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At least 19 recordsLinked to original sources
PubMed2000

The interactions of trialkyltin compounds with lysosomes from rat liver.

Interactions of two trialkyltin compounds with the lysosomes from a rat liver have been studied. It is shown that these compounds induce a fast alkalinisation in the matrix of energised lysosomes. The fast alkalinisation rate is similar to the one obtained with uncouplers of the oxidative phosphorylation. An identical effect has been obtained with lysosomes energised in a chloride-free medium. This supports the hypothesis that trialkyltin compounds behave not only as Cl-/OH- exchangers, but also as proton carriers in biological membranes. This result could explain the toxicity and in particular the neurotoxicity of trialkyltin compounds.

Animals↗
PubMed1985

Toxicity of triorganotin compounds: comparative in vivo studies with a series of trialkyltin compounds and triphenyltin chloride in male rats.

In 2-week feeding studies, a series of trialkyltin chlorides and triphenyltin chloride were fed to male weanling rats at different dietary concentrations to evaluate their toxic effects, especially on the brains and the lymphoid organs, thymus and spleen. The lower trialkyltin homologs, trimethyltin chloride (TMTC) and triethyltin chloride (TETC), were neurotoxic, causing neuronal degradation and cerebral edema, respectively, at dietary concentrations of 15 ppm. The intermediate homologs, tri-n-propyltin chloride (TPTC) and tri-n-butyltin chloride (TBTC), and the aromatic compound, triphenyltin chloride (TPhTC), caused a dose-related reduction of thymus weight. At a dietary concentration of 150 ppm decreases in thymus weight to 53, 39, and 81% of controls were found following treatment with TPTC, TBTC, and TPhTC, respectively. Microscopically, thymus atrophy was associated with a lymphocyte depletion in the thymic cortex. Only 16% of the total number of nucleated thymocytes could be isolated from rats fed 150 ppm TBTC. These effects were completely reversed within 2 weeks. Slight thymus atrophy was observed after feeding a relatively high dose of 150 mg tri-n-hexyltin chloride (THTC)/kg diet, whereas tri-n-octyltin chloride (TOTC) was ineffective. A dose-related decrease in spleen weight was noticed after 2 weeks feeding of TPTC, TBTC, and TPhTC. Liver weights were increased in rats fed TBTC, THTC, and TPhTC for 2 weeks. Nevertheless, no enlarged livers and normal spleen weights were found upon feeding 100 ppm TPTC or TBTC for 4 weeks, whereas thymus weight was severely decreased. Therefore, atrophy of the thymus was considered to be the predominant effect of the intermediate trialkyltins (TPTC, TBTC). From this study it is concluded that the lower trialkyltins (TMTC, TETC) are essentially neurotoxic, the intermediate trialkytins (TPTC, TBTC) and triphenyltin are primarily immunotoxic, and the higher homologs (THTC, TOTC) are only slightly toxic or not toxic at all.

Administration, Oral↗
PubMed1982

Intestinal uptake site, enterohepatic circulation, and excretion of tetra- and trialkyltin compounds in mammals.

The intestinal uptake site, enterohepatic circulation, and excretion into bile, feces, and urine of alkyltins (tetra and trialkyltin) were investigated after oral, sc, or intestinal administration of the compounds to rats and rabbits. Assays of tetra- and trialkyltins in biological materials were carried out by gas chromatography. The main uptake sites in the small intestine were the jejunum and duodenum for tetraalkyltins and the ileum and jejunum for trialkyltins. Tetra- and trialkyltins were detected in the small intestine and contents of the intestinal lumen after sc injection of these compounds in rats. These facts suggest that tetra- and trialkyltins are transported in the body through enterohepatic circulation. The route, rate, and amount of excretion of tetra and trialkyltins seem to depend on the velocity of dealkylation, doses, physical and chemical properties, and route of administration of the compounds.

Administration, Oral↗
PubMedDate not supplied

Studies on the flavor aversions induced by trialkyltin compounds.

