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PubMed1987

The pathogenesis of trimethyltin chloride-induced nephrotoxicity.

In exploratory studies aimed at elucidating CNS effects due to heavy metal toxicity, signs of compromised renal function were seen in rats. The studies reported here describe the sequential steps of the development of nephrotoxicity by trimethyltin chloride (TMT) in rats. Single doses of 12.25 mg/kg TMT administered orally to 150- to 175-g Long-Evans rats elicited overt signs of toxicity including behavioral abnormalities and marked weight loss. Concurrent with the development of these signs, nephrotoxicity was manifested as functional kidney compromise and associated histopathologic evidence of tubular damage. Pathological changes in the kidneys from treated rats were hyaline droplet inclusions, attenuated brush border, basolateral vacuolization, and eosinophilic granular casts in the proximal tubule cells. These lesions were detected as early as 2 days post-treatment and progressed with time in an orderly and sequential fashion. Renal lesions between 5 and 8 days were mild to severe cortical tubular dilatation, hydropic degeneration, and diffuse hyaline droplet deposition in the lower nephron tubules. Medullary edema and exfoliation of degenerated tubular epithelial cells with cast formation followed from 8 to 11 days. The morphological changes were accompanied by marked elevation of blood urea nitrogen, parallel with polyuria at Day 2 and oliguria by Day 14. Behavioral abnormalities as well as weight loss correlated well with the time course and severity of renal dysfunction and progression of morphological changes. A second experiment compared the effects of TMT in rats of different weights. Heavier rats were more sensitive than lighter rats to the nephrotoxic effects of TMT. These effects were independent of recognizable neurotoxic effects of TMT in the hippocampus.

Animals↗
PubMed1990

Chronic toxicity and carcinogenicity of bis(tri-n-butyltin)oxide (TBTO) in the rat.

In a 106-wk toxicity and carcinogenicity study, groups of 60 male and 60 female weanling Wistar rats were fed 0, 0.5, or 50 mg bis(tri-n-butyltin)oxide (TBTO)/kg diet. In males, feed consumption was increased in all treated groups and increased water consumption occurred at 5 and 50 mg/kg. During the second year, body weight decreased in the 50-mg/kg males, while the females in that group showed no weight gain. Excess mortality was confined to the 50-mg/kg group towards the end of the study. Haematological changes, comprising anaemia, lymphocytopenia and thrombocytosis were noted mainly at the high-dose level. Also, signs of decreased kidney function and increased plasma enzyme activities (alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase) were noted. No effects on serum hormone concentrations (thyrotropin, follicle stimulating hormone, luteinizing hormone or insulin) were observed, except for a decrease in the free thyroxin:thyroxin ratio in both sexes at the high-dose level. Higher serum IgM and IgA levels were present at 50 mg/kg, while, in females, IgG was decreased. At 50 mg/kg, the ovaries, adrenals, spleen (females), heart (males), pituitary, liver and kidneys were increased in weight, but the thyroid weight was decreased in females. The total tin concentrations in liver and kidneys showed a dose relationship and, in general, the concentrations were similar after 1 and 2 yr. Non-neoplastic histological alterations after 1 yr consisted of a decrease in the cell height of the thyroid follicles in all dose groups, with a reduced number of psammoma bodies at 50 mg/kg, a decrease in splenic iron content at 5 (females only) and 50 mg/kg, and a slight bile-duct activation. After 2 yr, only the thyroid changes were still present. In addition, at 2 yr, vacuolation and pigmentation of the proximal tubular epithelium and nephrosis were enhanced at 50 mg/kg. The incidence of benign tumours of the pituitary was significantly elevated and enhanced at 0.5 and 50 mg/kg. At 50 mg/kg increases in pheochromocytomas in the adrenal medulla and in parathyroid adenomas (males) were noted, while adrenal cortical tumours were decreased (males). There was a low, non-dose-related incidence of pancreatic carcinoma. Other tumour rates were in line with control data. It is concluded that lifetime feeding of 50 mg TBTO/kg diet induces toxicity in various organ systems. An increase in some common tumours was found at the high dose, probably due to hormonal or immunological changes.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex Neoplasms↗
PubMed1992

Effect of subchronic bis(tri-n-butyltin)oxide (TBTO) oral administration on haematological parameters in monkeys: a preliminary report.

