Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Trialkyltin Compounds”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 649 records · Page 36Linked to original sources
PubMed1984

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↗
PubMed1984

Pre- and postweaning indices of neurotoxicity in rats: effects of triethyltin (TET).

Pre- and postweaning measures of learning and locomotor activity were used as indices of CNS function after early perinatal neurotoxic insult. Triethyltin (0.0, 3.0, or 6.0 mg/kg, ip) administered on Postnatal Day 5 (PND5) was used as the neurotoxicant. Learning deficits and alterations in locomotor activity were observed during both the pre- and postweaning periods. Preweaning learning ability was evaluated with an appetitive alleyway paradigm, while an automated radial-arm maze (RAM) was used to assess juvenile learning. Preweaning open-field locomotion was evaluated in the presence and absence of homecage litter while postweaning activity was measured in an automated device, the Motron, or as a component of performance in the RAM. The 6.0-mg/kg TET-exposed animals required more trials to acquire the alleyway task. RAM subjects receiving 6.0 mg/kg of TET were less accurate than those given 3.0 mg/kg or vehicle control. TET did not affect open-field activity on PND10; low levels of spontaneous locomotion occurred regardless of treatment. On PND13, there was a dose-related decrease in locomotion over home-cage litter while all groups exhibited equivalent low rates of locomotion in the absence of home-cage cues. All treatment groups were more active when tested over litter than over no litter. In contrast, on PND21 and throughout the RAM testing period, TET-exposed subjects exhibited dose-related increases in activity. TET produced treatment-related decreases in wet weight of whole brain, hippocampus, and cerebellum in both developing (PND23) and adult (PND200) animals with the hippocampus being most affected on a percentage basis. In contrast, no treatment-related body weight differences were observed at these times. The neurotoxicity of TET can be demonstrated during the preweaning period whether a commonly used endpoint in assessing CNS function (locomotor activity) is monitored or a more complex endpoint (learning) is evaluated provied (1) the method used to monitor locomotor activity incorporates both the normally low levels of preweaning locomotion and the more elevated levels induced by home-cage cues and (2) the learning paradigms utilized are appropriate for the capabilities of the animal.

Animals↗
PubMed1984

Toxicity of bis(tri-n-butyltin)oxide in the rat. I. Short-term effects on general parameters and on the endocrine and lymphoid systems.

Male and female Wistar rats were fed bis(tri-n-butyltin)oxide (TBTO) at 0, 5, 20, 80, or 320 mg/kg diet for 4 weeks. Clinical signs and decreases in feed and water consumption were observed in the 80 and 320 mg/kg groups. The serum transferase activities (alanine amino transferase and aspartate amino transferase were increased at 20 (males only), 80, and 320 mg/kg. The serum glucose and liver glycogen concentrations were lowered in the 320 mg/kg group. At 80 and 320 mg/kg the serum IgG level was reduced and IgM level was increased. Compared to controls the mean relative weight of the thymus was decreased at 20 (males), 80, and 320 mg/kg. In the groups receiving 80 or 320 mg/kg microcytic anemia was found. The white blood cell counts were decreased, due to the reduction in the number of lymphocytes in the 80 (males) and 320 mg/kg groups. The concentration of neutrophilic granulocytes was increased in the highest dose group. Histopathologic effects included a dose-related lymphocyte depletion of thymic cortex and of T lymphocytes in spleen and mesenteric lymph nodes. In the spleen also depletion of iron stores was found, and in the medullary sinuses of mesenteric lymph nodes, rosettes of erythrocytes were found around mononuclear cells; the occurrence of rosettes increased with dose from 5 to 80 mg/kg, and appeared to be the most sensitive parameter. A low incidence of areas of liver necrosis with inflammatory reaction and bile duct hyperplasia was found in the 320 mg/kg group. A viral or bacterial etiology could be demonstrated for these liver lesions, but they appeared associated with TBTO-induced ulcerative inflammation of the common bile duct as shown in an additional study. In 6-week studies exposure of male weanlings to the 0, 20, and 80 mg/kg diets, the serum insulin concentration in the treated groups was decreased, although the response to glucose challenge was unaffected. The serum thyroxin and thyrotropin (TSH) concentrations were reduced, whereas the luteinizing hormone (LH) concentration was increased in the 80 mg/kg group. The concentrations of follicle-stimulating hormone (FSH) and corticosterone were not changed. The release of LH and FSH was enhanced in the 80 mg/kg group and a tendency toward reduced release was found for TSH. Using immunocytochemistry a dose-related reduction was found in the number and staining intensity of TSH-producing cells in the pituitary, correlating with histopathologically decreased activity of the thyroid.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Toxicity of bis(tri-n-butyltin)oxide in the rat. II. Suppression of thymus-dependent immune responses and of parameters of nonspecific resistance after short-term exposure.

