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PubMed1991

Acute ototoxicity of trialkyltins in the guinea pig.

Two trialkyltin compounds, trimethyltin chloride (TMT) and triethyltin bromide (TET) were evaluated for their acute effects on cochlear function in pigmented guinea pigs. Compound action potential (CAP) thresholds and 1 microV RMS cochlear microphonic (CM) isopotential curves were generated for 25 subjects following ip injection of TMT (2 mg/kg), TET (12 or 24 mg/kg) or inert vehicle (0.9% saline or 15% ethanol). The CAP is generated by the release of neurotransmitters from the inner hair cells and the subsequent depolarization of spiral ganglion cells. However, the sensitivity of the CAP is influenced by other cochlear structures including the outer hair cells which are thought to influence sensitivity of the inner hair cells. By contrast, CM reflects electromechanical function of the outer hair cells. CAP function was severely disrupted by organotin exposure while CM was unaffected by these agents. TMT administration impaired CAP thresholds at all frequencies within 30 min of administration. Thresholds deteriorated slightly more between 30 and 60 min. TET also reduced the sensitivity of the CAP to all frequencies. At the lower dose moderate impairments of function were observed at 30 min which became more noticeable at 60 min. Following 24 mg/kg TET injection, CAP sensitivity was markedly impaired even at 30 min. The CM isopotential values were not significantly altered 30 min or 60 min after either TMT or TET treatment at any of the 11 frequencies tested. These data document far more rapid toxic effects of TMT and TET than have been seen in most intact neuronal systems. They indicate that both organotins initially disrupt the functional integrity of either inner hair cells or spiral ganglion cells within the cochlea such that depolarization occurs only following a significant increase in stimulus intensity.

Action Potentials↗
PubMed1981

The microsomal metabolism of the organometallic derivatives of the group-IV elements, germanium, tin and lead.

The NADPH- and oxygen-dependent microsomal metabolism of the di-, tri- and tetra-ethyl-substituted derivatives of germanium, tin and lead was shown to give rise to ethylene as a major product and ethane as a minor product. These reactions were shown to be catalysed by the liver microsomal cytochrome P-450-dependent mono-oxygenase. Since formation of ethane and ethylene was differentially inhibited by anaerobiosis, the results suggest that at least a large portion of the ethane produced may be derived by a reductive mechanism. Triethyltin bromide in both the absence and presence of NADPH was shown to convert cytochrome P-450 into cytochrome P-420 and to affect the function of the mono-oxygenase in vitro. Tetraethyltin caused the NADPH- and time-dependent formation of cytochrome P-420, suggesting that tetraethyltin is converted into triethyltin salts in significant concentrations. The order of potency in formation of cytochrome P-420 was closely paralleled by the ability of the tin derivatives to induce microsomal lipid peroxidation in vitro.

Animals↗
PubMed1986

Effect of triethyltin on enzyme activity in human adult and cord red cells.

Since organotin compounds represent an environmental health hazard, we determined the effect of triethyltin bromide (TTB) on red blood cell (RBC) enzyme activity. TTB produced a concentration-dependent inhibition of hexokinase and pyrimidine 5'-nucleotidase for both adult and cord RBC. D-Glucose, but not ATP or MgCl2, prevented the hexokinase inhibition by TTB. Glucose-6-phosphate dehydrogenase, adenylate kinase, and hypoxanthine-guanine phosphoribosyltransferase were also inhibited by TTB. Cord RBC enzymes were more resistant to the effects of TTB than were adult RBC enzymes. Although TTB is a potent inhibitor of hexokinase, physiologic concentrations of glucose appear to protect the RBC during clinical tin intoxication.

5'-Nucleotidase↗
PubMed1996

Chemistry of indoles carrying a basic function, Part 3. Synthesis of spiro[cyclopropane-1,3'[3H]indol]-2'(1'H)-ones with antihypoxic effects.

Hydroxyindolones (1-6, 15-16) were transformed into isatinylidenes (7, 9-13, 17-19) by dehydration with 4-toluenesulfonic acid. The dimer-type compounds (14, 20) were also isolated in a few cases. The obtained isatinylidenes were transformed into 3-spiro-cyclopropane-oxindoles (21-32) with dimethyloxosulfonium methylide. Compound 22 shows protective effects against hypobaric hypoxia and triethyltin induced brain edema.

