Brain damage due to trimethyltin compounds.
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Animals↗
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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↗
Monomethyl-and trimethyltin compounds induce learning deficiencies in young rats.
Male rat pups were exposed to monomethyltin trichloride (MMTC) and trimethyltin chloride (TMTC) via their dams' drinking water throughout gestation and post partum until 21 days of age. At 11 days of age, the pups were tested for acquisition and extinction learning ability in an appetitive learning paradigm, and at 21 days for learning ability in a one trial swim escape learning test. At 11 days, pups from dams exposed to 120 mg/l Sn as MMTC and to 1.0 mg/l Sn as TMTC displayed statistically significant increases in acquisition time, while all dose groups (12, 40, 120 mg/l MMTC and 0.15, 0.5, 1.0 mg/l TMTC) displayed significant decreases in extinction learning ability as compared to controls. At 21 days of age, animals exposed to 12 mg/l and 120 mg/l MMTC displayed higher escape times than controls, as did animals exposed to 0.5 mg/l TMTC.
Animals↗
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↗
Automated measurement of freezing time to contextual and auditory cues in fear conditioning as a simple screening method to assess learning and memory abilities in rats.
In fear-conditioning paradigms, rats display a freezing response not only upon presentation of a conditioned stimulus (usually tone), but also when returned to a conditioning chamber (context) in which they received an unconditioned stimulus (usually a foot shock). These paradigms have intrinsic advantages for screening effects of chemicals on learning and memory, although the time-consuming monitoring of freezing time by human observers may be problematic. In this study, an automated apparatus was developed to optimize a fear-conditioning paradigm for screening. We developed an apparatus that records freezing time measured from body movements detected by passive infrared (PIR) sensors. The apparatus detected freezing time as accurately as the human scoring method, and these data were used to determine learning parameters (freezing time to context or to tone) and a non-learning parameter (freezing time to novel context) in the rats. Rats orally administered the neurotoxic compound trimethyltin (TMT) exhibited decreased freezing levels to context, but not to tone or to novel context. These results suggest that this automated method can be an effective part of a screening program.
Animals↗
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↗
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↗
[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↗
Effects of postnatal trimethyltin or triethyltin treatment on CNS catecholamine, GABA, and acetylcholine systems in the rat.
The effects on brain neurochemistry of two neurotoxic tin compounds, trimethyltin (TMT) hydroxide and triethyltin (TET) sulfate, were examined. Long-Evans rats were treated with TMT hydroxide (1 mg/kg, i.p.) on alternate days from day 2 to 29 of life. These treatments caused a weight deficit of 10-20% by the time the animals were killed on day 55 by head-focused microwave irradiation. These TMT treatments are known to cause severe neuronal loss in the hippocampus and lesser damage in other brain regions. Accordingly, the concentration of gamma-aminobutyric acid (GABA) was decreased in the hippocampus; however, acetylcholine and choline concentrations were unaffected. These data suggest that TMT-induced effects on GABA systems are greater than that due simply to generalized neuronal loss. The TMT treatments also caused a significant decrease in dopamine concentrations in the striatum, but did not alter the concentrations of dihydroxyphenylacetic acid or homovanillic acid, the acidic metabolites of dopamine. Conversely, concentrations of dopamine and norepinephrine in the brain stem and norepinephrine in the cerebellum were not altered. Despite reports in the literature of TMT-induced neuronal damage in areas of the cortex, no effects on GABA, acetylcholine, or choline levels were found in the cortical areas examined, or in the hypothalamus. TET sulfate (0.3 mg/kg/day) was administered for 6 consecutive days of every week during days 2-29 of life. This dose is lower than that needed to cause intramyelin edema, yet it does result in long-term behavioral changes. Despite this, no changes in the concentration of any of the measured neurotransmitters or their metabolites were detected. In concert, these data demonstrate that neurochemical methods should not be used as neurological "screens," but rather to define specific mechanisms suggested by detailed behavior, pharmacological, and/or physiological studies.
Acetylcholine↗
Microglial responsiveness as a sensitive marker for trimethyltin (TMT) neurotoxicity.
