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At least 19 recordsLinked to original sources
PubMed1979

The behavioral and neuropathologic sequelae of intoxication by trimethyltin compounds in the rat.

Trimethyltin, when given by gavage to rats, has an LD50 of 12.6 mg/kg. Signs of poisoning include tremors, hyperexcitability, aggressive behavior, weight loss, and convulsions. After single (10 mg/kg) or repeated weekly doses (a maximum of four) of 4 mg/kg, rats, up to a survival time of 70 days, were perfusion-fixed for light microscopy. Trimethyltin was assayed in brain and blood in rats after similar treatments. Trimethyltin is cumulative and persistent and binds with high affinity to hemoglobin. Trimethyltin, unlike triethyltin, does not produce white matter edema in rats but does cause bilateral and symmetrical neuronal alterations involving the hippocampus (largely sparing the Sommer sector), pyriform cortex, amygdaloid nucleus, and neocortex. The earliest alteration was loss or dispersal of Nissl substance, then clumping of nuclear chromatin, followed by shrinkage and fragmentation of the nucleus within shrunken eosinophilic cytoplasm. These changes were associated with approximately 1.4 microgram trimethyltin/g wet weight in brain tissue 1 day after the second dose of 4 mg/kg or 2 days after a single dose of 10 mg/kg. Signs of poisoning gradually disappeared, and 4 rats surviving 70 days appeared normal, although their brains had severe damage with cell loss in the hippocampi and each pyriform cortex. Treatment of rats with trimethyltin, therefore, provides a chronic preparation with consistent lesions in the hippocampus of use in other behavioral and neuroanatomic studies. (Am J Pathol 97:59--82, 1979).

Animals↗
PubMed1989

Variations in the neurotoxic potency of trimethyltin.

The organometallic compound, trimethyltin (TMT), is used as a selective denervation tool to validate morphological, biochemical and functional approaches to the detection and characterization of neurotoxicity. Variations in nervous system response TMT have been reported and may complicate the use of this compound as a research tool. We examined the contribution of sample-to-sample differences to variations in TMT-induced neurotoxicity. Seven samples of TMT obtained from three commercial sources were evaluated for neurotoxic potency in the rat. Hippocampus weight, histology and assays of the astrocyte protein, glial fibrillary acidic protein (GFAP), were used as indices of neurotoxicity. A single administration (8.0 mg/kg, IV) of different samples of TMT resulted in markedly different degrees of neurotoxicity as assessed by hippocampus weight and GFAP assays. Subsequent analysis of each sample for trace metal and speciated organotin content revealed that sample-to-sample differences in neurotoxic potency could be attributed to the presence of several impurities. Indeed, in several samples, sodium was present at levels high enough to affect neurotoxic potency simply by diluting the TMT content. A number of samples also showed contamination with the nonneurotoxic organotin, dimethyltin. The data indicate that different sources of TMT produce quantitatively different degrees of neurotoxicity, differences that may be attributed to sample-to-sample variations in TMT content.

Animals↗
PubMed1988

Early metabolic responses of retinal neurons to trimethyltin intoxication.

