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PubMed1995

Enhanced expression of peripheral benzodiazepine receptors in trimethyltin-exposed rat brain: a biomarker of neurotoxicity.

We have used the binding of the selective, high affinity, isoquinoline carboxamide, [3H]-PK11195, to measure the levels of Peripheral Benzodiazpine Receptors (PBR) in the brain of rats exposed to the well characterized neurotoxicant trimethyltin (TMT). The results demonstrate that autoradiograms of saggital sections of rats injected with a 8 mg/kg TMT dose, express a high level of [3H]-PK11195 binding in brain regions known to be damaged by TMT. The highest level of [3H]-PK11195 binding in the TMT-exposed rats occurred in the CA3/CA4 subfield of the hippocampus, followed by the primary olfactory cortex, the posteriomedial cortical amygdaloid nucleus, subiculum, and entorhinal cortex. These findings are consistent with the neuropathology of TMT in rats. The increase in [3H]-PK11195 binding in the brain of TMT-exposed rats was significant at 7 days after injection and remained elevated up to 42 days after exposure, the last time point measured in the study. This pattern is very similar to that observed for levels of the astrocyte intermediate filament protein, GFAP. The enhanced binding of [3H]-PK11195 in TMT-exposed rats was the result of a significant increase (p < 0.005) in the number of PBR with no change in affinity. The Bmax for [3H]-PK11195 binding in hippocampi from TMT-treated rats at 4 weeks post-injection was 606 +/- 25 (n = 4) fmoles/mg protein and 329 +/- 41 (n = 4) fmoles/mg protein for control. These findings suggest that the quantitative assessment of [3H]-PK11195 binding to PBR in the brain could represent a potential biomarker for assessing chemical-induced neurotoxicity. Since this ligand has been labeled with single photon (123I) or positron emitting (11C, 18F) radioisotopes, it can potentially be used with non-invasive imaging techniques such as Single Photon Emission Tomography (SPECT) or Positron Emission Tomography (PET) for human studies.

Animals↗
PubMed1997

Trimethyltin exposure in the rat induces delayed changes in brain-derived neurotrophic factor, fos and heat shock protein 70.

Trimethyltin chloride (TMT) treatment in adult rats leads to limbic brain lesions that are detectable with classical neuropathological techniques 3 days after exposure. In particular, the hippocampal cells of the CA3c region are affected. The temporal and regional characteristics of TMT toxicity as reflected in changes of activity-dependent factors were studied in adult male Sprague-Dawley rats using quantitative in situ hybridization and immunohistochemistry. No significant alterations in the BDNF mRNA were detected in hippocampus and cerebral cortex 1 and 4 h after 8 mg TMT/kg. Three days after TMT, a significant increase in BDNF mRNA was detected in CA1, and increases in BDNF mRNA were also seen in cortical layers. An increase in BDNF hybridization signal was seen over scattered neurons within and outside CA3c at 3 days. Four h after 8 mg TMT/kg, BDNF immunoreactivity was reduced in the pyramidal cells of the CA3c and CA1 regions as well as in the dentate gyrus. No significant change in BDNF immunoreactivity was seen in hippocampus or cerebral cortex 3 days after TMT. BDNF interacts with the high-affinity receptor tyrosine kinase B (trkB). No immediate alteration in trkB mRNA was seen in hippocampus or cerebral cortex after 8 mg TMT/kg, while at 3 days trkB mRNA was significantly reduced in the CA3c pyramidal cell layer. No changes could be detected in neurotrophin-3 mRNA at either 1, 4 h or 3 days after TMT. Three days after 8 mg TMT/kg, a major induction of hsp70 mRNA occurred in a subset of neurons in the CA3c region, concomitant with an increased expression of c-fos mRNA as well as Fos protein in the hilar region of hippocampus. Hence, an early and transient decrease in BDNF appears to occur after TMT exposure, which is succeeded at 3 days by increases in BDNF, c-fos and hsp 70 mRNAs, concomitant with a decrease in trkB mRNA in regions known to be vulnerable to TMT. These results demonstrate that TMT causes a delayed, spatially restricted increase in activity-dependent gene expression, making TMT-induced disturbances an interesting model of neurodegenerative events.

Animals↗
PubMed1997

Altered expression of polysialylated NCAM in mouse hippocampus following trimethyltin administration.