Activation of microglia is a well-documented phenomenon associated with diverse pathological conditions of the central nervous system. In order to investigate the involvement of microglial cells in the neurotoxic action of the heavy metal compound trimethyltin, three-dimensional brain cell cultures were treated during an early developmental period, using concentrations at or below the limit of cytotoxicity. Microglial cells were studied by cytochemical staining, using horseradish peroxidase-conjugated B4 isolectin (GSI-B4). In parallel, neurotoxic effects were assessed by determining the content of synaptophysin and synapsin I, both in the total homogenates and in the synaptosomal fraction of the cultures. Changes in the content of the specific growth cone protein, GAP-43, were also analyzed. It was found that low, non-cytotoxic concentrations of TMT (10(-9) to 10(-8) M) caused a significant increase in the number and/or the clustering of microglial cells. A decrease in the synaptic protein (synapsin I, synaptophysin) content was detected at 10(-8) M of TMT in synaptosomal fractions, whereas in the total homogenates, changes in synaptic proteins and GAP-43 were observed only at the cytotoxic TMT concentration (10(-6) M). Although it remains to be shown whether the microglial response is caused by direct or indirect action of TMT, the present findings show that microglial responsiveness can be detected prior to any sign of neuronal degeneration, and may serve as a sensitive indicator for heavy metal neurotoxicity in the brain.
Animals↗
Toxicity, bioaccumulation, and interactive effects of organotin, cadmium, and chromium on Artemia franciscana.
The effects of three organotin compounds-trimethyltin chloride, dimethyltin dichloride, and dibutyltin diacetate-and two heavy metals-cadmium and hexavalent chromium-on Artemia franciscana mortality are investigated in this study. Of all the compounds tested in this work, trimethyltin chloride was, by far, the most toxic. The toxicity order for the five compounds was trimethyltin chloride > potassium dichromate > dimethyltin dichloride > dibutyltin diacetate > cadmium chloride. The big difference in toxicity between dialkyltin and trialkyltin was not accompanied by an equally big difference in bioaccumulation. At a Sn concentration in water of 10 mg/L, the bioconcentration factor was 50 for dimethyltin dichloride and 75 for trimethyltin chloride. At a Sn concentration in water of 100 mg/L, the bioconcentration factor for 6 for dimethyltin dichloride and 9 for trimethyltin chloride. The interactive effect of trimethyltin chloride and cadmium, as well as that of trimethyltin chloride and chromium, was found to be synergistic. Also found to be synergistic was the interactive effect of trimethyltin chloride with cadmium and chromium applied together.
Animals↗
Expression of EMAP-II by activated monocytes/microglial cells in different regions of the rat hippocampus after trimethyltin-induced brain damage.
Endothelial monocyte-activating polypeptide-II (EMAP-II), a novel cytokine with proinflammatory and antiangiogenic properties, has previously been shown to be expressed by activated monocytes/microglial cells in the rat brain and was therefore considered a useful marker to stage microglial activation in inflammatory lesions. The aim of the present immunohistochemical study was to investigate expression of EMAP-II in the rat hippocampus after intoxication with the organotin compound trimethyltin (TMT). Administration of this neurotoxicant is known to produce brain damage mainly affecting the hippocampal formation, with severe neuronal cell loss being observed predominantly in regions CA-1 and CA-3. The maximum severity of TMT-induced brain damage is observed 21 days after a single ip administration. In this well-characterized model of neurodegeneration, activated microglial cells have been described to occur mainly in the early stages of TMT-induced neurotoxicity. Following TMT intoxication, we observed a significant increase in EMAP-II(+) monocytes/microglial cells in the CA-1 and the CA-3 regions. The CA-2 region, however, was largely spared. While appearance of single EMAP-II(+) microglial cells was observed already after 5 days, EMAP-II immunoreactivity reached its maximum after 21 days and persisted in some of the rats up to 35 days. These findings show a close correlation to the temporal and spatial pattern of neuronal damage described in the rat hippocampus after TMT administration previously. Thus, upregulation of EMAP-II by activated monocytes/microglial cells may serve as a sensitive marker of neurotoxic lesions in the rat brain.