These experiments were undertaken to determine the suitability of a flavor-aversion-conditioning paradigm for detecting the effects of trimethyltin and triethyltin. Both organotins produced flavor aversions whose magnitude depended jointly on the dosage administered and the number of flavor-organotin pairings. Estimated ED 50s (for triethyltin, 1.8 mg/kg; for trimethyltin, 3.1 mg/kg) were smaller than the dosages reported to affect other classes of behavior, but nevertheless represented a substantial percentage (25-45%) of the respective published LG-50 values. Flavor-aversion conditioning may represent a valuable tool for studying the effects of organic and inorganic heavy metals.

Animals↗
PubMed1984

Behavioral toxicity of trialkyltin compounds: a review.

Triethyltin (TET) and trimethyltin (TMT) are neurotoxic organotin compounds which produce different patterns of toxicity in adult animals. Exposure to TET produces behavioral toxicity (decreased motor activity, grip strength, operant response rate and startle response amplitude) which reflects impaired neuromotor function. These deficits are consistent with the reported myelin vacuolation and cerebral edema produced by TET, and with its direct effects on muscle. Exposure to TMT produces both hyperactivity and impaired learning and performance. These impairments are consistent with reported neuronal cell death produced by TMT, particularly in limbic system structures. While the behavioral deficits produced by repeated exposure to TET are reversible when dosing is terminated, the behavioral impairments produced by a single exposure to TMT appears to be irreversible.

Animals↗
PubMed1974

The action of trialkyltin compounds on mitochondrial respiration. The effect of pH.

1. Inhibition of 2,4-dinitrophenol-stimulated respiration by trialkyltins is dependent on the presence of Cl(-) in the assay medium and is only apparent at acid pH values. It appears to be a result of the Cl(-)-OH(-) exchange mediated by trialkyltins. 2. In a KCl medium at alkaline pH values, the maximum rate of respiration produced by uncouplers is further increased by the presence of trialkyltins. 3. The inhibition of uncoupled succinate oxidation at acid pH values is not reversed by increasing the external substrate concentration, suggesting that depletion of intramitochondrial succinate is not an important factor in the inhibition. 4. It is suggested that the probable explanation for these observations is that in the presence of Cl(-) trialkyltins alter the internal pH to a more acid value and this directly affects the activity of one or more steps in succinate oxidation. 5. The oligomycin-like action of trialkyltins in a Cl(-)-free medium shows considerable pH-dependence over the pH range 6.6-7.6 in the presence of 10mm-phosphate, but very much less pH-dependence in the presence of 1mm-phosphate. 6. The binding of triethyltin to mitochondria shows a pK at pH6.3 and does not change greatly over the pH range 6.6-7.6. 7. It is suggested that the pH-dependence of the oligomycin-like action described by Coleman & Palmer (1971) is the result of the pH-dependence of the formation of a hydrophilic complex between trialkyltins and P(i).

Animals↗
PubMed1984

Neuromuscular function and organotin compounds.

Mammalian exposure to toxic levels of the trialkyltin compounds, triethyltin (TET) and trimethyltin, results in pathological manifestations largely restricted to the nervous system. The remarkable features of TET toxicity are cerebral edema and muscular weakness. Rats exposed orally to TET (10-30mg TET Br/l of drinking water) progress through an increasingly compromised state beginning with mild ataxia and hindlimb weakness after one week, spastic paresis of the hindlimbs by two weeks; and hindlimb paraplegia and sensory changes by 3 weeks. Histopathological studies of chronic TET-exposed rats report minimal ultrastructural damage to distal peripheral nerves, myelin, and muscle. Chromatolytic reactions are observed in some alpha motor neurons; intramyelinic vacuolization in the ventral roots and horn is substantial by 3 weeks. Myelin vacuolization and degeneration are observed to a lesser extent in the dorsal roots of the spinal cord. Wet weights and myofiber diameters of EDL and soleus muscles are reduced during chronic TET intoxication, but no histopathology is evident using light microscopy. Conduction of compound action potentials in vivo along distal sensory fibers, ventral roots and distal motor fibers (in sciatic n.) is normal in 3 week TET rats as compared to control; however, nerve conduction velocity is decreased in the segment of the H-reflex arc involving the dorsal roots. Earlier studies by Stoner and coworkers led to suggestions that the neuromuscular junction may be preferentially affected by TET and could contribute, in part, to the symptoms of muscular weakness. In support of this hypothesis preliminary studies from our laboratory and others indicate that neurotransmission is functionally depressed at the myoneural junction following chronic TET treatment in vivo or when applied in vitro to isolated muscle preparations. Stimulated, but not unstimulated, release of acetylcholine from the vascular perfused rat phrenic nerve-hemidiaphragm preparation is decreased by TET especially at higher stimulation rates (20 Hz). In vitro administration of TET Br (10(-6)M) results in an irreversible decrease in the amplitude of evoked endplate potentials; chronic in vivo exposure to TET causes a decrease in the resting membrane potential of soleus muscle (in situ recordings) and provokes a peculiar post-stimulus (200Hz bursts) elevation of spontaneous miniature endplate potentials in isolated cut diaphragm preparations.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMedDate not supplied

