Isolation of Escherichia coli mutants which are resistant to an inhibitor of H+-ATPase, tributyltin and also to uncouplers of oxidative phosphorylation.
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Adenosine Triphosphatases↗
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Catalytic and activating protons follow different pathways in the H(+)-ATPase of potato tuber mitochondria.
The effect of some F0F1 inhibitors on the activation of the H(+)-ATPase by the electrochemical proton gradient was investigated in mitochondria extracted from potato tubers. Transient activated state of the ATPase was revealed by addition of ATP and of the detergent lauryldimethylamine oxide (LDAO) to energized mitochondria. Venturicidin, tri-n-butyltin and aurovertin at high concentrations did not affect the process of delta mu H(+)-activation, whereas oligomycin fully blocked it. The results support the idea of separate pathways or binding sites for catalytic and activating protons.
Aurovertins↗
Protease inhibitors block apoptosis at intermediate stages: a compared analysis of DNA fragmentation and apoptotic nuclear morphology.
The possible correlation between DNA digestion and changes in nuclear morphology in apoptosis was studied by blocking the apoptotic process at intermediate stages. The apoptogenic action of three drugs: etoposide, puromycin, tributyltin, was contrasted with protease inhibitors with different specificity on U937 cells. The inhibitors interfered with the development of the apoptotic features without shifting cell death to necrosis: treated cells showed abnormal morphologies, which could be recognized as intermediate stages of apoptosis; accordingly, DNA analysis showed an inhibitor-dependent block of the apoptotic DNA digestion. The comparison between size of DNA fragments and nuclear morphology suggested the following correlations: loss of normal nuclear shape with the appearance of a > or = 2 Mb DNA band; ongoing chromatin condensation with the progressive DNA digestion up to 50 kb; nuclear fragmentation with DNA laddering. Protease inhibitors in etoposide-treated cells did not allow the formation of 700-300 kb fragments, suggesting that they possibly derive from a cell-mediated effect.
Apoptosis↗
Specific gas chromatography-mass spectrometry analytical method for the determination of cyhexatin in animal feed.
The acaricide tricyclohexyltin hydroxide (cyhexatin) was determined in animal feed samples, using gas chromatographic--mass spectrometry in the electron impact mode. Sample extraction and derivatization (converting the analyte to an alkylated derivative) were performed using a tricyclopentyl analogue of this acaricide as internal standard to obtain a better analytical precision.
Animal Feed↗
Antinociceptive and hypothermic effects of trimethyltin.
Trimethyltin (TMT) induced a dose-dependent antinociceptive and hypothermic effect in mice. Antinociception was not attenuated by naloxone but was reversed by atropine. TMT, however, was ineffective in displacing (3H)-QNB binding in vitro and did not affect (3H)-QNB binding or acetylcholinesterase activity after in vivo administration. The ethyl ester of nipecotic acid, a specific inhibitor of synaptosomal GABA uptake, exerted a similar antinociceptive effect that could be blocked by atropine. The GABA receptor antagonist bicuculline attenuated antinociception induced by TMT and nipecotic acid ethyl ester but not by morphine or oxotremorine. Gamma-Vinyl GABA, an irreversible inhibitor of GABA metabolism, prolonged TMT but not morphine-induced antinociception. In contrast, neither the dose-response nor the time course of TMT-induced hypothermia were affected by any of the drugs tested. The findings suggest that the GABAergic system may be involved in TMT induced antinociception; however, the mechanism responsible for the hypothermic effect of TMT is not apparent.
Animals↗
Reversal of a trimethyltin-induced learning deficit by desglycinamide-8-arginine vasopressin.
Trimethyltin (TMT) is an organometal neurotoxin which produces lesions primarily in the limbic system. Selectivity seems to depend upon the dose, but the hippocampus and related entorhinal cortical structures, of importance for learning and memory, are most often described as target sites. We have previously demonstrated that subjects treated with a moderate dose of TMT prior to acquisition sessions, are unable to learn a forward autoshaping task with a 6 sec delay of reinforcement, but are capable of acquiring the same task when no delay of reinforcement is used. These data suggested that the performance deficit is one of learning (i.e. consolidation) rather than of memory (i.e. storage), retrieval, or sensorimotor impairment. To more rigorously test this hypothesis, we determined if performance of a task already learned would be impaired by the neurotoxin. Adult male Long Evans rats were given 10 acquisition sessions of 24 trials, following which TMT (6.0 mg/kg, p.o.) was administered. One month later, these rats performed the lever-touching behavior as well as controls, despite the fact that the same dose of TMT interfered with learning if given one month prior to acquisition sessions, thus confirming our hypothesis. In a second experiment we determined if the peptide analog of vasopressin, desglycinamide-8-arginine vasopressin (DGAVP), could reverse a learning deficit in a population of non-learners. Rats were treated with TMT or water vehicle one month prior to autoshaping. TMT significantly retarded acquisition. After 10 sessions of 12 trials each, non-learners (i.e. rats treated with TMT that failed to associate the lever with delivery of a reinforcer) were administered saline or DGAVP (7.5 micrograms/kg, s.c.) 1 hr before sessions 11-13; treatment was discontinued prior to sessions 14 and 15. Peptide treated subjects showed evidence of acquisition and exhibited higher levels of lever-directed behavior than saline treated nonlearners. Performance was maintained after DGAVP treatment was discontinued, indicating that the learning-enhancing action of DGAVP was not transient or state-dependent.