A preliminary study was conducted on adult male crab-eating monkeys (Macaca fascicularis) orally exposed to bis(tri-n-butyltin)oxide (TBTO) at doses of 0 and 160 micrograms/kg/day, 6 days/wk, for 22 wk. No treatment-related signs of toxicity or changes in body weight gain were detected during the course of the study. The haematological analyses performed every 2 wk indicated a decrease in total leucocyte count in the treated animals with significant values in wk 8, 10 and 22 of treatment. No differences from controls were noted in clinical chemistry and total tin concentration in blood. These preliminary data on the toxicity of TBTO in the primate model are intended to be an initial contribution towards a better evaluation of the potential toxicological hazard of TBTO to humans.

Administration, Oral↗
PubMed1982

Trimethyltin inhibits uptake of neurotransmitters into mouse forebrain synaptosomes.

Trimethyltin (TMT), in a concentration dependent manner, inhibits in vitro uptake of gamma-aminobutyric acid (GABA), norepinephrine and serotonin by mouse forebrain synaptosomes with IC50S of 75, 43 and 24 microM, respectively. At 2 h and 14 h following in vivo administration of TMT (4.26 mg/kg; i.p.) to mice, GABA and serotonin uptake by forebrain synaptosomes are decreased, although norepinephrine uptake was not significantly affected. In vitro kinetic analyses of TMT inhibition of forebrain synaptosomal uptake of GABA, norepinephrine and serotonin indicated that the inhibition was not of the competitive type. This inhibition of uptake of neurotransmitters could be responsible, at least in part, for altered neurotransmitter levels in the synaptic cleft and may contribute to altered nervous system function during TMT intoxication.

Animals↗
PubMed1986

Trimethyltin as a selective adrenal chemosympatholytic agent in vivo: effect precedes both clinical and histopathological evidence of toxicity.

Trimethyltin (TMT) is a potent neuronotoxiciant but there is little data regarding its systemic effects. In this study, female BALB/c mice were administered either 0.9% saline or 2.75 mg TMT/kg intraperitoneally (i.p.). The animals were then housed in room air or in glass chambers flushed with either 10%, 40%, or 100% oxygen. Mice were sacrificed at 4, 8, 24, and 48 h after treatment and adrenals analyzed for various neurotransmitters by ion-pairing HPLC with electrochemical detection. In addition, adrenal S-adenosylmethionine (SAM) and blood ketone bodies were determined Sections of adrenals were evaluated by electron microscopy for histopathological changes. In vivo treatment with the toxicant resulted in a significant decrease in adrenal epinephrine and norepinephrine levels as early as 8 h following treatment. This effect preceded the appearance of both clinical signs and histopathological changes in the hippocampus by 12-24 h. With exposure to TMT in room air, mouse adrenal content of epinephrine fell from 1861.3 +/- 97.3 ng/4 mg to 1493.3 +/- 137.0 ng/4 mg while norepinephrine levels fell from 779.6 +/- 32.3 ng/4 mg to 503.4 +/- 44.3 ng/4 after 8 h. Supplementation with 40% oxygen did not attenuate this effect but in the case of mice treated with TMT and housed in 100% oxygen for 48 h, actually exacerbated the adrenal epinephrine depletion. Housing in approximately half normal atmospheric oxygen (10%) neither prevented nor enhanced the effects of TMT. The epinephrine/norepinephrine ratios were: control, 2.44; TMT (room air), 1.56; TMT (10% O2), 1.72; TMT (40% O2), 1.44; TMT (100% O2), 1.07. None of the conditions used in this study caused a decrease in adrenal dopamine, 5-hydroxyindole acetic acid (5-HIAA), 5-hydroxytryptamine (5-HT) or in the level of SAM. TMT treatment significantly increased blood ketone bodies indicating additional metabolic dysfunction. The significance of these findings in relation to TMT neuronotoxicity and fatty liver syndrome are discussed.

3-Hydroxybutyric Acid↗
PubMed1990

Immune alterations in rats following subacute exposure to tributyltin oxide.

