[Acute trimethyltin chloride poisoning in 45 patients].
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PAR-1 upregulation by trimethyltin and lipopolysaccharide in cultured rat astrocytes.
We have previously shown that various protease-activated receptor (PAR) isoforms, mainly PAR-1, are upregulated in reactive astrocytes of rat hippocampus following i.p. administration of trimethyltin (TMT), a neurotoxicant which is known to cause neuronal death and reactive gliosis. In the present paper, we demonstrate that this PAR-1 upregulation was also mimicked in primary cultures of neonatal rat cortex astrocytes after exposure (24 and 48 h) to TMT (10-100 microM). This result suggests that the PAR-1 increase we have observed in vivo may represent a direct effect of TMT on astrocytes rather than a consequence of a complex astrocytic reaction following neuronal death. Furthermore, an evident upregulation of PAR-1 in cultured primary astrocytes also occurred following exposure to lipopolysaccharide (LPS) (a well-known inductor of glial cell activation) whereas other neurotoxic agents (such as staurosporine, hydrogen peroxide and sodium azide), which are known to induce cell death, were unable to determine any PAR-1 variation. Similarly to astrocytes, both TMT and LPS induced an upregulation of PAR-1 in the rat astrocytoma cell line, C6, thus indicating that this phenomenon was independent from microglial cells eventually contaminating astrocyte primary cultures. Furthermore, after exposure to TMT and LPS, the levels of tumor necrosis factor-alpha and interleukin-1beta were also increased in astrocyte cultures, suggesting that the PAR-1 upregulation we have detected may be involved in glial inflammatory response rather than in cell death.
Animals↗
Anatomical and behavioral sequelae of fetal brain transplants in rats with trimethyltin-induced neurodegeneration.
The effect of transplants of either fetal hippocampal or dorsal ventricular ridge (DVR) tissue into the brains of adult male rats exposed to TMT was determined for two behavioral tasks. Administration of TMT produced deficits in acquisition and performance of an operant differential reinforcement of low response rates (DRL) schedule and learning in the Morris water maze. The fetal transplants developed well within the TMT-damaged brains of the adult rats and numerous axons could be shown to cross the host-transplant interface. The transplants significantly reduced the DRL deficit produced by exposure to TMT. However, the TMT-induced deficit in water maze acquisition was made significantly worse by the hippocampal transplants. The improvement in DRL performance is attributed to the effect on the host brain of an unidentified trophic substance produced by the transplants. However, this positive effect may not protect the brain sufficiently to produce recovery in tasks demanding more complex neural computations than are required to withhold lever-press responses. The transplant-induced deficit observed in some aspects of water maze acquisition and performance may be attributable to either a tumor-like deleterious effect of the mass of the transplant or to abnormal neuronal activity transmitted from the transplant to the host brain. The results of the present study, and those from other similar studies, suggest that transplants of fetal tissue may be useful in producing changes in the brain of an animal exposed to an environmental neurotoxin, but that research should be focused upon development of transplant methodology that will minimize adverse effects of the grafts.
Animals↗
Nutrition, neurotoxicants and age-related neurodegeneration.
The National Institute on Aging supports a program of investigation of "biomarkers" of aging (biological parameters that change in magnitude with age), some of which may be among the, as yet unknown, causes of Alzheimer's disease. Exposure to neurotoxicants can also produce symptoms similar to Alzheimer's disease and has been proposed as a causative factor. We have examined the role of dietary factors and age on Alzheimer's disease-like neurohistological and behavioral symptoms as well as on the neurochemical effects of treatment with a prototypical neurotoxicant, trimethyltin (TMT). We found that aging greatly increased the susceptibility of hippocampal neurons to TMT-induced neurodegeneration. Limiting the dietary intake of calories, which has been reported to slow the aging process, also reduced the neurotoxic effects of a given dose of TMT. Our current research focuses on the use of neurotoxins to model neurodegenerative conditions of aging in animals. We propose that by identifying an age-amplified biomarker or biomarkers somewhere along the chain from neurotoxic stimulus to neuronal necrosis we may also discover an up- or down-regulated gene, via it's gene product, that contributes to the etiology of human dementias. Our preliminary data suggest that up-regulated synthesis of post-synaptic glutamate receptors of the kainic acid-preferring subtype may be such a biomarker.