Proper structuring of neural connections in the hippocampus is mediated by cell adhesion molecules, membrane-linked proteins involved in cell recognition and stabilization of cytoarchitecture. Modulated expression of the neural cell adhesion molecule (NCAM) at the synapse permits plasticity required for both learning and memory. Polysialylation of NCAM, particularly the synapse-specific 180 kDa isoform (NCAM180), allows hippocampal neurons to alter their neuronal connections during learning acquisition and memory consolidation in mature brain. These activity-dependent changes in NCAM expression represent a sensitive target for neurotoxicity. Trimethyltin (TMT), a potent hippocampal neurotoxicant, alters total NCAM expression in whole mouse hippocampus and impairs learning in rodents. To investigate the expression of polysialylated NCAM following TMT administration, Swiss-Webster mice were injected (i.p.) with 2.0 or 3.0 mg TMT/kg and sacrificed 6 hrs to 7 days later. Immunocytochemical staining for polysialylated NCAM (PSA-NCAM) revealed marked reduction of staining of hippocampal dentate granule cells 6-72 hours after TMT treatment. Partial recovery of hippocampal polysialylated NCAM was observed after 7 days. Immunoblot data indicated that loss of PSA-NCAM expression paralleled reductions seen in NCAM180 and markers of cytoskeletal integrity. Assays for proteolytic activity in hippocampus revealed rapid, reversible protease activation which correlated temporally with the reduction of NCAM180 and PSA-NCAM. Proteolytic degradation following hippocampal injury may serve to disrupt NCAM-mediated adhesion. Protracted loss of polysialylated NCAM in dentate gyrus following injury may serve as a useful marker in toxicant-induced learning disorders.

Animals↗
PubMed1998

Interleukin-1 receptor antagonist inhibits transient increase of plasma corticosterone in the initial phase of trimethyltin-induced hippocampal necrosis.

The temporal increase of plasma corticosterone (CORT) levels at 3 or 4 days after a single oral administration of trimethyltin (TMT) was suppressed by intracerebroventricular administration of the interleukin-1 receptor antagonist (IL-1ra). On the other hand, glutamate receptor antagonist (MK801) did not affect the TMT-induced CORT level increase. These results indicate that this transient activation of the hypothalamo-pituitary-adrenocortical axis in TMT-treated rats may be in part attributable to the neuroendocrine effects of IL-1 produced by microglia.

Administration, Oral↗
PubMed1984

Developmental neuropathology of organotin compounds.

The literature concerning the developmental neuropathology of organotins is reviewed. To date, neuropathological effects have been convincingly demonstrated for trimethyltin (TMT) and triethyltin (TET). Both compounds may damage the developing CNS; however they have different cellular targets. TMT is a neuronotoxin which damages areas of the limbic system, cerebral cortex, and brainstem. TET is a myelinotoxin which causes massive myelinic edema by yet undetermined mechanisms. Neuronal death is also seen following TET intoxication during the neonatal period, possibly as a result of elevated intracranial pressure. The neuropathological features of TMT and TET intoxication during early life are presented. Neurochemical and behavioral alterations resulting from congenital and/or neonatal exposure to organotins are also discussed.

Animals↗
PubMed1983

A methodology for speciation of methyltins in mammalian tissues.

Exposure to methyltin compounds results in morphologically detectable damage to several mammalian organ systems. Although reliable dose-response relationships have been described, a fast method for quantitating levels of various methyltin species in target organs has been unavailable. It has been possible to measure organotins as total tin using atomic absorption spectrometry, but speciation of methyltins has proved difficult. We present a rapid method for quantitative analysis and speciation of methyltins, direct from mammalian tissues. Methyltin compounds (monomethyltin trichloride, dimethyltin dichloride, trimethyltin chloride, and tetramethyltin) are purged from freshly homogenized mouse kidney and brain tissues using NaBH4. The volatile organotin hydrides produced are cryogenically trapped on the head of a gas chromatographic column (at -40 degrees C) and eluted using a linear temperature program (15 degrees C/min to 190 degrees C). The compounds are detected using selected ion monitoring in a Hewlett Packard 5985-B mass spectrometer. Quantitation is achieved by integration of the areas of the chromatographic peaks. Linear response is obtained over the range of 1 ng to 30 micrograms for each compound. Recoveries of methyltins spiked into tissues are greater than 85%.