Adult male Fischer 344 rats were dosed by oral gavage with bis(tri-n-butyltin)oxide (TBTO) in peanut oil for 10 consecutive days, at dosages ranging from 1.25 to 15 mg/kg/day. Other groups of rats were dosed daily for 10 days by oral gavage with cyclophosphamide (CY) at dosages ranging from 0.75 to 6 mg/kg/day. These rats served as positive controls for the immune assays employed. The immune function parameters examined included the following: delayed-type hypersensitivity (DTH) and antibody responses to bovine serum albumin (BSA), primary antibody responses to sheep red blood cells (SRBC) and trinitrophenyl lipopolysaccharide (TNP-LPS) and enumeration of splenic lymphocyte populations. The DTH and antibody responses to BSA were not affected by TBTO exposure; however these responses were suppressed in rats dosed with CY at 6 mg/kg/day. The plaque forming cell (PFC) response to the T cell-dependent antigen SRBC was enhanced in rats dosed with TBTO at from 5 to 15 mg/kg/day. On the other hand, the PFC response to the T cell-independent antigen TNP-LPS was unaffected by TBTO exposure. Rats dosed with CY had suppressed PFC responses to SRBC and TNP-LPS at dosages of 3 and 6 mg/kg/day, respectively. Enumeration of splenic lymphocyte populations from TBTO-exposed rats revealed a reduction in OX8- but not W3/25- or IgG-positive cells. These results, as well as results from an earlier study from this lab, suggest that T lymphocytes are a primary target for TBTO-induced immune alterations and that the enhancement of the PFC response to SRBC in TBTO-exposed rats may be mediated by alterations in the suppressor (OX8-positive) T lymphocyte population.

Animals↗
PubMed1995

Further evaluation of the developmental toxicity of tributyltin chloride in rats.

The objective of this study was to further evaluate the developmental toxicity of tributyltin chloride (TBTCl) in rats. Pregnant rats were given TBTCl by gastric intubation at a dose of 25, 50 or 100 mg/kg on days 7-9, days 10-12 or days 13-15 of pregnancy. A significant increase in the incidence of post-implantation loss was found in the groups treated with TBTCl on days 7-9 at 25 and 50 mg/kg and on days 10-12 at 100 mg/kg, but not in the groups treated with TBTCl on days 13-15. No significant increase in the incidence of malformed fetuses was observed after treatment with TBTCl on days 7-9. A significant increase incidence of malformed fetuses was detected when TBTCl was given on days 10-12 at 100 mg/kg and on days 13-15 at 25, 50 and 100 mg/kg. The most predominant malformation was cleft palate. It could be concluded that the manifestation of deviant development induced by TBTCl varies with the developmental stage at the time of administration and TBTCl possesses teratogenic potential with developmental phase specificity.

Abnormalities, Drug-Induced↗
PubMed1984

Alterations in regulatory and locomotor behaviors following trimethyltin exposure in the rat: a time and dose analysis.

Adult male hooded rats were tested pretreatment for spontaneous alternation and open-field behaviors. Animals were then intubated with either 5 or 7 mg/kg trimethyltin chloride (TMT Cl) or the isotonic saline vehicle. Post-treatment, animals were again tested for spontaneous alternation and open-field behaviors during three separate 5-day periods: days 14-18, days 56-60 and days 106-110. Additionally, both body weight and water intake were assessed. The larger dose of TMT Cl resulted in significant, but temporary reduction in body weight, elevated water intake for approximately 3 weeks, and a persistent increase in open-field activity. The smaller dose of TMT Cl resulted in elevated water intake for approximately 3 weeks and a temporary increase in open-field activity. Since the tendency to enter choice arms decreased in all groups across testing sessions, the effects of TMT Cl on spontaneous alternation could not be accurately assessed.

Animals↗
PubMed1988

Trimethyltin-induced neuronal damage in the rat brain: comparative studies using silver degeneration stains, immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins.

