selectivity for the L-CPA-induced lesion are as yet unknown. We examined whether blockade of sodium and calcium channels may reduce the neurotoxicity through a reduction of glutamate release from granule cells. None of the sodium channel antagonists examined, i.e. phenytoin, lamotrigine or rilazole nor the mixed sodium/calcium channel blocker, lifarazine, altered the L-CPA neurotoxicity. However, L-type calcium channel blockers, verapamil and nifedipine enhanced the L-CPA-induced granule cell necrosis, assessed by measuring the degree of L-CPA-induced reductions in cerebellar aspartate concentration, increases in cerebellar glycine concentrations and the development of cerebellar oedema. In addition, the locomotor activity of rats receiving both L-CPA and either verapamil or nifedipine was significantly lower than when rats received L-CPA alone, suggesting an enhancement of the neurotoxicity of L-CPA by L-type calcium channel blockade. The data suggest that L-CPA may interfere with non-L-type calcium channels located on granule cell bodies and nerve terminals leading to reduction of the calcium entry into the cells. We suggest that a combination of L-type channel blockade and non-L-type channels which are sensitive to L-CPA produces reductions in intracellular calcium concentrations below that required for neuronal survival.

Keywords: Key wordsl-2-Chloropropionic acid; Cerebellum; Sodium channels; Calcium channels; Neurotoxicity

Release of dopamine, GABA and EAA in rats during intrastriatal perfusion with kainic acid, NMDA and soman: a comparative microdialysis study by Stig O. P. Jacobsson; Gudrun E. Cassel; Britt M. Karlsson; Åke Sellström; Sven-Åke Persson (pp. 756-765).

There is an increasing amount of experimental evidence that excitatory amino acids (EAAs) are involved in the brain lesions observed after severe intoxication with the highly toxic organophosphorus compound soman. This study was undertaken to compare the acute actions of soman, and the glutamatergic receptor agonists kainic acid and N-methyl-d-aspartate (NMDA) on striatal release of dopamine and amino acids. The neurotoxic compounds were administered in high (10 mM) concentrations by unilateral intrastriatal microdialysis perfusion in freely moving rats. During the microdialysis the animals were observed for toxic signs related to convulsion. The glial fibrillary acidic protein (GFAP) was monitored as a marker of neurotoxicity in parts of prefrontal cortex, hippocampus, striatum and cerebellum. Acetylcholinesterase (AChE) inhibition in six brain regions was measured after soman perfusion in order to assess its cerebral distribution. We found that soman perfusion induced a major release of dopamine, GABA and aspartate in the striatum. Kainic acid also induced a release of dopamine and aspartate. NMDA was not as potent an inducer of striatal neurotransmitter release as soman and kainic acid. Soman and kainic acid perfusion produced convulsive behaviour in the rats. The main neurochemical event in the striatum during soman- and kainate-induced convulsions is the release of dopamine. We suggest that this major dopamine release might be as important as an increase in EAA in the cascade of pathological events leading to the brain damage in the striatum observed after soman intoxication.

Keywords: Key words Dopamine; Excitatory amino acids; EAAs; Kainic acid; N-methyl-d-aspartic acid; NMDA; Soman

Cardiotoxicity of chlorodibromomethane and trichloromethane in rats and isolated rat cardiac myocytes by S. P. Müller; P. Wolna; U. Wünscher; D. Pankow (pp. 766-777).

The cardiovascular effects were investigated after acute and subacute treatment with chlorodibromomethane (CDBM; 0.4 to 3.2 mmol/kg p.o.), trichloromethane (TCM; 0.31 and 1.25 mmol/kg p.o.) and mixtures of CDBM and TCM (acute, 0.8 mmol CDBM/kg + 1.25 mmol TCM/kg p.o.; subacute, 0.4 mmol CDBM/kg+0.31 mmol TCM/kg p.o.) in conscious and urethane anaesthetized male Wistar rats (n=610 per treatment). Furthermore it was observed whether cardiovascular responses were modified in CDBM or TCM treated rats after administration of exogenous catecholamines (epinephrine, 1 μg/kg; norepinephrine, 2 μg/kg) and underpinned with in vitro alterations of Ca²⁺ dynamics in cardiac myocytes. The present findings demonstrated that single and subacute oral administration of CDBM or TCM and mixtures of CDBM and TCM resulted in arrhythmogenic and negative chronotropic and dromotropic effects in conscious and urethane anaesthetized rats. The atrioventricular conduction time and the intraventricular extension time were extended. A slight shortening of the repolarization velocity was observed. The myocardial contractility was depressed and the heart was sensitized to the arrhythmogenic effects of epinephrine. After catecholamine injection the adrenergic cardiovascular responses in urethane anesthetized rats were modified: increased hypertensive epinephrine and norepinephrine action as well as augmentation of negative chronotropic and negative dromotropic cardiac effects of catecholamines were observed. The positive inotropic adrenergic response was diminished. The present in vivo findings, myocardial depression after acute CDBM treatment, as determined by different indices of contractility, correlate well with the observed inhibitory actions of CDBM on Ca²⁺ dynamics in isolated cardiac myocytes. All cardiovascular alterations found after CDBM or TCM treatment were not intensified after treatment with mixtures of CDBM and TCM. The effects observed were distinctly stronger after TCM (1.25 and 0.31 mmol/kg) treatment compared to CDBM (0.8 and 0.4 mmol/kg) treatment.

Keywords: Key words Chlorodibromomethane; Trichloromethane; Cardiotoxicity; [Ca2+] i transients; Catecholamine

Reduced vascular β-adrenergic receptors and catecholamine response in rats with lead induced hypertension by Huoy-Rou Chang; Shun-Sheng Chen; Der-An Tsao; Juei-Tang Cheng; Chi-Kung Ho; Hsin-Su Yu (pp. 778-781).

β-Adrenergic receptor-mediated relaxation of blood vessels declines in lead induced hypertension although the mechanism is unknown. We have utilized the aorta of lead hypertensive rats to investigate this problem. In an effort to elucidate the mechanism responsible for this alteration we examined plasma catecholamine levels, vascular β-adrenergic receptor density, and cyclic adenosine monophosphate (cAMP) production in lead hypertensive rats. The density of β-adrenergic receptors was 41% lower in the blood vessels of lead hypertensive rats compared with control rats. The corresponding apparent K _d values were not significantly different between two groups. The plasma catecholamine level was significantly higher in lead hypertensive rats compared with controls (P < 0.001). Stimulation of the vascular β-adrenoceptor resulted in significantly lower levels of cAMP in lead hypertensive rats compared with controls (P < 0.001). The present results suggest that there is reduced β-adrenoceptor density and diminished cAMP accumulation in blood vessels from lead hypertensive rats. Plasma catecholamine may play a role in the diminished β-adrenoceptor and responsiveness to cAMP-mediated vascular relaxation in lead exposure.

Keywords: Key words Lead; Catecholamine; β-Adrenergic receptor; cAMP; Blood vessel

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Archives of Toxicology (v.71, #12)

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Archives of Toxicology (v.71, #12)