Chronic systemic exposure of rats to the neuronotoxic compound trimethyltin (TMT) results in increased incorporation of radioactive precursors into retinal proteins and glycoproteins. Because this increased metabolic activity is accompanied by minimal subcellular pathological alterations and almost no neuronal necrosis, we suggested that it may represent an early, reactive (compensatory) response (Brain Res. 398, 298-304; 1986). We have now investigated the development of this metabolic response to TMT in more detail. Beginning at 30 d of age, rats received weekly doses of TMT (4 mg/kg body wt) by gavage for up to 7 wk; rates of incorporation of [35S]methionine and [3H]fucose into retinal proteins and glycoproteins, respectively, were then determined using in vitro retinal incubations. The apparent rates of protein synthesis and glycoprotein glycosylation in retinas from TMT-treated animals were normal or slightly decreased after 1-3 wkly doses, but were increased after 4 doses and more markedly increased after 7 doses. Glycoprotein glycosylation was increased to a greater degree (192% of control after 7 wk of dosing) than was protein synthesis (134% of control). The increased incorporation in retinas from TMT-treated animals persisted when retinas were incubated with "flooding" concentrations of precursor (1 mM), suggesting that these increases were not owing to alterations in the size of retinal precursor pools. The preferential increase in glycoprotein glycosylation was partially owing to a selective increase in glycosylation of two molecular species with apparent mol wt of 32 and 45 KDa. Quantitative autoradiographic analysis of newly synthesized proteins and glycoproteins indicated that the TMT-induced increase in metabolic activity was not specific or selective for any retinal layer or cell type. We suggest that the preferential activation of glycoprotein glycosylation, and in particular the increased glycosylation of the 32 and 45 KDa glycoprotein species, may represent part of a compensatory metabolic response of retinal neurons to TMT-induced neuronal injury.

Animals↗
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↗
PubMed1977

[Migration behavior and toxicology of methyltin stabilizers].

With a view to studying the possible use of methyltin compounds as PVC stabilizers in food industry, the authors elaborated a method for the thin-layer chromatographic and subsequent spectrophotometric or polarographic determination of mono-, di- and trimethyltin compounds in the stabilizer and after migration. Monmethyltin compounds are determined spectrophotometrically after reaction with quercetin. Dimethyltin compounds are incinerated by the wet method using sulphuric and nitric acids, and inorganic tin is then estimated polarographically. Prior to identification trimethyltin compounds must be converted into dimethyltin compounds by ultraviolet irradiation or by treatment with triethylamine and bromine. Corresponding to the different conditions of use, the authors investigated the migration of the methyltin stabilizer from PVC into distilled water, 3% acetic acid, 20% alcohol, 50% alcohol und Fettsimulans HB 307. They stated that its tendency to migration into foods is not greater than that of the octyltin stabilizer. The experimentally obtained migration values are discussed in connexion with toxicological data.

Acetates↗
PubMed1991

Organotin compounds induce aneuploidy in human peripheral lymphocytes in vitro.

In vitro exposure of PHA-stimulated human lymphocytes to organotin compounds resulted in statistically significant increases in the frequencies of hyperdiploid cells. When taken together with our previous study demonstrating spindle inhibiting effects of the same organotin compounds by an indirect method (Jensen et al., 1989), the present study strongly indicates that organotin compounds are able to induce aneuploidy, probably by affecting spindle function.

Adult↗
PubMed1989

The effect of organotin compounds on chloride secretion by the in vitro perfused rectal gland of Squalus acanthias.

The effects of various organotins on membrane function and electrolyte transport were studied in the marine elasmobranch, Squalus acanthias. The isolated perfused rectal gland was used as a model of electrolyte transport. This gland can be stimulated to secrete chloride by atrial natriuretic peptide, veratrine, and vasoactive intestinal polypeptide although the mechanism of action of each secretagogue is different. By analysis of the inhibitory effect of an organotin in the presence of each secretagogue, the mechanism of inhibition can be inferred. Tributyltin (TBT) produced a reversible inhibition of epithelial transport at 10(-8) to 10(-7) M which resulted from inhibition of stimulus-secretion coupling in VIP-containing neurons within the gland. The transporting epithelial cells were unaffected at these concentrations. Trimethytin (TMT) produced inhibition at 10(-7) M which was not reversible and which affected primarily the transporting epithelial cells. Triethyltin and triphenyltin were without effect. The inhibitory effect of TBT and TMT was not affected by simultaneous administration of dithiothreitol. TBT also produced inhibition of oxygen consumption, Na+,K-ATPase, and proton ATPase in dispersed rectal gland cells. These results indicate that organotins are toxic to cell membrane functions which are intimately involved in the movement of electrolytes. This is the first evidence of toxicity to membrane transport functions in a marine species which is at risk from environmental exposure.