To evaluate the functional significance of bis(tri-n-butyltin)oxide (TBTO)-induced thymus atrophy, lymphocyte depletion in spleen and lymph nodes, lymphopenia, and increased serum IgM and decreased IgG concentrations, in vivo and in vitro function studies were performed for specific and nonspecific resistance. Weaned male rats were fed diets containing 0, 20, or 80 mg TBTO/kg for at least 6 weeks. Regarding the thymus-dependent immunity, delayed-type hypersensitivity reactions to ovalbumin as well as tuberculin were significantly depressed at both dietary concentrations. Resistance to the nematode Trichinella spiralis was significantly suppressed as shown by a retarded expulsion of adult worms from the small intestine, increased counts of muscle larvae, reduced inflammatory reaction in parasitized musculature, and suppressed serum IgE titers. Also the secondary mercaptoethanol-resistant (presumably IgG) hemagglutinating antibody titer to sheep red blood cells was significantly reduced, while no significant alterations were found in IgM and IgG titers to T. spiralis, ovalbumin, and tetanus toxoid. TBTO exposure reduced the response of thymocytes in both treatment groups and of spleen cells in the 80-mg/kg group upon stimulation with T-cell mitogens and increased the response of spleen cells to B-cell mitogens. When calculated per whole spleen, the response to T-cell mitogens was strongly impaired but unaltered by B-cell mitogens. This difference can be explained by a relative increase of splenic B cells as a result of reduced numbers of T cells, as shown by cell surface marker analysis using monoclonal antibodies. Reduced splenic T-cell numbers appeared equally due to a decreased number of T helper and to T suppressor cells. From these data and from results of a time-sequence study in which effects of TBTO on cell count and cell viability of thymus, spleen, and bone marrow were investigated, it is concluded that TBTO-induced immunodeficiency was primarily due to its direct toxic action on thymocytes. When cultured in vitro in the presence of TBTO, viability of thymus and bone marrow cells was equally reduced, while after in vivo treatment viability of bone marrow cells was unaffected. Thus, the in vitro situation does not mimic the in vivo one. Concerning the nonspecific resistance, TBTO reduced macrophage function as shown by impaired splenic clearance of Listeria monocytogenes bacteria. From in vitro studies it is concluded that impaired in vivo splenic clearance was due to a reduction in both the number of adherent cells in the spleen and bacterial digestion on a cell for cell basis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Effects of trimethyltin on dopaminergic and serotonergic function in the central nervous system.

The effects of trimethyltin (TMT) administration on regional concentrations of dopamine (DA), serotonin (5-HT), and their metabolites were determined. Acute administration of 3 or 7 mg/kg TMT (as the chloride) to adult male Long-Evans rats caused alterations in both dopaminergic and serotonergic function in brain at 7 days posttreatment. Dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations were decreased in the nucleus accumbens of rats treated with 7 mg/kg, with a trend occurring with the 3-mg/kg dose group. Conversely, concentrations of DA or DOPAC were not altered in striatum, olfactory tubercle, septum, or amygdala/pyriform cortex. Administration of 3 mg/kg TMT decreased the concentration of serotonin in striatum and nucleus accumbens, and increased the concentration of 5-hydroxyindoleacetic acid (5-HIAA) in hippocampus. The 7-mg/kg dose resulted in increased concentrations of 5-HIAA in striatum, nucleus accumbens, septum, amygdala/pyriform cortex, and hippocampus, and also decreased the concentration of 5-HT only in amygdala/pyriform cortex. The ratio of 5-HIAA to 5-HT (an indirect estimate of serotonin turnover) was increased in all brain regions of rats treated with 7 mg/kg, and in nucleus accumbens and amygdala/pyriform cortex of rats treated with 3 mg/kg. Conversely, no alteration in the DOPAC to DA ratio was found in any region of brain in rats killed at 7 days, nor was there a change in dopamine receptors (as measured by [3H]spiperone binding) in rats treated with 7 mg/kg TMT and killed 7 days following exposure. Thus, the acute sequelae of TMT neurotoxicity appears to involve primarily serotonergic systems, and these effects may be related to the behavioral effects resulting from TMT administration.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Tin distribution in adult and neonatal rat brain following exposure to triethyltin.