Air Pressure↗
PubMed1975

Modification and inheritance of pleiotropic cross resistance and collateral sensitivity in Saccharomyces cerevisiae.

A meiotic segregant (oliPR1) was isolated with a phenotype of multiple cross resistance and collateral sensitivity. Strain oliPR1 has increased sensitivity to ethidium bromide, dequalinium chloride, acriflavin, paromomycin and neomycin, and increased resistance to oligomycin, rutamycin, venturicidin, triethyltin bromide, antimycin, carbonylcynamide-m-chlorophenylhydrazone, tetra-N-butylammonium bromide, dibenzyldimethylammonium chloride, triphenylmethlphosphonium bromide, chloramphenicol, carbomycin, tetracycline, triton X-165 and cycloheximide. Single gene inheritance of the cross resistance and collateral sensitivity was shown by 2:2 parental ditype segregation and reversion of the complete phenotype by a spontaneous revertant. The locus conferring the oliPR1 phenotype was mapped 11.7 units from an unspecified centromere. Antibiotic resistance showed incomplete dominance, with the level of hybrid resistance dependent upon the inhibitor tested. Resistant diploids that produced four resistant ascospores were the result of mitotic recombination prior to meiosis. A partial revertant phenotype (sensitive to all inhibitors except oligomycin, antimycin and carbonylcyanide-m-chlorophenylhydrazone) was shown to be due to a single nuclear gene causing partial suppression of oliPR1. Anaerobic pretreatment, 37degrees and 0.5 MKC1 were observed to reduce the growth of oliPR1 when challenged with seven diverse inhibitors (antimycin, carbonylcyanide-m-chlorophenylhydrazone,-chloramphenicol, cycloheximide, oligomycin, triethyltin bromide, and triphenylmethylphosphonium bromide). Resistance to cycloheximide was not altered by the [rho--] state. A revertant of oliPR1 (sensitive to the above inhibitors but resistant to ethidium bromide, paromycin and neomycin) showed anaerobic and temperature sensitization to ethidium bromide, paromomycin and neomycin. Continuous monitoring of oxygen uptake by the revertant afteranaerobic pretreatment revealed that anaerbiosis sensitized respiratory adaptation of the revertant to neomycin. It is proposed that oliPR1 is a mutation resulting in the alteration of plasma membrane permeability to many diverse inhibitors.

Antimycin A↗
PubMed1979

Effect of organotin compounds and hexachlorophene on brain adenosine cyclic 3',5'-monophosphate metabolism.

The effect of triethyltin (TET), triphenyltin (TPT), hexachlorophene (HCP) and cuprizone on adenosine cyclic 3',5'-monophosphate (cyclic AMP) production in rat brain was examined both in vitro and in vivo. TET and TPT inhibited basal adenylate cyclase activity of brain homogenate at a concentration as low as 1 microM in vitro but these compounds had no effect on norepinephrine (NE) and dopamine(DA)-stimluated enzyme activity. HCP and cuprizone failed to inhibit adenylate cyclase activity. In vivo TET given intravenously at a dose rate of 10 mg/kg decreased the cyclic AMP content of cerebrum, but not of medulla. TPT and HCP give intravenously and intraperitoneally respectively failed to decrease the cyclic AMP content of the cerebrum. In the case of TET the reduction in cyclic AMP content of the cerebrum was prevented by maintaining the rats normothermic after treatment. On the basis of these results the inhibition of adenylate cyclase produced by TET in brain homogenates in vitro would not appear to be involved in the development of nervous changes associated with acute TET toxicity, or in the production of progressive brain oedema caused by TET, HCP and cuprizone.

Adenylyl Cyclases↗
PubMed1997

Capillary electrophoresis of organotin compounds with indirect UV detection.

A capillary electrophoresis (CE)-indirect UV absorbance detection method for organotin compounds is described. The five triorganotin cations, viz., trimethyltin (TMT), triethyltin (TET), tripropyltin (TPT), tributyltin (TBT) and triphenyltin (TPhT), were efficiently separated by CE in 10 min with a 5 mM acetate buffer (pH 4.5) containing 3 mM 4-aminopyridine (4-AP). 4-AP also functioned as a UV-absorbing coion for the indirect detection of these UV-transparent organotin species. Simultaneous separation of di- and triorganotins was achieved with the addition of alpha-cyclodextrin (alpha-CD) as a modifier in the electrophoresis buffer. Linearity (r > or = 0.995) of about two orders of magnitude was generally obtained. The concentration limits of detection for the organotin compounds studied were between 2 and 20 microM (as tin). The relative standard deviation (RSD) values were in the range 1.3-7.1%. The applicability of the method for the analysis of marine sediment was examined.