Animals↗
PubMedDate not supplied

Trimethyltin ototoxicity in albino rats.

The toxicity of alkyltin compounds is of exceptional interest due to the dissimilar toxic effects of some very closely related structural analogues among this class of compounds. Since several features of the toxicity of trimethyltin appeared to be consistent with a mechanism involving accumulation of the toxicant on melanin pigments, the ototoxicity induced by TMT exposure was examined in albino rats. Hearing thresholds for tones sampling the mid- and high-frequency range of the rat's audibility function were assessed by reflex inhibition audiometry. TMT produced a frequency dependent loss of auditory sensitivity that was most severe in the high frequency range. The TMT-induced impairment of auditory function was similar to that previously observed in pigmented Long-Evans rats. These results extend the observation of TMT-induced hearing loss to a non-pigmented rodent strain and suggest that the accumulation of TMT on cochlear melanin is not critical to the production of hearing impairment by TMT.

Animals↗
PubMedDate not supplied

Acquisition, steady-state performance, and the effects of trimethyltin on the operant behavior and hippocampal GFAP of Long-Evans and Fischer 344 rats.

Strain differences represent an overlooked variable that may play an important role in neurotoxic outcomes that can impact regulatory decision making. Here, we examined the strain-dependent effects of trimethyltin (TMT), a compound used as a positive control for behavioral and neurochemical assessments of neurotoxicity. Adult male Long-Evans (LE) and Fischer 344 (F344) rats (n=12 each) were trained to respond under a multiple, fixed-interval 3-min fixed-ratio 10-response (multi FI 3-min FR10) schedule of milk reinforcement. Acquisition was characterized by time-dependent changes in several behavioral endpoints in both strains, although rate of acquisition of the fixed-interval pattern of responding was slower in F344 rats. Steady-state (baseline) performance was characterized by slower overall rates of responding in F344 rats. There was little evidence of strain differences in many of the other baseline performance measures. Rats of each strain were then divided into two equal groups that received either 1 ml/kg saline or 8.0 mg/kg iv TMT approximately 18 h before the next test session. TMT produced transient changes in the performance of LE and F344 rats that lasted for several sessions. For many behavioral measures, F344 rats were more affected by TMT than were LE rats. TMT-induced reactive gliosis, as assessed by assaying glial fibrillary acidic protein (GFAP), was also greater in F344 rats than in LE rats. These results suggest F344 rats may be more susceptible to TMT-induced neurotoxicity than are LE rats.

Animals↗
PubMed1985

Does phenobarbital protect against trimethyltin-induced neuropathology of limbic structures?

Because of the similarity in the pattern of limbic sites damaged by both compounds, it has been suggested that trimethyltin (TMT) may be an excitotoxin like kainic acid (KA). KA produces seizures which eventually result in neuronal damage similar to that found in epilepsy. Anticonvulsants reduce both the seizures and pathology associated with KA. Because TMT may also produce seizures, we undertook to determine whether or not some of the TMT-induced limbic neuropathology could result from seizure activity. To do this, a single dose of TMT chloride (either 7.5 or 15 mg/kg) was given per os to rats, and then phenobarbital (30 mg/kg) was administered subcutaneously in repeated doses. Treatment with phenobarbital did not prevent pathologic changes in the hippocampus, dentate gyrus, and pyriform or prepyriform cortex. Since phenobarbital did not protect against TMT-induced neuronal damage, as it has been reported by others to protect against KA-induced damage, the present findings suggest that these two toxicants probably produce hippocampal pathology via different mechanisms and that the TMT-induced pathologic changes do not require sustained electrical seizure activity.

Animals↗
PubMed1984

Central neurotransmitter effects of organotin compounds: trials, tribulations and observations.

Administration of trimethyltin (TMT) or triethyltin (TET) compounds to rats during postnatal development has known behavioral and neuropathological consequences. By measuring the concentrations of dopamine, norepinephrine, homovanillic acid, dihydroxyphenylacetic acid, gamma-aminobutyric acid, acetylcholine, and choline in different brain areas of TMT and TET-treated animals, an attempt was made to correlate these functional deficits with changes in CNS neurotransmitter alterations in vivo. TET had no effect on any of the substances measured whereas TMT significantly decreased gamma-aminobutyric acid and dopamine levels, but only in hippocampus and striatum, respectively. All other neurotransmitter substances measured were not affected. These findings illustrate the complexity inherent in attempting to use neurochemical techniques alone as an index of toxicity in the absence of specific defined hypotheses.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Glia increase degeneration of hippocampal neurons through release of tumor necrosis factor-alpha.