Animals↗
The neurotoxicity of environmental pollutants: the effects of tin (Sn2+) on acetylcholine-induced currents in greater pond snail neurons.
Inorganic and organic tin compounds present in aqueous ecosystems have diverse effects on the behavior of living organisms. With the aim of identifying possible correlates of these actions, we studied the effects of both types of Sn2+. The effects of SnCl2 and Sn(CH3)2 on acetylcholine-activate currents were studied on identified neurons of the mollusk Lymnaea stagnalis L. using a two-microelectrode membrane potential clamping technique and by intracellular dialysis with potential and ion concentration clamping. Experiments were performed on single neurons after isolation and on whole ganglion preparations. SnCl2 decreased acetylcholine-induced influx currents; the effect was dose-dependent. The effective threshold concentration, measured by the two-microelectrode membrane potential clamping method, was 0.1 microM, with saturation occurring at 5 microM SnCl2. After a 10-min preapplication of SnCl2, the effect was stronger (20%) than after treatment for 3 min (7%). Similar results were obtained after application of tin using the intracellular dialysis method with potential and ion concentration clamping. After preapplication of 10 microM SnCl2 for 1 min, acetylcholine-induced influx currents decreased by 41%, we compared differences in the effects induced by inorganic and organic tin compounds. Sn(CH3) induced a decrease in the amplitude of acetylcholine-induced currents in the same way as inorganic tin. The effect of Sn(CH3)2 was irreversible and stronger as the preapplication time increased. These results support the previous conclusion that agonist-activated channels are an important target for the actions of toxic metals. It is concluded that direct actions on neuron membranes represent an important component in the modulation of synaptic transmission and that this should be considered in studies of the mechanisms of toxicity of tin.
Acetylcholine↗
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↗
Distribution of tin in brain subcellular fractions following the administration of trimethyl tin and triethyl tin to the rat.
The time course of tin distribution in homogenates and subcellular fractions of rat brain was determined following the acute administration of trimethyl tin (TMT) and triethyl tin (TET) to the rat. Exposure to TMT resulted in lower concentrations but greater persistence of tin in subcellular fractions compared to exposure to TET. A delayed accumulation of tin in the mitochondrial fraction was observed following the administration of TMT but not TET. Analysis of total protein and mitochondrial markers did not reveal differences between the compositions of mitochondrial fractions prepared from control and TMT-treated subjects.
Animals↗
Organometal-induced antinociception: a time- and dose-response comparison of triethyl and trimethyl lead and tin.
Recent reports have demonstrated that organolead and -tin compounds can alter behavioral reactivity to noxious stimuli. To further define the dose response and temporal characteristics of these neurobehavioral effects, male Fischer 344 rats were injected sc with either one-fourth, one-half, or three-fourths the acute LD50 of triethyl lead (TEL), triethyl tin (TET), trimethyl lead (TML), trimethyl tin (TMT), or distilled water and tested on a 57.5 degrees C hot plate 1, 7, 14, 21, and 28 days after dosing. All four organometals altered hot plate latencies, but the magnitude and time course of these effects differed among the compounds. TEL produced a dose-related increase in latencies which was maximal 1 and 7 days postdosing and had dissipated by 28 days. In contrast, the group administered TML (3/4 LD50) exhibited a late developing antinocioception which became evident 14 days after dosing and persisted throughout the period of testing. The intermediate dose of TMT (1/2 LD50) also produced a delayed increase in response times which was observed 21 and 28 days post-treatment. The 3/4 LD50 dose of TMT produced increased hot plate latencies on all post-treatment test days except Day 14. TET (1/2 LD50) produced increased hot plate latencies 1, 7, 14, and 21 days postdosing and also induced a reversible ataxia and akinesia. Higher doses of TET proved lethal to 80% of the animals and lower doses failed to alter response times in the hot plate. These data demonstrate that trialkyl lead and tin compounds can produce time- and dose-related increases in hot plate latencies.
Animals↗
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↗
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↗