Calibration↗
PubMed1986

Toxicity of organotin compounds for polymorphonuclear leukocytes: the effect on phagocytosis and exocytosis.

Phagocytosis and concomitant release of enzymes by rabbit polymorphonuclear leukocytes (PMNs) are inhibited by micromolar concentrations of triphenyltin and tributyltin; inhibition by triethyltin occurs at higher concentrations. Chemotactic peptide-induced exocytosis is inhibited at the same concentrations as phagocytosis. Tributyltin causes cell lysis at slightly higher concentrations as required for inhibition of phagocytosis and exocytosis. The organotin compounds have little effect on ATP level in PMNs, which makes an effect on metabolic energy providing processes unlikely. The increase of Ca2+-permeability of the plasma membrane, induced by chemotactic peptide, is inhibited by the organotin compounds. Inhibition of exocytosis by triphenyltin can be counteracted by a number of sulfhydryl compounds. The results suggest that the organotin compounds interfere with PMN function in an early phase of cell activation, where all functions have a common pathway, and where vulnerable sulfhydryl groups play a pivotal role.

Adenosine Triphosphate↗
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↗
PubMed1997

Interactions of triethyltin-chloride (TET) with the energy metabolism of cultured rat brain astrocytes: studies by multinuclear magnetic resonance spectroscopy.

The effect of triethyltin-chloride (TET), a highly neurotoxic compound, on the cellular metabolism of rat brain astrocytes in vitro was examined by nuclear magnetic resonance (NMR) spectroscopy. 5-week-old cultures were exposed to TET (0.2-40 microM) either for (1) acute (3h), (2) 24 h, or (3) chronic treatment (8 d). Cells were labeled with 1-(13)C-glucose, cell extracts were prepared and 31P, 1H, and 13C spectra were analyzed. Cytotoxic effects of TET were assessed by vital dye uptake assay using neutral red (NR) and by exclusion of trypan blue (TB). Cells were examined ultrastructurally by electron microscopy. The data show that the major target of TET at concentrations already causing morphological effects on cultured astrocytes is not the energy metabolism, but that TET rather alters the intracellular concentrations of organic osmolytes, such as myo-inositol, taurine and hypotaurine, which are part of the control of ion and volume regulation and osmotic balance in astrocytes.

Animals↗
PubMed1998

Comparative studies on the induction of muscle contracture in mouse diaphragm and Ca2+ release from sarcoplasmic reticulum vesicles by organotin compounds.

Effects of organotins, including triethyltin and tributyltin, on skeletal muscle were studied with diaphragm and isolated sarcoplasmic reticulum membrane vesicles. Triethyltin induced muscle contracture in mouse diaphragm while tributyltin had comparatively less potency and efficacy in inducing the muscle contracture. The contracture induced by tributyltin was inhibited when the diaphragm was pretreated with low Ca2+ medium or caffeine while the contracture induced by triethyltin persisted in the Ca2+-free medium but was inhibited by pretreatment of caffeine. Pretreatment of dithiothreitol blocked the contracture induced by tributyltin but not that by triethyltin. Triethyltin dose-dependently induced Ca2+ release from sarcoplasmic reticulum vesicles and inhibited the Ca2+-ATPase activity. These results suggested that triethyltin induced contracture in mouse diaphragm was mainly by induction of Ca2+ release and inhibition of Ca2+ uptake of the internal Ca2+ storage site the sarcoplasmic reticulum, while the tributyltin induced contracture might be due to enhancement of extracellular Ca2+ influx which further induce the release of internal Ca2+ through the Ca2+-induced Ca2+ release mechanism.

Animals↗
PubMed1991

Pattern of organotin inhibition of methanogenic bacteria.