Trimethyltin is a neurotoxicant which produces a distinct pattern of neuronal cell death following peripheral administration of a single dose (8 mg/kg, i.p.) in rats. The cupric-silver degeneration stain was used to produce an atlas documenting the distribution and time course of trimethyltin-induced neuronal damage in adult, male Long-Evans rats. Animals were examined at survival times of 1, 2, 3, 4, 5, 7, 10 and 18 days after intoxication. The earliest degeneration was observed at day 1 in the intermediate and ventral divisions of the lateral septal nucleus, followed by development of degeneration on days 2-4 in neuron populations including the septohippocampal nucleus, septohypothalamic nucleus, anterior olfactory nucleus, bed nucleus of the stria terminalis, endopiriform nucleus, parafascicular nucleus, superior colliculus, interstitial nucleus of the posterior commissure, inferior colliculus, pontine nuclei, raphe nuclei, pars caudalis of the spinal trigeminal nucleus, the caudal aspect of nucleus tractus solitarius, dorsal vagal motor nucleus, granule cells in the dentate gyrus, pyramidal cells in CA fields of the hippocampus, and of neurons in the subiculum, pyriform cortex, entorhinal cortex and neocortex (mainly layer Vb and VI). This was followed by degenerative changes on days 5-7 in other structures, including the amygdaloid nuclei, the ventral posterolateral and ventral posteromedial thalamic nuclei and the periaqueductal gray. The distribution of terminal degeneration from these neurons indicate that specific pools of cells are affected in each structure, and the time course suggests somatofugal degeneration. The trimethyltin damage was also assessed with immunocytochemical visualization of a neuronotypic protein, protein-O-carboxyl methyltransferase and a radioimmunoassay for glial fibrillary acidic protein. Protein-O-carboxyl methyltransferase immunoreactivity was altered in neuronal populations damaged by trimethyltin, but did not appear to be either as sensitive or selective an assay of neuronal damage as the silver stain, especially at short survival times. Glial fibrillary acidic proteins were dramatically elevated 21 days after trimethyltin intoxication, particularly in areas of extensive damage. These studies revealed advantages and problems encountered in the use of each technique in assessing neurotoxic effects, forming a basis for discussion of the relative merits of using a battery of specific molecular probes for neurotoxicity evaluations.

Animals↗
PubMed1987

The effects of trimethyltin on the Ca+2, Mg+2 and Ca+2 + Mg+2-dependent ATPases of human neuroblastoma GM 3320.

Data presented here indicate neuroblastoma GM 3320 tissue homogenates exhibit ouabain insensitive Ca+2-dependent, Mg+2-independent, Mg+2-dependent, Ca+2-independent and Ca+2 + Mg+2-dependent ATPase activities. Inclusion of trimethyltin in homogenate preparations of these cells appears to discriminate between these various ATPase activities. At low concentrations (25 microM), trimethyltin preferentially stimulated the Ca+2-dependent, Mg+2-independent ATPase activity while inhibiting the Ca+2 + Mg+2-ATPase activity approximately 70%. At 75 microM trimethyltin, the Ca+2 + Mg+2-dependent ATPase activity is inhibited greater than 95% while the Ca+2-dependent, Mg+2-independent activity is essentially unchanged from control activity and the Mg+2-dependent, Ca+2-independent activity is inhibited approximately 50%. At concentrations greater than 75 microM, trimethyltin significantly inhibits the Ca+2-dependent, Mg+2-independent ATPase activity. Thus, at trimethyltin concentrations of 50-75 microM, preferential inhibition of the Mg+2-dependent, Ca+2-independent and Ca+2 + Mg+2-dependent ATPase activities of neuroblastoma GM 3320 is achieved.

Adenosine Triphosphatases↗
PubMed1992

Isolation and characterization of tributyltin chloride-resistant marine Vibrio.

Tributyltin chloride (TBTCl)-resistant marine bacteria were isolated from coastal sea water. One of these bacteria (Vibrio M-1) was highly resistant when grown in medium containing 125 microM of TBTCl. This strain was sensitive to other metals. Two polypeptides, 30 kDa and 12 kDa, increased when the strain was cultured in the medium supplemented with TBTCl. Initially TBTCl was taken up by the cell; however, the amount of TBTCl determined in the cellular fraction was low after the exponential growth phase of Vibrio M-1, suggesting the existence of a TBTCl-efflux system.

Biological Transport↗
PubMed1982

Effect of trimethyltin on chemically-induced seizures.

The effect of trimethyltin (TMT; 4.26 mg/kg i.p.), at 1 and 14 h following administration, on chemically-induced seizures in mice is reported. At 1 h following administration, TMT decreased seizure responsiveness and protected animals from bicuculline, isonicotinic acid hydrazide (INH) and pentylenetetrazol (PTZ) induced seizures. At 14 h following administration, TMT provided little protection against bicuculline, INH or PTZ induced seizures. Only slight decreases in seizure responsiveness were observed with strychnine induced seizures at either 1 or 14 h. By 16 h following administration, animals exhibited spontaneous tremors and convulsions. The results indicate that TMT exerts a biphasic effect on central nervous system excitability.

Animals↗
PubMed1984

Trimethyltin disrupts acoustic startle responding in adult rats.