Aging↗
Effects of hippocampal neurotoxicant, trimethyltin, on corticosterone response to a swim stress and glucocorticoid binding capacity in the hippocampus in rats.
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Animals↗
Interaction of trimethyltin with hippocampal glutamate.
Trimethyltin (TMT) produces selective hippocampal lesions similar to that caused by convulsants which interact with the brain excitatory amino acid transmission. The hippocampal glutamate system was studied because of its possible contribution to neuronal damage produced by TMT. At 24 hr following administration of TMT (3 mg/kg; ip) to mice, hippocampal glutamate levels were decreased, although no changes in levels were observed at 1 hr, 6 hr or 15 hr. In partially depolarized hippocampal slices, TMT (10 microM), produced a release of endogenous glutamate. Continuous monitoring by fluorometry found glutamate release to occur immediately following addition of TMT to partially depolarized slices; this release was dependent on extracellular calcium. These results indicate TMT can activate the endogenous excitotransmitter system, which may contribute to the neuronal damage associated with TMT exposure.
Animals↗
Benzodiazepine-like behavioral effects following withdrawal from chronic delta-9-tetrahydrocannabinol administration in rats.
Chronic exposure to cannabis extract or delta-9-tetrahydrocannabinol (THC) has been reported to produce hippocampal neuropathology in rats, as well as classical "hippocampal" behavioral deficits. In an attempt to replicate and extend these findings, male rats were exposed to THC for 13 consecutive weeks, beginning in early adolescence. Drugs were administered five consecutive days a week (Monday through Friday). There were five dose levels: vehicle control, 5, 10, or 20 mg/kg, p.o., and 20 mg/kg THC four days a week (Monday-Thursday), followed by 60 mg/kg on Friday. Following THC exposure, all animals were withdrawn from drugs for seven weeks prior to behavioral testing. Three behavioral tasks previously shown to be sensitive to hippocampal damage were assessed. These were habituation of open-field activity, 24-hr passive avoidance response retention, and complex maze performance. A fourth task, emergence latency, was also included because it has been determined to be sensitive to "anxiety" levels. To facilitate interpretation of the complex maze data, two additional experiments are also reported. One experiment tested rats exposed to trimethyltin (TMT, a potent hippocampal neurotoxicant) on the complex maze. The second assessed the affects of chronic/acute benzodiazepine (BZ) exposure upon maze performance. Test results did not suggest that chronic THC exposure produced behavioral deficits resembling those seen following hippocampal damage. Habituation rates in an activity monitor were identical for all exposure groups, and there was no passive avoidance retention deficit. Further, while TMT caused pronounced abnormalities in the complex maze, chronic THC exposure at the two highest dose levels significantly improved maze performance, similar to BZ effects on this task. Chronic THC also appeared to reduce freezing on the emergence task, another anxiolytic-like effect. These results support other reports of persistent long-term behavioral effects of chronic THC exposure. However, they suggest that some behavioral effects may more closely resemble the effects of minor tranquilizers rather than hippocampal damage.
Animals↗
Quantitative changes in the synaptic vesicle proteins synapsin I and p38 and the astrocyte-specific protein glial fibrillary acidic protein are associated with chemical-induced injury to the rat central nervous system.