Seven organotin compounds and tin chloride were tested for their effects on the methanogenic bacteria Methanococcus thermolithotrophicus, Methanococcus deltae delta LH, and Methanosarcina barkeri 227. The methanogens were strongly inhibited by triethyltin, tripropyltin, and monophenyltin compounds, generally at concentrations below 0.05 mM. Less inhibition by tributyltin and diphenyltin was observed at levels below 0.1 mM, but complete inhibition was observed at a 1 mM concentration. Tin chloride inhibited all methanogens, with nearly complete inhibition at a 1 mM concentration. There was no inhibition by tetra-n-butyltin and triphenyltin compounds even at 2 mM, the highest concentration tested. The 50 and 100% inhibitory concentrations of all compounds were estimated; these values varied with both the compound tested and the bacterium tested. The 50% inhibitory concentration estimate generally decreased (i.e., giving a higher toxicity) as the total surface area of the alkyltin molecules decreased. These results differ considerably from those reported previously for aerobic microorganisms (G. Eng, E. J. Tierney, J. M. Bellama, and F. E. Brinckman, Appl. Organometallic Chem. 2:171-175, 1988), where a clear correlation between increasing total molecular surface area and increasing toxicity was documented with a variety of organisms. Using the same procedures as for the methanogens, we examined the effects of organotin compounds on Escherichia coli growing aerobically or anaerobically. The E. coli inhibition pattern clearly resembled that seen in the data of Eng et al., under both aerobic and anaerobic conditions.

Escherichia coli↗
PubMed1979

Triethyltin binding to cat haemoglobin. Evidence for two chemically distinct sites and a role for both histidine and cysteine residues.

Triethyltin binding to cat haemoglobin was measured after pretreatment of the protein with diethyl pyrocarbonate at pH 6.0,iodoacetamide or phenylmercuric acetate or by photo-oxidation in the presence of Methylene Blue. The pentaco-ordinate nature of the binding of triethyltin to cat haemoglobin is confirmed by the inability of intramolecularly pentaco-ordinate tin compounds to compete. Consideration of the symmetry of the haemoglobin molecule in the light of the above results suggests that a unique arrangement of histidine and cysteine residues is required for the binding of triethyltin. The effects of treatment with diethyl pyrocarbonate of other preparations which bind triethyltin (rat liver supernatant, a fraction from rat liver mitochondria and rat brain myelin) were determined and shown to be complex.

Animals↗
PubMed1994

Rapid cytoskeleton modification in thymocytes induced by the immunotoxicant tributyltin.

Treatment of rat thymocytes with the immunotoxic environmental pollutant tributyltin (TBT) caused a rapid decrease in the F-actin content resulting in the depolymerization of 80% of the total thymocyte F-actin in 10 min. Removal of extracellular Ca2+ and pretreatment of the thymocytes with the intracellular Ca2+ chelator, 1,2-bis(2-aminophenoxy)ethane-N',N',N',N',-tetraacetic acid, abolished the TBT-induced increase in cytosolic free Ca2+ concentration but reduced the depolymerization of F-actin by only 25%. Thus, the data suggest that 75% of the decrease in F-actin content in the thymocytes was due to other effects of TBT. Pretreatment of rat thymocytes with the alkylating agent N-ethylmaleimide completely inhibited TBT-induced F-actin disruption, suggesting that thiol group modification is involved. The TBT-induced decrease in thymocyte F-actin was not specific for any particular subpopulation of thymocytes. Furthermore, triphenyltin and the metabolite of TBT, dibutyltin, were also found to induce depolymerization of thymocyte F-actin, whereas nonimmunotoxic organotin compounds like trimethyltin and triethyltin had no effect. In conclusion, TBT was found to induce rapid depolymerization of F-actin in thymocytes through both Ca(2+)-dependent and Ca(2+)-independent mechanisms, suggesting that the potent immunotoxic effect of TBT may involve cytoskeletal modifications in addition to the perturbation of thymocyte Ca2+ homeostasis reported previously.

Actin Cytoskeleton↗
PubMed1985

Effect of alkyltins on rabbit articular and growth-plate chondrocytes in monolayer culture.

The effect of four different alkyltins (trimethyltin, triethyltin, dibutyltin, and dioctyltin) on the metabolism of rabbit articular and growth-plate chondrocytes was investigated using a monolayer cell-culture system. In most instances the compounds tested exhibited a general cytotoxic effect on these cells, inhibiting the synthesis of both DNA and sulfated proteoglycans. The effect of these compounds on proteoglycan synthesis was both quantitative and qualitative, as demonstrated by CsCl isopycnic density gradient centrifugation and gel exclusion chromatographic techniques. However, certain tin compounds tested, at specific concentrations, exerted a stimulatory effect on chondrocyte proliferation. Regarding DNA synthesis, growth-plate chondrocytes were more sensitive to the effect of the triethyltin, dibutyltin, and dioctyltin than were articular chondrocytes. The data are discussed in relation to the possible effects of the alkyltins on skeletal growth and development as well as the mechanism of action of the alkyltins at the molecular level.