This study characterizes the role of glial cells in chemically induced neurodegeneration. We evaluated the effect of trimethyltin, a trisubstituted organotin compound that elicits distinct lesions in the central nervous system in vivo, on a sandwich co-culture of neurons and glia. Exposure of a 98% pure culture of rat hippocampal neurons to 0.1-1 microM trimethyltin for 24 h caused neural cell death and nuclear changes typical of apoptosis; at these doses glial cells viability was not affected but the cells released significant amounts of tumor necrosis factor-alpha (TNF-alpha). Neuronal apoptosis and TNF-alpha release from glial cells both increased when the two cell types were exposed together to trimethyltin, which indicates synergy. Treatment of a neuron-glia co-culture with TNF-alpha antibody prevented the increase in neuronal apoptosis, and TNF-alpha administration induced apoptosis in hippocampal cells. We conclude that glial cells and TNF-alpha both modulate trimethyltin-induced neurodegeneration.

Animals↗
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↗
PubMedDate not supplied

Neonatal exposure to trimethyltin disrupts spatial delayed alternation learning in preweanling rats.

Trimethyltin is an organotin compound that produces marked neurotoxicity in both adult and developing animals. The limbic system is a primary CNS target site for this toxicity, and a prominent behavioral effect of TMT is disruption of learning and memory. Impairment of cognitive development has also been suggested by studies showing that rats neonatally exposed to TMT cannot perform spatial working memory tasks during adulthood. However, the question of how early in ontogeny such deficits can be detected has not been addressed. The present study examined this question with a T-maze delayed alternation learning paradigm. Long-Evans rat pups, injected IP on Postnatal Day 10 (PND 10) with 6 mg/kg TMT and tested on PND 18, were unable to learn delayed alternation in the manner shown by vehicle control pups. However, TMT- and vehicle-treated groups were both able to learn a simple position discrimination. These findings indicate a selective impairment of spatial working memory by neonatal TMT exposure and show that this impairment can be demonstrated during the preweanling period in the rat.

Aging↗
PubMed1965

Uncouplers of rat-liver mitochondrial oxidative phosphorylation.

1. The ability of a series of compounds to uncouple oxidative phosphorylation of rat-liver mitochondria has been investigated. 2. The compounds were: 2-amino-1,1,3-tricyanopropene; carbonyl cyanide phenylhydrazone and its m-chloro and p-trifluoromethoxy derivatives; 4,5,6,7-tetrachloro-, 5-chloro-4-nitro-, 5-nitro-and 4,5,6,7-tetrachloro-1-methyl-benzotriazole; 4-hydroxy-3,5-di-iodo-, 3,5-di-bromo-4-hydroxy- and 3,5-dichloro-4-hydroxy-benzonitrile; and pentafluorophenol. 3. In a medium the components and physical condition of which were, as far as possible, kept constant, each compound was tested for ability to stimulate adenosine triphosphatase, to stimulate respiration in the presence of pyruvate as substrate, to inhibit phosphate uptake and to prevent swelling by trimethyltin. 4. Each compound was also examined with respect to its ability to produce rapid rigor mortis in mice. 5. The biological properties were compared with the dissociation constant and the hexane-water partition coefficient for each compound. 6. With the exception of 4,5,6,7-tetrachloro-1-methylbenzotriazole, all the compounds behaved qualitatively as 2,4-dinitrophenol. 7. Within each class of compound there is a relation between biological activity and the physical attributes measured. 8. The most efficient uncouplers were the most acidic and the most hydrophobic.

Animals↗
PubMed2000

Activation of mitogen-activated protein kinases by tributyltin in CCRF-CEM cells: role of intracellular Ca(2+).