Measurements of neuron-specific and glia-specific proteins were used to characterize chemical-induced injury to the rat CNS. Trimethyltin (TMT), a neurotoxicant that preferentially damages neurons in limbic structures, was employed to produce consistent, time-dependent, dose-related, cell type-specific alterations in CNS morphology. Brain weights and histology were used to verify the cytopathological effects of TMT. Accompanying changes in 2 synaptic vesicle-associated proteins, synapsin I and p38, and the astrocyte-associated protein, glial fibrillary acidic protein (GFAP), were measured by radioimmunoassay (RIA). Immunohistochemistry of GFAP and incorporation of 3H-thymidine into GFAP-positive astrocytes also were used to characterize astrocytic responses to TMT-induced injury. Finally, quantitative 2-dimensional PAGE was employed to detect additional proteins affected by TMT. Acute administration of TMT caused large dose- and time-dependent decreases in synapsin I and p38 in hippocampus; the same proteins were largely unaffected in a nonlimbic structure, the frontal cortex. Twelve weeks after dosing, the concentrations of synapsin I and p38 and, to a lesser extent, the absolute amount of these proteins in hippocampus had returned to near control values, findings that are suggestive of reactive synaptogenesis. TMT caused large dose- and time-dependent increases in GFAP that were not confined to hippocampus. Twelve weeks after dosing, the amounts of GFAP in hippocampus and frontal cortex had returned to near control values, findings indicative of a transient astrocytic response to brain injury. Immunohistochemistry of GFAP revealed widespread astrocytic reactivity as a consequence of exposure to TMT, a response that resulted in part from the proliferation of astrocytes. Additional neurotypic proteins altered by TMT-induced injury included one of the neurofilament (NF) triplet proteins (p68) and a protein with the electrophoretic characteristics of neuron-specific enolase (NSE). The data indicate that measurements of neurotypic and gliotypic proteins may be used to characterize the temporal and regional patterns of neuronal and glial responses to injury.
Animals↗
Characterizing neurotoxicity using the in vitro hippocampal brain slice preparation: heavy metals.
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Animal Testing Alternatives↗
Use of neurophysiological challenges for the detection of toxicity.
The concept that a challenge to a system may overcome compensatory mechanisms and thereby reveal otherwise hidden neurotoxicant-induced damage is reviewed from a neurophysiological perspective. Two broad classes of neuronal challenges, poststimulation neuronal recovery processes and epileptogenesis, are discussed in terms of their potential value for detection and characterization of neurotoxicity. Neuronal recovery studies have typically involved presentation of pairs or trains of stimuli with various interstimulus intervals. Studies involving simple (e.g., monosynaptic) systems may allow mechanistic interpretation of alterations. Paired-pulse studies involving more complex (e.g., polysynaptic sensory) systems have detected alterations more readily than other electrophysiological methods, but interpretation may not be as straightforward as the monosynaptic case. The properties of elicited seizures, as well as the threshold for production of seizures, have been used with some success for detection of neurotoxicity. Several seizure models are discussed. It is concluded that both classes of neuronal challenge hold promise for future studies of neurotoxicity.
Acrylamides↗
Chemical exposures and animal activity: utility of the figure-eight maze.
In 1975, Norton and coworkers (11) described a figure-eight maze system for measuring motor activity in rodents. Since their original report, a number of studies have appeared in the literature which have utilized the figure-eight maze to evaluate the behavioral toxicity of a variety of chemical and physical agents (Table 1). The present paper describes a number of salient features of the maze which have emerged from these studies which support its continued use in toxicological studies. These features are described in the context of EPA's Test Guidelines for motor activity (4).
Age Factors↗
Differential response of microtubule-associated protein 2 (MAP-2) in rat hippocampus after exposure to trimethyltin (TMT): an immunocytochemical study.
Several neurotoxins induce changes in microtubule-associated protein 2 (MAP-2), the cytoskeletal protein primarily and highly enriched in the dendritic compartment of neurones. The present study aimed to investigate the fate of MAP-2 after administration of trimethyltin (TMT), an environmental neurotoxin. An immunocytochemical staining was performed in the hippocampus, known to be the most vulnerable brain region after TMT exposure. Prolonged survival time (21 days) following i.p. injection of a single dose of TMT (8 mg/kg) led to a considerable changes in intensity and pattern of distribution of MAP-2 immunoreactivity within the structure. A significant decrease in the staining was observed in the hippocampus proper especially in CA4/CA3 and CA1 subfields. This decrease was correlated with the severity in pyramidal cell loss previously reported by others. On the contrary, an increased density of MAP-2 immunostained dendrites was found in the molecular layer of dentate gyrus. Since TMT has been recognized as an agent damaging not only the hippocampus but also other limbic structures, the latter result might be interpreted in terms of postsynaptic changes due to hippocampal deafferentation.