Trimethyltin (TMT) is a limbic-system toxicant which also produces sensory dysfunction in adult animals. In the present experiment, we examined the effects of TMT on the acoustic startle response. Adult male, Long-Evans rats (N = 12/dose) received a single i.p. injection of either 0, 4.0, 5.0 or 6.0 mg/kg TMT hydroxide as the base. The number of responses, latency and peak amplitude of the startle response to a 13 kHz, 120 dB tone were measured 2 h, 2 weeks, and 4 weeks after dosing. For each test session, 10 stimuli were presented at each of three background noise levels (50, 65 and 80 dB). By 2 h after dosing, the number of responses and response amplitude were decreased following 4.0-6.0 mg/kg TMT; these treatment effects persisted through 4 weeks after dosing. Increases in latency were also seen following all dosages of TMT. These data suggest that TMT produces disruption of function within the acoustic-startle pathway.

Acoustic Stimulation↗
PubMed1984

Effects of trimethyltin on the immune system of rats.

Treatment with trimethyltin (TMT) induced atrophy of the thymus, spleen and lymph nodes within 2 days, but no changes in the bone marrow were observed. Atrophy of thymus and spleen did not occur in adrenal-ectomized rats treated with TMT. Antibody responses to sheep erythrocytes (SRBC) and proliferative responses of spleen lymphocytes to phytohemagglutinin (PHA), concanavalin A (ConA) and lipopolysaccharides (LPS) were suppressed significantly in treated rats. Delayed hypersensitivity to oxazalone, natural killer (NK) cell activity and the phagocytic activity of peritoneal macrophages (PEM) were not affected significantly.

Animals↗
PubMed1985

Nephrotoxic effect of trimethyltin in rats.

Male Wistar (Porton) rats were dosed by gavage with trimethyltin chloride in arachis oil at doses of 3, 6 and 10 mg/kg. Water consumption and urine production were monitored for 3 days after dosing and at the end of this period the rats were killed and the kidneys were examined histologically. Within 6 h of dosing there was an increase in urine production and in the pH of the urine in all treated groups. Within 24 h of dosing there was an increase in water consumption. Histopathological examination of the kidney at 3 days post-treatment showed nephrotoxic changes ranging from slight vacuolisation of the proximal tubular cells with loss of the brush borders in the 3 mg/kg group to extensive vacuolar degeneration with tubular dilation and evidence of cellular regeneration in the 10 mg/kg group. The results suggest that trimethyltin causes a rapid kidney dysfunction in rats by cytotoxic action on the cells of the proximal tubular epithelium and that this action is dose-related.

Animals↗
PubMed1985

Effect of plictran on beef heart mitochondrial ATPases.

The in vitro effects of plictran on oligomycin-sensitive Mg2+-ATPase and Ca2+-ATPase activities in beef heart mitochondria were studied. Beef heart mitochondrial fractions were prepared by the conventional centrifugation method. ATPase activities were measured by determining the inorganic phosphate released by the hydrolysis of ATP. Plictran inhibited both oligomycin-sensitive (o.s.) Mg2+-ATPase and Ca2+ ATPase activities at nanomolar concentrations. However, plictran did not affect the oligomycin-insensitive (o.i.) Mg2+-ATPase activity at any concentration studied. Substrate activation kinetics revealed that plictran inhibited o.s. Mg2+-ATPase uncompetitively and Ca2+-ATPase non-competitively. These results clearly indicate that plictran affects ATP synthesis and calcium ion transport in beef heart mitochondria.

Adenosine Triphosphatases↗
PubMedDate not supplied

Increased forebrain beta-adrenergic ligand binding induced by trimethyltin.

Systemic injection of the organometal neurotoxin trimethyltin (TMT) into rats causes impairments in learning and memory. However, there is a discontinuity in dose-response functions, such that the deficit which emerges with a higher, acutely toxic dose, is qualitatively different from the impairment induced after lower doses. To investigate synaptic receptor changes associated with behavioral deficits, neurotransmitter-receptor ligand binding assays were done in forebrain areas of rats given TMT (3.6 or 7.5 mg/kg). Binding of the beta-adrenergic ligand, dihydroalprenolol in frontal cortex and amygdala/pyriform cortex was an inverted U-shaped function of TMT dose, with rats given the median dose exhibiting increased binding. The curvilinear dose-response functions in behavioral and biochemical assays suggest that altered forebrain noradrenergic neurotransmission could play a role in behavioral deficits.

Animals↗