Effects of tributyltin chloride (TBT) and other organotin compounds on mitogen-activated protein kinases (MAPKs) were examined in CCRF-CEM human T lymphoblastoid cells. In response to the incubation with 0.25-2 microM TBT for 1 h, the levels of the phosphorylated form of extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK increased in a dose-dependent manner. The phosphorylation was observed after 15 min and lasted for 4 h following exposure to 1 microM TBT, while the cell viability was not lowered significantly within 6 h. On the other hand, no clear changes were found in the total protein levels of ERK, JNK, and p38 MAPK. The in vitro activities of MAPKs also increased in response to TBT exposure. The potentials of MAPKs phosphorylation and of cellular damage were TBT > dibutyltin dichloride (DBT) > monobutyltin trichloride (MBT). When compared to other triorganotin compounds such as trimethyltin chloride (TMT), triphenyltin chloride (TPT), and triethyltin bromide (TET), TBT exposure induced the most marked phosphorylation of MAPKs. Chelation of intracellular Ca(2+) suppressed TBT-induced MAPKs phosphorylation almost completely, but removal of external Ca(2+) did not. The present results showed that tributyltin is a potent activator of ERK, JNK, and p38 MAPK pathways, and Ca(2+) mobilized from intracellular stores plays an important role for the phosphorylation of MAPKs in this human T cell line.

Apoptosis↗
PubMed2002

Synthesis of B/Ga and B/In heteronuclear bidentate Lewis acids: formation of intramolecular pi-arene-gallium(III) and -indium(III) complexes.

Reaction of 1,8-dilithionaphthalene x TMEDA (TMEDA=tetramethylethylenediamine) with dimesitylboron fluoride in diethyl ether followed by treatment with THF affords the Li(THF)(4) salt of dimesityl-1,8-naphthalenediylborate (1). Compound 1-Li(THF)(4) undergoes a ring-opening reaction with trimethyltin chloride to afford high yields of 1-(dimesitylboron)-8-(trimethyltin)naphthalenediyl (2), a compound in which a boryl and a stannyl moiety coexist at the peri positions of a naphthalene core. Compound 2 has been characterized by multinuclear NMR spectroscopy, elemental analysis, and X-ray single-crystal analysis which reveal the existence of a sterically crowded structure. Compound 2 is a useful starting material for the synthesis of other heteronuclear naphthalene derivatives. Thus, the transmetalation reaction of 2 with GaCl(3) or InCl(3) in THF results in high yields of 1-(dichlorogallium)-8-(dimesitylboron)naphthalenediyl (3) and 1-(dichloroindium)-8-(dimesitylboron)naphthalenediyl (4), respectively. These unprecedented boron/gallium and boron/indium heteronuclear bidentate Lewis acids have been characterized by multinuclear NMR spectroscopy, elemental analysis, and X-ray single-crystal analysis. Owing to the presence of a short contact between the ipso-carbon atom of a mesityl group and the heavy Group 13 element (C(ipso)bondGa 2.279(4) A for 3, C(ipso)bondIn 2.442(6) A for 4), compounds 3 and 4 are best described as intramolecular pi-arene complexes and are the first examples of such complexes. As shown by (1)H and (13)C NMR spectroscopy, this pi interaction subsists in solution.

Journal Article↗
PubMed2003

Inorganic tin and organotin interactions with Candida maltosa.

As a consequence of the widespread industrial and agricultural applications of organotins, contamination of various ecosystems has occurred in recent decades. Understanding how these compounds interact with microorganisms is important in assessing the risks of organotin pollution. The organotins, tributyltin (TBT), trimethyltin (TMT) and inorganic tin, Sn(IV), were investigated for their physical interactions with non-metabolising cells and protoplasts of the yeast Candida maltosa, an organism that is often associated with contaminated environments. Uptake, toxicity and membrane-acting effects of these compounds, at concentrations approximating those found in polluted environments, were assessed. Sn(IV) and TBT uptake occurred by different mechanisms. Uptake of Sn(IV) was 2-fold greater in intact cells than protoplasts, underlining the importance of cell wall binding, whereas TBT uptake levels by both cell types were similar. TBT uptake resulted in cell death and extensive K+ leakage, while Sn(IV) uptake had no effect. TMT did not interact with cells. Of the three compounds, TBT alone altered membrane fluidity, as measured by the fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene incorporated into cells. Anisotropy of 1-(4-trimethylaminophenyl-6-phenyl-1,3,5-hexatriene) was not affected, implying that TBT is not confined to the surface of the cytoplasmic membrane, but acts within membrane lipids. These results indicate that the cell wall is the dominant site of Sn(IV) interactions with yeast, while lipophilic interactions play an important role in uptake and toxicity of TBT.

Candida↗
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↗