Animals↗
Time-course of trimethyltin effects on the monoaminergic systems of the rat brain.
The normalization of certain behavioral functions after a trimethyltin (TMT) insult indicates that compensatory processes may occur (Paule and McMillan, 1986; Bushnell and Angell, 1992). The monoamine (MA) neurons are known to be sensitive to TMT, however, a detailed temporal description of the effects is lacking. One week after TMT exposure, 8 mg/kg i.p. to adult male Sprague-Dawley rats, the levels of serotonin (5-HT) and noradrenaline (NA) were decreased in several brain regions, whereas the levels of dopamine were unaltered. In addition, a reduced density of 5-HT immunoreactive fibers was seen in hippocampus and cortex. The lesion in the serotonergic and noradrenergic systems was followed by a recovery. Twelve weeks after TMT treatment, 5-HT and NA levels were increased in hippocampus, and 5-HT levels in striatum. In cerebellum, NA, 5-HT and 5-HIAA levels were decreased at 12 weeks. Compensatory processes led to recovered levels of 5-HT and NA in all regions but cerebellum, although regionally specific increases developed with time possibly due to hyperinnervation. Inhibition of the aromatic amino acid decarboxylase with NSD1015 yields accumulation of catecholamine and 5-HT precursors. Two weeks after TMT, levels of 5-HTP and L-dopa were not different in the TMT-treated rats as compared to controls, indicating that TMT does not affect MA synthesis.
Animals↗
Potential efficacy and toxicity of GM1 ganglioside against trimethyltin-induced brain lesions in rats: comparison with protracted food restriction.
GM1 ganglioside (one week each at 10, 5, and 2.5 mg GM1/kg per day, ip) or gradual food restriction leading to a reduction in body weight to 75% of control were tested for their ability to block or reverse histopathologic and behavioral effects of trimethyltin (TMT) poisoning in rats. TMT (a single oral gavage of 6.0 mg TMT HCI/kg body weight) reduced hippocampal weight, decreased hippocampal cell counts, decreased autoshaped learning measures, and suppressed progressive fixed ratio (PFR) lever pressing without affecting stable lever pressing. Neither GM1 nor greater food restriction affected hippocampal weight. Greater food restriction prevented TMT's effects on autoshaping but not on PFR behavior, was without behavioral effects in animals not treated with TMT, and did not affect hippocampal histology. GM1 prevented certain TMT-induced decrements in autoshaping and PFR behavior but also suppressed autoshaping and stimulated stable fixed ratio behavior in animals not treated with TMT. GM1 also reduced hippocampal serotonin concentration, another "lesion-like" change. GM1 blocked TMT-induced hippocampal CA3b cell loss, but did not protect CA3c cells, the main locus of TMT hippocampal damage. The results support the idea that exogenous GM1 is a potent neuroactive agent with complex actions in intact organisms, potentially beneficial and potentially toxic. Like GM1, food restriction induces complex and potentially beneficial effects, but it lacked GM1's biochemical and behavioral "side effects" (i.e. toxicity) in these experiments.
Animals↗
Effects of trimethyltin (TMT) on glial and neuronal cells in aggregate cultures: dependence on the developmental stage.