Animals↗
PubMed1996

Induction of apoptosis by organotin compounds in vitro: neuronal protection with antisense oligonucleotides directed against stannin.

Immortalized cell lines and primary neuronal cultures were used to characterize the selective toxicity of trimethyltin (TMT),triethyltin (TET) and tributyltin (TBT). TBT and TET were cytotoxic at similar concentrations in the immortalized cell lines tested; the 50% toxic concentration (TC50) was 1 to 11 microM. In contrast, immortalized cell lines varied considerably in their sensitivity to TMT, with sensitive cell lines (neuroblastomas, T-, B-cell lines) showing TC50 values of 2 to 8 microM, whereas insensitive cells (NIH-3T3 fibroblast, HTB-14 glioma, TC-7 kidney cells) had TC 50 values > 100 microM. Primary neuronal cell cultures were very sensitive to organotins (TC50 values, 1-10nM), and showed patterns of selective toxicity with respect to neuronal and glial cells. Because organotin toxicity evolves over 24 to 48 hr. we determined whether these compounds induced apoptosis in primary cultures. TMT increased (P < .05) the fraction of apoptotic cells 6 and 12 hr after treatment with TMT at TC50 concentrations. Prior studies suggested that a protein, stannin, was localized in cells sensitive to organotins. Stannin was expressed in several TMT-sensitive cell lines (PC12, T, B cells) and in primary neurons in culture. Stannin was absent in the resistant HTB-14 glioma cell line. The role of stannin in mediating TMT toxicity in primary cultures was investigated by blocking stannin expression with specific antisense oligonucleotides. Treatment of primary cultures with antisense oligonucleotides for 48 hr before and during TMT treatment significantly protected neurons from the neurotoxic and apoptotic effects of TMT. This effect was not observed with scrambled oligonucleotide controls. Thus, TMT may induce apoptosis in sensitive cells, which is partly mediated by stannin. Based on the available data we conclude that stannin expression is necessary, but not sufficient for TMT toxicity.

Animals↗
PubMed1986

Peripheral and central nervous system lesions caused by triethyl- and trimethyltin salts in rats.

Both trimethyltin and triethyltin salts are known to produce toxic lesions in the central nervous system. Triethyltin intoxication has been associated with central intramyelin edema, while trimethyltin has been shown to produce neuronal necrosis in selected limbic and sensory regions of the brain. Only scant attention has been paid to peripheral nerves of animals treated with alkyltins. In this study, we have treated rats with 6 or 8 mg/kg trimethyltin, and 1, 2, 4, 6, or 8 mg/kg triethyltin (single or multiple exposure), and evaluated in detail at the light microscope level both central and peripheral nervous system lesions. In addition to the central neuron necrosis or myelin edema described previously, both compounds produced peripheral axon degeneration and chromatolysis of large spinal cord and brain stem neurons. Chromatolysis was seen in reticular neurons of the brain stem and ventral horn or spinal cord in rats receiving high doses (6 or 8 mg/kg) of triethyltin, and in these same areas plus mesencephalic trigeminal nucleus in animals treated with trimethyltin. Wallerian-like degeneration of peripheral axons was seen in sciatic and tibial nerve and ventral roots of animals receiving 3 injections of 4 mg/kg or single or multiple injections of 6 or 8 mg/kg triethyltin. Axon degeneration was also seen in sciatic and tibial nerves 21 days after a single exposure to 8 mg/kg trimethyltin. Since myelin edema is believed to be reversible, the axonal changes described here may be of greater clinical significance in relation to human exposure.

Animals↗
PubMed1984

General toxicology of tin and its organic compounds.

The toxicology of tin is almost entirely the toxicology of the organic compounds of tin, for the metal itself and its inorganic compounds appear to be nearly harmless for practical purposes. Furthermore, the neurotoxicity of organotin is essentially that of trimethyltin and triethyltin.

Animals↗