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PubMed1988

Dose-specific effects of trimethyltin poisoning on learning and hippocampal corticosterone binding.

The organometal neurotoxin trimethyltin (TMT) damages limbic forebrain, and impairs acquisition of lever-directed behaviors in an autoshaping task, in which a lever is presented according to a random time schedule, and rats learn to associate its presentation/retraction with food delivery (Cohen et al., 1987). This impairment is evident only if a sufficiently long delay of reinforcement is interposed between lever retraction (which occurs either automatically after 15 sec, or immediately upon a touch response) and food pellet delivery. Paradoxically, rats given a higher (7.5 mg/kg) dose show a smaller acquisition impairment, perhaps because they are generally more reactive to the lever than controls. These rats sustain a larger hippocampal lesion (measured by wet weight of the structure). The experiment reported here was done to investigate (1) an autoshaping deficit related to hippocampal weight loss, and (2) biochemical changes in hippocampus which might be related to behavioral impairments. Rats were treated with water vehicle or TMT four weeks before autoshaping using a 6 sec reinforcement delay. In addition to lever touching, touches of the food trough were measured. The timing of trough-touching behaviors within a trial was used as an indication of the strength of the association formed between the lever and the site of food delivery. Following autoshaping rats were adrenalectomized and killed for measurement of cytosolic [3H]corticosterone binding in hippocampus. As before, rats treated with 6.0 mg TMT/kg showed a deficit in acquisition of lever-directed behaviors. Also, as hypothesized, the proportion of total trough-directed behaviors made during the 6 sec reinforcement delay intervals (when reinforcement probability was high) diverged significantly from control values as learning progressed. These rats also showed a reduction in hippocampal weight compared with controls, but significant decreases in hippocampal steroid binding were observed only in groups given the low and median dose of TMT. Further, steroid binding was correlated with lever-directed behaviors. It thus appears that lever and trough behaviors can be used to simultaneously assess different aspects of impairment in associative learning which are accompanied by differential cell loss and biochemical deficit.

Animals↗
PubMed1993

In vitro organotin administration alters guinea pig cochlear outer hair cell shape and viability.

Trimethyltin (TMT) and triethyltin (TET) disrupt auditory function at doses far below those shown to be neurotoxic. In vivo studies suggest that the initial effect of TMT on hearing occurs at the inner hair cell/spiral ganglion cell synapse, while later, the outer hair cell (OHC) undergoes structural and functional damage. TET produces acute effects upon afferent neurotransmission similar to those observed following TMT, but TET's effects on OHC structure and function have not been examined. OHCs are motile elements within the cochlea, believed to modulate the sensitivity and tuning within the inner ear. Changes in OHC length may alter hearing function, and length changes have been reported following exposure to various ototoxic agents in vitro. In the present study, 77 OHCs from 45 pigmented male guinea pigs were isolated in primary culture and exposed for 90 min to concentrations between 30 microM and 1.0 mM of TMT or TET and then to bathing medium for 30 min to remove the toxicant. Significant shortening of the OHC cell body occurred at all doses to both organotins, with a mean reduction in length of 15.1 and 20.2% for 1.0 mM TMT and TET, respectively, at the end of testing; control cells were only 3.4% shorter at the end of 90 min of perfusion with bathing medium. The effect of organotin exposure on OHC volume was not consistently related to either TMT or TET concentration or altered cell length. In addition, disruption of the plasma membrane characterized by bleb formation, the forceful ejection of cytoplasm, or bursting was seen in 80% of cells exposed to 1.0 mM TET, although not TMT; lower concentrations of both organotins disrupted the cell membrane in 10-30% of cells. Membrane rupture was not reliably associated with either increased cell volume or decreased length, implicating a weakening of the plasma membrane or cortical lattice as the basis for this effect. Consistent with the irreversible structural weakening of the lateral wall, resorption of organotin-induced cytoplasmic blebs was never evidenced. Qualitatively, subcellular elements in the central core of many organotin-treated OHCs appeared pathological. These changes are similar to histopathological changes observed following in vivo organotin administration and may represent one target of acute alkyltin ototoxicity.

Animals↗
PubMed1986

Effect of triethyl lead chloride on delta-aminolevulinic acid dehydratase.