Animals↗
Studies on storage effects and the negative synergism between trenimon and X-rays in Drosophila.
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Animals↗
Antagonism by d-amphetamine of trimethyltin-induced hyperactivity evidence toward an animal model of hyperkinetic behavior.
In male rats of the Long-Evans strain, either 7.0 mg/kg of trimethyltin (TMT) or 0.9% NaCl was administered by intragastric gavage. After a period of recovery from the typical signs of trimethyltin toxicity, each rat was tested at 72-hr intervals for its locomotor activity in an open field apparatus, the floor of which was divided into square grids. The baseline activity of each of the trimethyltin-treated rats was significantly greater than the saline-treated controls. d-Amphetamine, injected intraperitoneally in a dose of 0.5 or 2.0 mg/kg, augmented the hyperactivity of the trimethyltin-treated animals. However, a 4.0 mg/kg dose of d-amphetamine markedly attenuated the hyperactivity of trimethyltin-treated rats while elevating that of the controls. Since trimethyltin produced an autism-like behavioral disorder involving hyperactivity, preservation, aggressiveness and impairment in problem-solving and memory function, the placating effect of amphetamine supports the proposition that the pathology due to trimethyltin may represent an experimental analogue to the hyperkinetic syndrome in children.
Animals↗
The role of the rat submandibular gland in the excretion of bis (tributyltin) oxide: electron microscopy, X-ray microanalysis and atomic absorption analysis.
The role of the submandibular glands in the excretion of parenterally administered bis (tributyltin) oxide (TBTO) was studied. Fine structural alterations of the submandibular glands were observed with an electron microscope. Accumulation sites of TBTO were determined with an X-ray microanalyzer and tin concentrations in saliva and blood were measured by atomic absorption spectrophotometry.
Animals↗
Interactions of triethyltin bromide with components of the red cell.
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Adenosine Triphosphatases↗
Quantitation of cutaneous toxicity: an in vitro approach using skin organ culture.
A short-term (48 hr) organ culture system for maintaining metabolically viable and structurally intact mouse skin has been developed. With the culture system, the responses of skin to in vitro physical and chemical insults were assessed by histologic examination and selected biochemical measurements in an attempt to establish a quantitative basis for the evaluation of cutaneous toxicity in vitro. In studies with mouse skin in organ culture following either freeze-thaw treatment (physical insult) or a single in vitro topical application of tributyltin chloride (10 to 1000 nmole/cm2), deleterious morphologic changes were observed. The degree of cellular injury was reflected by inhibition of in vitro incorporation of [3H]thymidine and [14C]leucine into epidermal DNA and protein, respectively; there also was leakage of intracellular enzymes into the culture medium in a dose and time related manner. These biochemical parameters are sensitive indicators of cellular injury; as such they may offer a simple, sensitive, and quantitative measure for assessing cutaneous toxicity of chemicals in vitro.
Animals↗
Triethyltin decreases maximal electroshock seizure severity in adult rats.
Acute and subacute treatment of adult rats with triethyltin bromide (TET) caused dose-dependent and time-dependent decreases in maximal electroshock seizure (MES) severity. This decrease in excitability was characterized by both a decrease in the percentage of animals exhibiting a maximal seizure and a corresponding decrease in the extension durations and an increase in the flexion durations. Acutely treated rats received (ip) 0, 1, or 5 mg/kg TET while subacutely exposed (po) received 0, 1, 5, or 10 ppm TET in the drinking water for 10 days. Experiments were designed so that the total consumed dose of TET, on a milligram per kilogram basis, equaled that in the acute experiment. No alterations in body weight were observed in either experiment. Acutely, the onset of action of TET was detectable within 0.5 hr. For the 1 mg/kg group, the effect peaked between 4 and 24 hr and completely recovered by 72 to 96 hr. For the 5 mg/kg group, the marked effect peaked at 4 hr, however, no recovery was observed. Subacute exposure for 1 to 2 days produced marked decreases in MES severity which were still present in the 5- and 10-ppm groups 14 days after cessation of exposure. Comparison of the onset and recovery data in the acute and subacute experiments revealed a close correspondence in similarly dosed rats. Comparison with other MES data from our laboratory revealed that adult rats were more sensitive to TET than adult mice or developing rats. Additionally, the MES test was able to detect subtle functional alterations in the central nervous system at lower doses of TET than previously reported neurobehavioral evaluation procedures.