Animals↗
PubMed1985

Hippocampal muscarinic receptor loss following trimethyl tin administration.

The effects of trimethyl tin on passive and active avoidance behavior, hippocampal muscarinic receptors and hippocampal cell destruction were examined in male rats. The animals were intubated with 18 mumoles/kg (3.5 mg/kg) of TMT hydrochloride or vehicle. When tested two weeks later treated animals exhibited marked deficits in retention of passive avoidance and extinction of active avoidance tasks. Receptor binding analysis, using 3H-QNB, revealed a significant decrease (21%) in muscarinic receptor density in the hippocampus. Histological examination of the hippocampus revealed a concomitant loss in pyramidal cells in these animals. These results suggest that muscarinic receptors reside on the hippocampal pyramidal cells and that these cells and receptors may be involved in retention of passive avoidance behavior.

Animals↗
PubMed1989

Synthesis of radioiodinated N-succinimidyl iodobenzoate: optimization for use in antibody labelling.

N-succinimidyl-3-(tri-n-butylstannyl)benzoate (m-BuATE), N-succinimidyl-3-(tri-methylstannyl)benzoate (m-MeATE) and N-succinimidyl-4-(tri-n-butylstannyl)benzoate (p-BuATE) were synthesized and radioiodinated using either N-chlorosuccinimide (NCS) or t-butylhydroperoxide (TBHP) as the oxidant. Radiohalogenation of m-MeATE proceeded more rapidly than m-BuATE. NCS was the more efficient oxidant at reaction times less than 15 min; use of both TBHP and NCS resulted in nearly quantitative yields after 15 min when m-MeATE was used. Using NCS, achieving optimal antibody coupling and specific binding required purification of the active ester by HPLC; in contrast, with TBHP, only Sep-Pak purification was needed.

Antibodies, Neoplasm↗
PubMedDate not supplied

Radioiodination of antibodies via N-succinimidyl 2,4-dimethoxy-3-(trialkylstannyl)benzoates.

We have previously shown that use of N-succinimidyl 3-iodobenzoate (SIB) for radioiodination of monoclonal antibodies (MAbs) decreases the loss of radioiodine in vivo compared to MAbs labeled by using conventional methods. Herein, the synthesis of N-succinimidyl 2,4-dimethoxy-3-(trialkylstannyl)benzoates (alkyl = Me, Bu) are described as is their use as precursors for the radiosynthesis of N-succinimidyl 2,4-dimethoxy-3-iodobenzoate (SDMIB). A MAb F(ab')2 fragment labeled with SDMIB retained its ability to bind specifically to tumor homogenates. Paired-label tissue distribution studies indicate that the thyroid uptake (an indicator of deiodination) of hydrolyzed SDMIB was about 20 times that of hydrolyzed SIB. In contrast, thyroid uptake for SDMIB, when conjugated to a MAb, was only 1.4-2.8 times that for SIB and was considerably lower than levels reported in the literature for MAbs labeled by using direct, electrophilic iodination methods. Although MAbs labeled with SDMIB are significantly more inert to dehalogenation than those labeled by conventional methods, compared to the original SIB reagent, addition of two methoxy groups decreased retention of label in vivo.

Animals↗
PubMedDate not supplied

N-succinimidyl 5-(trialkylstannyl)-3-pyridinecarboxylates: a new class of reagents for protein radioiodination.