The effect of various organic metal compounds on delta-aminolevulinic acid dehydratase (ALAD, porphobilinogen synthetase) activity has been studied. Various organic tin and lead compounds have little effect on this enzyme. However, triethyl lead chloride has a potency similar to that of inorganic lead nitrate in inhibiting ALAD both for in vitro study and after in vivo dosing. Liver and blood ALAD have a similar sensitivity to lead compounds, which is reduced in the presence of zinc. Trimethyl lead chloride inhibits ALAD in vitro to a lesser extent. The results suggest that amphiphilic organic lead compounds may directly inhibit ALAD without prior degradation to inorganic lead. The diffusibility and persistence of triethyl lead combine to make it an especially hazardous lead compound.

Animals↗
PubMed2006

Neurochemical analysis of amino acids, polyamines and carboxylic acids: GC-MS quantitation of tBDMS derivatives using ammonia positive chemical ionization.

The GC-MS quantitation of a large number of neurochemicals utilizing a single derivatization step is not common but is provided by the reagent N-(tert-butyldimethylsilyl)-N-methyltrifluro-acetamide (MTBSTFA). Previous workers have utilized this derivative for GC-MS analyses of amino acids, carboxylic acids and urea with electron impact (EI) and with positive chemical ionization (PCI; methane as reagent gas). However, these conditions yield significant fragmentation, decreasing sensitivity and in some cases reducing specificity for quantitation with selected ion monitoring (SIM). Additionally, the majority of studies have used a single internal standard to quantitate many compounds. In this study we demonstrate that using isotopic dilution combined with ammonia as the reagent gas for PCI analyses, results in high precision and sensitivity in analyzing complex neurochemical mixes. We also demonstrate for the first time the utility of this derivative for the analysis of brain polyamines and the dipeptide cysteinyl glycine. In the case of ammonia as the reagent gas, all amino acids, polyamines and urea yielded strong [MH](+) ions with little or no fragmentation. In the case of carboxylic acids, [M+18](+) ions predominated but [MH](+) ions were also noted. This approach was used to analyze superfusates from hippocampal brain slices and brain tissue extracts from brain lesion studies. The advantages of this methodology include: (i) simple sample preparation; (ii) a single derivatization step; (iii) direct GC-MS analysis of the reaction mix; (iv) high precision as a result of isotopic dilution analyses; (v) high sensitivity and specificity as a result of strong [MH](+) ions with ammonia reagent gas; (vi) no hydrolysis of glutamine to glutamate or asparagine to aspartate; and (vii) applicability to a wide range of neurochemicals.

Acetamides↗
PubMed1998

Glutathione modifies the toxicity of triethyltin and trimethyltin in C6 glioma cells.

It has been demonstrated that exposure to mercury or cadmium compounds causes alterations in the glutathione system in a model glial cell line, C6. Here we report that two organic tin compounds, triethyltin (TET) and trimethyltin (TMT), are also toxic to these cells with EC50 values for cell death of c. 0.02 microM and 0.8 microM respectively. Exposure for 24 h to either of these compounds at sub-toxic concentrations caused increases in the amount of reduced glutathione (GSH) per cell. Increases in glutathione-S-transferase enzyme activity were also demonstrated after TET or TMT exposure. This suggests that glutathione increases occur in glial cells after toxic insults below that required to cause cell death, possibly acting as a protective mechanism. To test whether GSH plays a role in organotin-induced cell death we manipulated GSH in the culture media or via intracellular GSH and looked at the effects on sensitivity to TET or TMT toxicity. Adding GSH to the culture media did not protect the cells. Depletion of intracellular GSH with buthionine-[S,R] sulphoximine did not alter cytotoxicity of TET or TMT. However, pre-treatment with (-)-2-oxo-4-thiazolidine carboxylic acid (OTC), which increases intracellular GSH levels, protected the cells against both compounds. The EC50 for TMT was increased from 0.77 to 1.8 microM, a 2.3-fold shift, whereas the EC50 for TET was increased > 20-fold, from 0.022 to 0.47 microM. One interpretation of these results is that GSH protects cells against the toxicity of organic tin compounds without reacting directly with them to any significant extent. Under conditions where GSH is depleted, additional protective mechanisms may be active.

Animals↗
PubMed2004

Metal cation-methyl interactions in CB11Me12(-) salts of Me3Ge+, Me3Sn+, and Me3Pb+.