Animals↗
Immediate and long-term alterations in maximal electroshock seizure responsiveness in rats neonatally exposed to triethyltin bromide.
Neonatal rats were injected (sc) with 0, 0.25, 0.5, 1.0, 2.5, or 5.0 mg/kg triethyltin bromide (TET) in a 2% ethanol vehicle on Days 0, 5, 10, 15, and 20 postnatally. TET-exposed neonates exhibited a dose-dependent delay in the ontogenetic appearance of both the clonic and tonic maximal electroshock seizure (MES) responses which were apparent up to Day 45, as evaluated by the MES grade distributions and the durations of the individual phases of the MES. In marked contrast, adult rats (exposed to TET only as neonates) exhibited long-term increases in MES severity, as evaluated by the durations of the individual phases of the MES. At 75 days of age, a time when the 1.0 mg/kg developmentally TET-treated group exhibited an increased seizure severity, a single challenge dose of 1.0 mg/kg TET (ip) produced a proportional decrease in MES severity in both developmentally treated and control rats. No changes in preweaning or postweaning body weight were observed in the animals in the 0.25, 0.5, 1.0, or 2.5 mg/kg groups. A 30% decrease in weaning weight and an approximate 15% decrease in postweaning weight were observed in the 5.0 mg/kg group. These seizure results demonstrate that developmental exposure to TET produces immediate and long-term alterations in central nervous system functioning, which are of an opposite character. Interesting, we have previously shown that developmental lead exposure produces a similar developmental/adult dichotomy of effects with regard to the MES severity; however, the two patterns are reversed (D. A. Fox, S. R. Overmann, and D. E. Woolley (1979).
Aging↗
Discrimination of auditory from nonauditory toxicity by reflex modulation audiometry: effects of triethyltin.
The evaluation of toxicity in sensory systems presents particular problems because of the need to distinguish specific sensory loss from other toxic effects. It has recently been shown that modulation of reflex behavior by low-intensity test stimuli can be used to provide a rapid assessment of sensory acuity and of ototoxic hearing loss. In this report the ability of the method to distinguish the known neuromuscular consequences of triethyltin (TET) from hearing loss is demonstrated. Rats treated with TET bromide (30 mg/liter) in their drinking water for 3 weeks showed a profound decrease in acoustic startle reflex amplitudes which was apparent prior to overt neuromuscular weakness and subsequent hindlimb paralysis. Following cessation of treatment, startle levels recovered to preexposure values. Despite these large changes in startle reflex amplitudes, TET treatment did not alter the ability of pure tone stimuli to modulate reflex behavior. These results indicate that TET as administered in these studies disrupted neuromuscular function but did not affect hearing.
Analysis of Variance↗
Inhibitory effect of triethyltin on taurine transport by glioma cells.
The effects of triethyltin (TET) on the transport of taurine, glutamate, lysine, Na+, K+ (using 86Rb+ as tracer), and Cl- by LRM55 glioma cells were examined. Taurine transport was inhibited by TET at much lower concentrations (IC50 = 2.5 microM) than either glutamate or lysine transport (135 and 110 microM, respectively). TET had no significant effect on Na+, Cl-, or 86Rb+ influx at the low concentrations greater than 100 microM. The failure of low concentrations (less than or equal to 10 microM) of TET to affect ion transport indicated that inhibition of taurine transport was not secondary to effects of TET on ion movements or gradients. This conclusion was supported by the observation that neither ouabain nor furosemide, which do affect ion movement and gradients, strongly inhibited taurine transport. Uncouplers and inhibitors of oxidative phosphorylation (cyanide, 2,4-dinitrophenol, and carbonyl cyanide-m-chlorophenyl hydrazone) also had only small effects on taurine transport, suggesting that inhibition by TET was not secondary to possible effects on oxidative phosphorylation. TET had no effect on the efflux of taurine from LRM55 cells at the low concentrations that inhibit uptake, but it induced a nonspecific increase in membrane permeability at much higher concentrations (greater than 100 microM). Tri-n-propyltin and tri-n-butyltin were also potent inhibitors of taurine transport (IC50 = 2.3 and 11 microM, respectively), but trimethyltin was much less potent (144 microM).