The toxicity and neuropathology of dimethylethyltin and methyldiethyltin in rats.

Triethyltin causes an increase in brain water with vacuolation of myelin sheaths, whereas trimethyltin is selectively damaging to neurons, especially of the hippocampal formations, causing chromatolysis, accumulation of cytoplasmic dense bodies and often cell death. The effects on rats of the analogues, dimethylethyltin and methyldiethyltin (oral LD50 14 mg/kg and 7.5-10.0 mg/kg respectively) are now reported. The dimethylethyl compound produces functional changes resembling those caused by trimethyltin, while the methyldiethyl compound causes responses similar to those produced by triethyltin. Structurally, however, the dimethylethyl compound, while producing marked nerve cell changes of the trimethyltin type also causes moderate vacuolation of myelin sheaths. By contrast, methyldiethyltin causes marked vacuolation of myelin sheaths of the triethyltin type and relatively minor neuronal changes of the trimethyltin type. These findings are discussed in terms of the structure-activity relationships of trialkyltin compounds.

Animals↗
PubMed1983

Direct in vitro effects of bis(tri-n-butyltin)oxide on hepatic cytochrome P-450.

Bis(tri-n-butyltin)oxide, an agriculturally important biocidal agent, when added in vitro to liver microsomes containing the phenobarbital-induced form of cytochrome P-450, produced a typical type I binding spectrum (an absorption maximum at 390 nm; an absorption minimum at 420 nm). Studies with microsomal preparations containing cytochrome P-448, induced by 3-methylcholanthrene or beta-naphthoflavone, revealed that this hemeprotein was more susceptible to direct degradation by bis(tri-n-butyltin)oxide than was the uninduced or phenobarbital-induced forms of cytochrome P-450. The disappearance of spectrally detectable cytochrome P-450 was accompanied by an increase in cytochrome P-420. The formation of cytochrome P-420 was both time and temperature dependent, and it also occurred to a greater extent in microsomal preparations containing cytochrome P-448 than in microsomes containing the phenobarbital-induced form of cytochrome P-450. In all cases, the decreases in spectrally detectable cytochrome P-450 produced by the organotin were not accompanied by decreases in microsomal heme or cytochrome b5 content. The findings provide evidence for the direct interaction followed by conversion of cytochrome P-450 to cytochrome P-420 produced by a trialkyltin compound in vitro, and indicate that different susceptibilities to degradation exist within the various subspecies of this hemeprotein.

Animals↗
PubMed1989

Flow cytometric comparison of the effects of trialkyltins on the murine erythroleukemic cell.

Cellular effects of exposure to tributyltin (TBT), triethyltin (TET), or trimethyltin (TMT) were investigated by flow cytometry employing the murine erythroleukemic cell (MELC) as a model cellular system. Cell viability was investigated by the carboxyfluorescein diacetate (CFDA) uptake/propidium iodide (PI) exclusion method: above a critical concentration (exposure for 4 h), which was specific for each of the trialkyltin compounds, the cell becomes permeable to PI, indicating loss of viability. Cellular CF fluorescence (derived from intracellular hydrolysis of CFDA) increased as a function of alkyltin concentration below the critical concentration and decreased as viability decreased above the critical concentration. Relative membrane potential, monitored with a cyanine dye (DiOC6), correlated with viability (PI exclusion), remaining essentially unaltered below the critical concentration and decreasing above it. At/above 1 microM TBT, 5 microM TET, or 100 microM TMT, the cell cycle was blocked in the G2/M phase. The 90 degrees light scatter (a measure of refractive index), axial light loss (a measure of volume), and fluorescein isothiocyanate (FITC) fluorescence (a measure of protein content) of nuclei isolated from trialkyltin-treated MELC by detergent treatment, increased as a function of organotin dose. Fluorescence and interference microscopy revealed increased quantities of residual cytoplasmic tags adherent to the nuclei as a function of organotin dose, apparently resulting from increased cytoplasmic resistance to detergent-mediated solubilization. The effects of the trialkyltins correlated with their lipophilicity (octanol/water coefficient). These data support the hypothesis that fixation (protein denaturation, cross-linking, etc.) is an important mode of organotin cytotoxicity.