N-Succinimidyl 5-(trialkylstannyl)-3-pyridinecarboxylates (alkyl = Me, Bu) have been prepared and used as a precursor to label N-succinimidyl 5-[131I]iodo-3-pyridinecarboxylate (SIPC). SIPC was obtained in greater than 80% yield from either the methyl or butyl precursor with N-chlorosuccinimide and heating at 60-65 degrees C. Significantly lower yields were observed with tert-butyl hydroperoxide. After a 30-min incubation with [131I]SIPC at pH 8.5, goat IgG, an intact monoclonal antibody (MAb), and a MAb F(ab')2 fragment were labeled in 60-65% yield. Specific binding of the MAb and MAb fragment after SIPC labeling was identical with that observed with N-succinimidyl 3-iodobenzoate and higher than that reported previously for these MAbs after labeling by using the Iodogen method. When 5-[131I]iodonicotinic acid was injected into normal mice, thyroid uptake was less than 0.2% of the injected dose, reflecting the inertness of this compound to deiodination. Paired-label biodistribution studies indicate that for both the MAb and the F(ab')2 labeled by using SIPC, accumulation of activity in the thyroid and other tissues is comparable to that observed when these proteins were labeled by using N-succinimidyl 3-iodobenzoate. The results of this study suggest that SIPC may be a reagent for labeling MAbs with halogen nuclides.

Animals↗
PubMed1990

The neurotoxicology and pathology of organomercury, organolead, and organotin.

The toxicities of many metals, such as mercury and lead, are known to man since the dawn of civilization. Organic compounds of some heavy metals are known to have a particular toxic impact on the central nervous system. Organomercury, particularly alkyl-mercuric compounds (e.g. methylmercury), has a selective effect on the granule cells of the cerebellum, the nerve cells of the calcarine cortex, and the sensory neurons in the dorsal root ganglia. The well known Minamata Bay disease is the result of a massive epidemic episode of human exposure to alkylmercury contaminated food sources. Mental retardation and other developmental defects are also known to be a consequence of exposure to this toxic metal. Organic lead compounds have been employed as gasoline additives and in other industrial purposes. Unlike its inorganic counterpart, organolead compounds have a more prominent impact on the central nervous system. Pathological changes of the brain stem neurons have been described. Organotin compounds have been used in plastic industries and as agricultural chemicals. Both trimethyl and triethyl tin compounds are found to be extremely neurotoxic. Despite the similarity of their chemical structures, trimethyl and triethyl tins have a diversely different toxic property and effects. While triethyl tin is myelinotoxic, producing edematous and vacuolar changes in the central myelin, trimethyl tin is neurotoxic, producing prominent toxic changes in the neurons of the limbic system (hippocampus, entorhinal cortex, etc.). The factors which determine the specificity and selectivity of the neurotoxic impacts by various organometals are still unknown. In view that most of the organometals are still widely employed by many countries for industrial and for agricultural purposes, caution must be made for their proper handling and disposure to avoid undesirable exposures to workers and environmental contamination of water sources and food-chain for the common public. Since organometals are difficult to eliminate from the central nervous system, injuries usually lead to permanent neurological deficits, such tragedies are frequently long lasting and create not only a medical problem, but also a social economical problem for the society.

Animals↗
PubMed1989

Assessment of chemically-induced alterations in brain development using assays of neuron- and glia-localized proteins.

Chemical-induced injury of the developing central nervous system (CNS) is often manifested by alterations in the cellular ontogeny of specific neuroanatomical regions. Within the affected area, critical developmental processes encompassing a variety of neuronal and glial cell types may be transiently or permanently altered. Because the cellular heterogeneity of the developing CNS is expressed by unique neuronal and glial proteins, we proposed that radioimmunoassays of these proteins can be used to define normal and chemically- altered patterns of CNS development. We are testing this hypothesis by administering prototype neurotoxicants to the developing rat and then assessing the effects of these agents on previously characterized neuronal and glial proteins. Using this approach, we have characterized several features associated with perinatal chemical exposure: (1) region-dependent patterns of altered brain development are revealed by changes in the amounts of specific neuronal and glial proteins; (2) chemical-induced changes in neuronal and glial proteins depend on the time of exposure and nature of the insult; and (3) significant changes in neuron- and glial-localized proteins can be observed in the absence of cytopathology or decreases in brain weight. Data obtained from studies of toxicant-induced injury of the CNS will be presented as models for the use of neuron- and glial-localized proteins as biochemical indicators of altered brain development.

Animals↗