Oxidation of Me(6)M(2) (M = Ge, Sn) and Me(4)Pb with the CB(11)Me(12)(*) radical in alkane solvents produced the insoluble salts Me(3)M(+)CB(11)Me(12)(-), characterized by CP-MAS NMR and EXAFS. The cations interact with methyl groups of CB(11)Me(12)(-) with coordination strength increasing from Pb to Ge. Density functional theory (DFT) calculations for the isolated ion pairs, Me(3)M(+)CB(11)Me(12)(-) (M = Ge, Sn), revealed three isomers with the cation above methyl 2, 7, or 12, and not above a BB edge or a BBB triangle. The interaction has a considerable covalent component, with the cation attempting to perform a backside S(E)2 substitution on the methyl carbon. In a fourth less favorable isomer the cation is near methyl 1, inclined toward methyl 2, and interacts with hydrogens. DFT atomic charge distributions and plots of the electrostatic potential on the surface of spheres centered at the CB(11)H(12)(-) and CB(11)Me(12)(-) icosahedra display the effects of uneven charge distribution within the anion and contradict the common belief that the negative charge of the cage anion is concentrated primarily on the cage boron atoms 7-12; in CB(11)Me(12)(-), roughly half is on the cage carbon and the rest on methyls 7-12.

Boron Compounds↗
PubMedDate not supplied

Trimethyltin, a selective limbic system neurotoxicant, impairs radial-arm maze performance.

Rats were trained for fifteen sessions in an automated eight arm radial maze prior to treatment with 6 mg/kg trimethyltin chloride. This compound is a neurotoxicant which primarily damages the limbic system, in particular pyramidal cells in the CA3 region of the hippocampus. Following treatment the animals exhibited a marked and persistent impairment of maze performance characterized by decreased selection accuracy and an altered spatial pattern of responding within the maze. These results offered additional evidence that CA3 pyramidal neurons or their connections play an important, if not essential, role in radial-arm maze performance. It was suggested that trimethyltin might be a useful tool for elucidating the neural substrates of both radial maze performance and learning and memory processes.

Analysis of Variance↗
PubMed1996

Repeated acquisition and the assessment of centrally acting compounds.

Repeated acquisition (RA) procedures are behavioral preparations in which subjects learn new sequences of responses during each experimental session. They have been used with great success to assess the effects of drugs and other compounds on learning processes. As learning can be measured over many sessions in individual subjects, RA procedures can prove invaluable when conducting studies of the effects of chronic drug administration, aging and the long-term effects of exposure to toxic compounds. Analyzing the patterns of responding during acquisition can provide insights into the behavioral mechanisms underlying the effects of drugs and other centrally acting compounds on learning. Systematic comparisons are needed on the influence of many procedural variables on RA and the extent to which they may modulate the effects of chemicals.

Animals↗
PubMed1990

Tributyltin stimulates apoptosis in rat thymocytes.

Treatment of rat thymocytes with micromolar concentrations of tributyltin caused a rapid increase in the cytosolic free Ca2+ concentration that was inhibited by Ni2+, which blocks Ca2+ influx through membrane channels. The elevation of cytosolic Ca2+ was associated with extensive DNA fragmentation, which was prevented by pretreatment of the cells with either of the intracellular Ca2+ chelators quin-2 or 1,2-bis(2-amino-phenoxy)ethane-N',N',N',N',-tetraacetic acid. Loss of thymocyte viability, which followed DNA fragmentation, was also prevented by the two Ca2+ chelators or by removing extracellular Ca2+ with ethylene glycol bis(beta-aminoethyl ether)N,N'-tetraacetic acid. The pattern of DNA fragmentation was characteristic of that produced by agents which activate a Ca2(+)- and Mg2(+)-dependent endogenous endonuclease during apoptosis or programmed cell death. Additional studies showed that other organotin compounds, including trimethyltin, triphenyltin, and dibutyltin had minimal effects on cytosolic Ca2+, DNA fragmentation, and cell viability. These results are consistent with a greater susceptibility of thymocytes to tributyltin and provide a basis for understanding its selective immunotoxicity in vivo.

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↗
PubMed1996

How does trimethyltin affect the brain: facts and hypotheses.

Trimethyltin, an organic compound of tin, is a potent neurotoxicant of a mechanism of action yet to be uncovered. The neuropathological findings that trimethyltin causes selective hippocampal damage with several unique features, highly reminiscent of Ammon's horn sclerosis as a final result, have raised the possibility that there is a link between trimethyltin neurotoxicity and other degenerative events for which an imbalance between neuronal inhibition/excitation has been proposed. However, there still exists a whole catalog of issues which await clarification. One of the greatest importance is how does trimethyltin reach the critical sites within the brain and what are they? Available data concerning the long-term consequences related to trimethyltin neurotoxicity are also far from being completed. This review summarizes current data from in vitro and in vivo studies on neurotoxic effects of trimethyltin. Several hypotheses on mechanisms that may lead to neuronal death induced by the toxin are presented.