Animals↗
PubMedDate not supplied

Developmental and behavioral toxicity following acute postnatal exposure of rat pups to trimethyltin.

The purpose of this study was to extend our investigations on the developmental neurotoxicity of trialkyltin compounds. On postnatal day 5 (PND 5), rat pups received a single intraperitoneal injection of either 0 (saline), 4, 5 or 6 mg/kg trimethyltin hydroxide (TMT) calculated as the base. The size of the milk bands was decreased in 6 mg/kg TMT pups 48-96 hr after dosing, while in 5 mg/kg TMT pups, milk bands were reduced 96 hr after dosing only. Dosages of 5 and 6 mg/kg TMT reduced growth and impaired performance in rope descent during the preweaning period. As adults, motor activity in figure-eight mazes was increased for 6 mg/kg TMT animals. The startle response to an acoustic stimulus (a 13 kHz, 120 dB tone) was also affected by TMT when measured both during ontogeny and in adulthood. During development, on days 10-21, both 5 and 6 mg/kg TMT reduced the number of responses during 30-trial sessions for both males and females. Amplitudes were decreased for the 5 and 6 mg/kg dose on days 12-13, and for all dosages on days 18-19 and 20-21. Startle amplitude of adults was decreased at all dosages for males but not for females. These behavioral changes were accompanied by decreases in adult brain weight for both sexes. Whole brain weight and weight of the olfactory bulbs were decreased following all dosages of TMT, while hippocampal weight was decreased following both 5 and 6 mg/kg TMT. These results indicate that acute postnatal exposure to TMT produces long-term effects on the nervous system and behavior.

Animals↗
PubMed1980

Effects of trialkyllead compounds on growth, respiration and ion transport in Escherichia coli K12.

Triethyllead and tripropyllead cations affected growth, energy metabolism and ion transport in Escherichia coli K12. The tripropyllead compound was more liposoluble than the triethyl analogue and was also more effective in inhibiting cell growth and the oxygen uptake of both intact cells and membrane particles. Triethyllead acetate (5 microM) inhibited growth on non-fermentable carbon sources, such as glycerol and succinate, more markedly than on glucose. At higher concentrations, triethyllead caused significant inhibition of respiration rates of intact cells; the concentration giving 50% inhibition was 60 microM for glycerol-grown cells and 150 microM for glucose-grown cells. Oxidation of succinate by membrane particles was less sensitive to inhibition by the tripropyl- or triethyllead compounds than were the oxidations of DL-lactate or NADH. Triethyllead acetate [1.9 mumol (mg membrane protein)-1] inhibited the reduction by NADH of cytochromes; evidence for more than one site of inhibition in the respiratory chain was obtained. Membrane-bound ATPase activity was strongly inhibited by triethyllead acetate in the absence or presence of Cl-. The concentration of inhibitor giving 50% inhibition [0.02 mumol (mg membrane protein)-1] was about two orders of magnitude lower than that required for 50% inhibition of substrate oxidation rates in membranes. Triethyllead acetate (1 microM) induced swelling of spheroplasts in iso-osmotic solutions of either NH4Cl or NH4Br, presumably as a result of the mediation by the organolead compound of Cl-/OH- and Br-/OH- antiports across the cytoplasmic membrane. Similar exchanges of OH- for F-, NO3- or SO4(2)- or the uniport of H+ could not be demonstrated. Comparisons are drawn between the effects of trialkyllead compounds and those of the more widely studied trialkyltin compounds.

Adenosine Triphosphatases↗