Biological Transport↗
Tin distribution in adult rat tissues after exposure to trimethyltin and triethyltin.
The time course of distribution of tin in the adult rat was determined in brain, liver, kidneys, heart, and blood following single ip administrations of trimethyltin hydroxide (TMT) and triethyltin bromide (TET). Adult Long-Evans rats were killed 1, 4, 12, and 24 hr, and at 5, 10, or 22 days following injection of TMT and TET (N = 6/time), and tissues were analyzed for total tin by atomic absorbance spectroscopy. TET exposure resulted in higher tin concentrations in brain, liver, and kidney tissues, while the two trialkyltins resulted in approximately equal tin concentrations in the heart and blood. Rates of elimination of tin (expressed as elimination rate constants, Kel) were greater in all tissues following TET exposure than following TMT exposure. The concentration of tin in the brain 12 hr after TMT exposure was 4.4, 8.5, and 12.7 ng tin/mg protein for dosages of 3.0, 6.0, and 9.0 mg/kg, respectively. Tin was evenly distributed across the cerebellum, medulla-pons, hypothalamus, hippocampus, and striatum following TMT exposure. These results describe major differences in the disposition and rates of elimination of tin from body tissues after TMT and TET exposure, and demonstrate that the regional disposition of tin is not related to the region-specific pathology reported following TMT exposure.
Animals↗
Behavioral effects of trimethyltin in two strains of mice. I. Spontaneous motor activity.
Adult male mice (C57BL/6N and BALB/c) were administered single doses of trimethyltin X Cl (TMT) by the ip route. The effects of TMT administration were determined on lethality (3-6 mg/kg), spontaneous motor activity (SMA), and the physical appearance of the mice (0.3-3 mg/kg). The effects of TMT on lethality were strain dependent in that a single dose of 3 mg/kg, ip, produced approximately 35% lethality in the C57BL/6N strain during the first 72 hr following administration. Less than 15% lethality was observed at this dose in the BALB/c strain. In both strains, 3.5 mg/kg, ip, produced more than 70% lethality during the first 144 hr after administration. Higher doses produced proportionally greater lethality. The SMA of both strains was not affected significantly at doses below 1 mg/kg, ip. At 1 mg/kg a small decrease in activity was observed during the first 24 hr. At 3 mg/kg, SMA was initially decreased in both strains. However, the decrease was of smaller magnitude in the C57BL strain and was followed by a large increase in SMA which did not return to control levels for approximately 1 week. An increase in SMA was observed in the BALB/c strain on the fifth day following TMT but returned to control values by Day 6. At 3 mg/kg, ip, the C57BL mice were observed to have severe whole body tremors and were hypersensitive to external stimuli. The whole body tremor was not as marked in the BALB/c strain. Neuropathological studies on the treated mice indicated that the behavioral studies paralleled the pathology produced by TMT. These data confirm the initial observation of greater sensitivity of the mouse to toxic effects of TMT compared to the rat.
Animals↗
Behavioral effects of trimethyltin in two strains of mice. II. Multiple fixed ratio, fixed interval.
Adult male C57BL/6N and BALB/c mice were trained to respond under a multiple fixed-ratio 30, fixed-interval 600-sec schedule of milk presentation. After performance had stabilized, each mouse received a single dose of trimethyltin X Cl (TMT) by ip administration. Three hours after administration, behavioral testing was started and continued at 24-hr intervals thereafter. The behavior of mice receiving 0.3 mg/kg was unaffected at 3, 27, and 51 hr after administration. Likewise, no effects were seen at 3 and 27 hr after 1 mg/kg. However, at 51 hr after administration there was a significant change in the temporal patterning of fixed-interval responding in the C57BL/6N strain, as shown by a decrease in the fixed-interval quarter-life. There was no significant change in the BALB/c strain at this dose. At 3 mg/kg the responding of both strains was greatly affected, and responding remained disrupted for at least 6 to 7 weeks. Neuropathological examination of the brains of both strains of mice showed no significant lesions (light microscopy) at 0.3 and 1 mg/kg. At 3 mg/kg, severe neuronal necrosis was observed in the fascia dentata region in both strains. Thus, in mice receiving TMT, the behavioral deficits were closely paralleled by the presence or absence of significant neuropathology.
Animals↗