Animals↗
PubMed2002

Preventable exposure to trimethyl tin chloride: a case report.

Trimethyl tin chloride (TMTC) is a highly toxic organotin compound that affects four main target organs: the brain, liver, immune system and skin. Exposure can occur by inhalation, ingestion or direct skin absorption. Trimethyl tin is but one of many hazardous substances with potentially serious health consequences to which individuals working in research laboratories may be exposed. We report a preventable case of TMTC exposure. Better understanding of the Canadian Workplace Hazardous Materials Information System (WHMIS) legislation and its applicability to the research laboratory situation would prevent such unnecessary exposure to hazardous substances.

Adult↗
PubMed2001

N-chlorotaurine, a novel endogenous antimicrobial agent: tolerability testing in a mouse model.

OBJECTIVE: To investigate the tolerability of N-chlorotaurine, a new antimicrobial agent, by application to the middle ear in a mouse model. METHODS: Five BALB/c mice were each injected through the tympanic membrane with 5 microL of 0.1%, 1.0%, and 10% N-chlorotaurine and compared with animals in which 0.9% isotonic sodium chloride solution, 0.2% gentamicin sulfate, and 0.25% trimethyltin chloride were instilled. Auditory brainstem responses to clicks were evaluated repeatedly between 4 and 75 days after injection, and histologic investigations of the inner ear were performed subsequently. Three additional groups of mice were injected with isotonic sodium chloride solution, 1.0% N-chlorotaurine, and 0.25% trimethyltin, and brainstem responses to tone bursts of 8, 16, and 32 kHz were tested. In addition, the middle ear was examined histologically. RESULTS: Mice treated with isotonic sodium chloride solution, 0.1% N-chlorotaurine, and 0.2% gentamicin sulfate did not show changes in response threshold. Treatment with 1.0% and 10% N-chlorotaurine caused a reversible increase in auditory brainstem response threshold by 20 dB 4 days after application because of local irritation around the perforation of the tympanic membrane. In contrast, 0.25% trimethyltin showed a permanent elevation of auditory brainstem response threshold of 10 to 15 dB and a scattered loss of outer hair cells predominantly in the apical turn. No alterations of the inner ear were observed in the other treatment groups. The mucous membrane of the middle ear remained unaffected in all test groups. CONCLUSION: Application of N-chlorotaurine to the middle ear is well tolerated without adverse effects and may be a useful new endogenous antimicrobial agent for local treatment of otologic infections.

Animals↗
PubMed1999

Calcitonin gene-related peptide immunoreactivity in the hippocampus and its relationship to cellular changes following exposure to trimethyltin.

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is regionally regulated following peripheral insult and in central nervous system (CNS) damage models targeting limbic structures. Functional studies have shown this neuropeptide to be involved in neuronal protection and remodeling, vasodilation, immunomodulation, and apoptosis, thus making it an important constituent of the acute phase response. In the present study, we characterized the anatomic expression and distribution of CGRP immunoreactivity (CGRP-IR) after exposure to the toxin, trimethyltin (TMT). We chose this model because TMT causes dramatic changes in the endocrine system, the limbic system, particularly the hippocampus, as well as in the immune response. We have specifically focused on comparing the changes in CGRP-IR with the pattern of apoptosis (via TUNEL staining), cell-cycle activation (Ki67-IR), and in alteration in microglia (OX-42-IR) and astrocyte (gGFAP-IR) immunocytochemistry in TMT-treated hippocampus. Our results show a marked change in CGRP-IR in regions of the hippocampus that are temporally and anatomically correlated with the induction of apoptosis and activation of microglia, astrocyte, and the cell-cycle marker. Given the known effects of CGRP on these cell types and on programmed cell death elsewhere, these findings are consistent with a regional immunoregulatory/injury response role for CGRP following organotin poisoning.

Animals↗
PubMed1998

Trimethyltin intoxication induces marked changes in neuropeptide expression in the rat hippocampus.