Long-term effects of trimethyltin (TMT) applied at concentrations below the cytotoxic level were examined in three-dimensional cell cultures of fetal rat telencephalon using biochemical, immunochemical and morphological criteria. It was found that in immature cultures low concentrations of TMT (10(-8) M) specifically induced a gliotic response in astrocytes, with increased immunoreactivity for glial fibrillary acidic protein, and a greater number of astrocytic processes. Significant changes in oligodendrocytic and neuronal parameters were found only at 10(-6) M of TMT. In differentiated cultures, distinct changes in cell type-specific parameters occurred at 10(-6) M of TMT (the lowest effective concentration). In addition, different patterns of responses were found for astrocytes and oligodendrocytes, as compared to immature cultures. These results suggest that among neural cells, astroblasts are most sensitive to TMT, and that the glial responses to this neurotoxicant are development-dependent.
Animals↗
Induction of trimethyltin neurotoxicity by dietary administration.
Groups of 12 male and 12 female rats were fed diets containing 0 or 8ppm trimethyltin chloride for up to 25 days. All the animals were observed prior to the study start and daily throughout the study for any changes in clinical condition. In addition, detailed clinical observations, including quantitative assessments of landing foot splay, sensory perception, muscle weakness and locomotor activity were monitored during the study. At the end of the study, the rats were killed and subjected to a full Post-mortem. Selected nervous system tissues were removed, processed and examined microscopically. Clinical signs typical of trimethyltin neurotoxicity (e.g. aggression, shaking and convulsions) were seen in rats receiving diets containing 8ppm trimethyltin chloride for as little as 22 days. Neuropathological lesions consisting of extensive neuronal cell necrosis in the limbic region of the brain, vacuolar degeneration of ventral horn cells of the spinal cord and a marginal increase in Wallerian-type degeneration were seen. The study demonstrates that trimethyltin neurotoxicity can be induced by dietary administration and that both male and female rats are equally sensitive.
Animals↗
The use of an unbaited tunnel maze in neurotoxicology: I. Trimethyltin-induced brain lesions.
In our laboratory we use an unbaited 6-arm radial tunnel maze (6-arm RTM) to assess working and reference memory in the course of neurotoxicity studies. The 6-arm RTM is believed to measure parameters comparable to those assessed in radial-arm mazes, but without the need of food deprivation and rewarding of animals. This is especially useful in the course of neurotoxicity studies as interferences of e.g. food deprivation with drug pharmacokinetics can be avoided. Since the 6-arm RTM is less evaluated than conventional mazes the aim of this study was to further confirm mean error score as measure of 'working memory', left-right discrimination within each radial arm (expressed as percent "blind-alley" visits) as measure of 'reference memory', and number of arm entries/min as a measure of motor activity. Therefore, hippocampal lesions were induced by injecting animals with the neurotoxicant trimethyltin (TMT). TMT at a dose of 5 mg/kg slightly lesioned hippocampal CA3 pyramidal cells in 3 of 8 animals, but did not affect behavioral measures in the 6-arm RTM. In all surviving animals treated with 7 or 9 mg/kg TMT moderate to marked loss of CA3 pyramidal cells was observed, while in 4 of these 7 rats CA4 pyramidal cells were also affected. Other brain lesions were not observed. TMT-induced brain lesions led to increased mean error score and number of arm visits during the retention phase and after changing maze configuration, whereas percent "blind-alley" visits were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
The effects of various levels of ascorbic acid on the response of the ODS rat to trimethyltin.
The effects of trimethyltin (TMT) on behavioral and histological parameters were investigated in rats maintained on low, mid, and high levels of ascorbic acid (AA). Male osteogenic disorder Shionogi (ODS) rats were used. Like man, ODS rats are unable to synthesize AA. AA was administered in the drinking water. Radial arm maze (RAM) performance and locomotor activity were measured before (i.e., baseline) and after (i.e., retest) TMT administration. During baseline, all rats learned the RAM task. Also during baseline, locomotor activity of rats maintained on high levels of AA was found to be lower than the other groups. After administration of 7.5 mg/kg TMT chloride (p.o.), RAM performance of all the groups declined, but RAM performance of rats maintained on low levels of AA appeared least affected by TMT. Also, rats in the high AA group had a significant increase in locomotor activity compared to baseline. These results suggest that in the ODS rat, TMT toxicity may be influenced by levels of AA intake.
Animals↗