In situ hybridization and immunocytochemistry were applied to investigate changes in the expression of somatostatin, neuropeptide Y, neurokinin B, cholecystokinin, dynorphin, and Met-enkephalin in the rat hippocampus after administration of a single peroral dose of trimethyltin hydroxide (9 mg/kg). Two time intervals were investigated: 5 days after trimethyltin treatment, when CA3 damage becomes manifest and is associated with increased aggression, seizure susceptibility, and memory deficit, and 16 days after trimethyltin, when neuronal damage is almost maximal and seizure susceptibility is declining. Robust but transient increases of neuropeptide Y, neurokinin B, and Met-enkephalin mRNA levels were revealed in the granule cell layer of the dentate gyrus and increased neuropeptide Y and neurokinin B immunoreactivities were found in mossy fibers. In reverse, dynorphin mRNA and immunoreactivity were decreased transiently in the dentate gyrus and mossy fibers, respectively. Strong over-expression of NPY mRNA was also observed in hilar interneurons and in CA1 and CA3 pyramidal cells as well as in the cortex at 5 days postdosing. Cholecystokinin- or neurokinin B-containing basket cells were preserved, while somatostatin-bearing interneurons were damaged by trimethyltin exposure. These neurochemical changes induced by trimethyltin intoxication strikingly parallel to those observed in animal models of temporal lobe epilepsy and may reflect activation of endogenous protective mechanisms. It is also suggested that hilar interneurons respond differently to trimethyltin exposure, for which neuropeptides are valuable markers.

Animals↗
PubMed2000

Chemical-induced hippocampal neurodegeneration and elevations in TNFalpha, TNFbeta, IL-1alpha, IP-10, and MCP-1 mRNA in osteopetrotic (op/op) mice.

The osteopetrotic (op/op) mouse, deficient in biologically active colony stimulating factor 1 (CSF-1), was used to examine the role of microglia in chemical-induced trauma. Op/op mice and normal phenotype littermates (non-op/op) received an acute i.p. injection of the hippocampal toxicant, trimethyltin hydroxide (TMT; 1.5 or 2.0 mg/kg). At 2.0 mg/kg, both mice displayed severe degeneration of dentate granule neurons. At 1.5 mg/kg, non-op/op mice showed a limited punctate pattern of neuronal death while op/op mice showed prominent neuronal death. TMT-induced astrocyte reactivity was similar in both groups. RNase protection assays were conducted on hippocampal tissue at 24 hr post-TMT. Elevations were seen in mRNA levels for the host response genes: intercellular cell adhesion molecule (ICAM-1; non-op/op 80%, op/op 85%), the protease inhibitor EB22 (non-op/op 60%, op/op 300%), and glial fibrillary acidic protein (GFAP; non-op/op 300%, op/op 480%) within 24 hr. Macrophage-1 antigen (Mac-1) mRNA levels were lower in all op/op mice and were not induced by TMT exposure. Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta mRNA levels were elevated in non-op/op mice while mRNA levels for interferon inducible protein (IP-10) and monocyte chemoattractant protein (MCP-1) were elevated in op/op mice. Tumor necrosis factor alpha (TNFalpha) mRNA levels were significantly elevated in both non-op/op (100%) and op/op (600%) mice. TNFbeta mRNA levels in op/op mice were elevated 200% and interleukin 1alpha (IL-1alpha) 150%. Reverse transcriptase polymerase chain reaction (RT-PCR) showed a TMT-induced elevation in INFalpha and INFbeta mRNA levels and no elevation of INFgamma. mRNA levels of the CSF-1 receptor, c-fms, were unaltered.

Animals↗
PubMed1994

Trimethyltin-induced expression of GABA and vimentin immunoreactivities in astrocytes of the rat brain.

Adult Sprague-Dawley rats were given a single dose of trimethyltin chloride (TMT). Three days following treatment, a neuronal alteration was observed in the CA3c pyramidal cell layer of hippocampus which was not accompanied by any apparent astrocyte reaction. At 1 as well as 2 weeks after treatment, a gliosis in hippocampus, piriform, and entorhinal cortices was detected by glial fibrillary acidic protein (GFAP) immunohistochemistry. Concomitant with the enhanced astrocytic GFAP, astrocytes were swollen and expressed immunoreactivity to vimentin and gamma-aminobutyric acid (GABA). The astrocytic GABA immunoreactivity may reflect a trimethyltin-induced alteration in astrocyte phenotype, or alterations in compartmentalization and/or metabolism of GABA.

Animals↗