The uptake, distribution, and elimination of tin were determined in adult and neonatal (Postnatal Day 5) rat brain following ip administration of triethyltin bromide (TET). Groups of five adult CD rats were killed at 10 min, 1 hr, 4 hr, 24 hr, 5 days, or 10 days following acute exposure to 6.0 mg/kg TET; an additional group of adult animals was killed at 24 hr following exposure to either 3.0, 6.0, or 9.0 mg/kg (N = 5/dosage). The time course for tin distribution in 5-day-old rat pups was determined by killing pups 10 min, 30 min, 1 hr, 4 hr, 8 hr, 12 hr, 24 hr, 5 days, 10 days, or 22 days following exposure to either 3.0 or 6.0 mg/kg TET (N = 4/dosage/time). Tin analyses were performed by flameless atomic absorption spectrophotometry. The t1/2 for total tin in the adult rat brain following 6.0 mg/kg TET was determined to be 8.0 days. The maximum concentration in the adult was reached at 24 hr and corresponded to 4.6, 9.6, and 16.6 ng tin/mg protein for dosages of 3.0, 6.0, and 9.0 mg/kg, respectively. Tin was evenly distributed across all brain areas studied. For animals exposed to 6.0 mg/kg TET on Postnatal Day 5, the t1/2 for total tin in the brain was 7.3 days. A maximum concentration of 9.9 ng tin/mg protein was reached at 8 hr postexposure. The rate of elimination of tin from the brain (as measured by the elimination rate constant kel) did not differ significantly between adults and neonates. However, due to a dilution effect by the rapid brain growth of the neonate, the concentration of tin in the neonatal brain following TET administration decreased significantly faster than that in the adult.

Animals↗
PubMed1985

Acute trimethyltin intoxication in the monkey (Macaca fascicularis).

Adult cynomolgus monkeys were administered trimethyltin (TMT) iv in dosages ranging from 0.75 to 4.0 mg TMT/kg and observed for behavioral changes. Animals were subsequently killed for light and electron microscopic examination. TMT showed a dose-related toxicity, with high dose animals (4.0 and 3.0 mg/kg) dying within 24 hr, and low dose animals (0.75 mg/kg) surviving without morphological effects. Animals given 1.10 mg TMT/kg displayed a reproducible clinical course, characterized by tremor, hyperactivity, and ataxia which progressed to stupor and finally unconsciousness. By light microscopy, neuropathology was most pronounced in the CA-3 and CA-4 regions of Ammon's horn. Degenerating pyramidal neurons, micro- and astrogliosis, and neuronophagia were commonly observed. Mild degenerative changes were identified in amygdala, medulla, spinal cord, and Purkinje cells. The fascia dentata remained intact. Ultrastructurally, injured neurons contained accumulations of lysosomes and lysosome-like structures within perikarya and neurites. Demyelination or vascular damage was not observed. Data indicate the monkey to be highly sensitive to TMT, with morphological injury most severe in limbic structures.

Animals↗
PubMed1985

The effects of triethyltin and trimethyltin in rats responding under a DRL schedule of reinforcement.

Rats were trained to respond under a schedule of reinforcement in which only those responses separated by a 10-to 14-sec period of no responding produced a feed pellet (DRL 10 to 14 sec). Each rat received a single dose of trimethyltin (TMT) (5.6, 7.5, or 10 mg/kg) or triethyltin (TET) 1, 3, 4.25, or 5.6 mg/kg). The lowest dose of TMT (5.6 mg/kg) and the lowest dose of TET (1 mg/kg) were without significant effect. At 7.5 mg/kg and 10 mg/kg TMT, the percentage of the total responses spaced 10 to 14 sec apart decreased over the first 8 to 12 days after TMT. Those rats receiving 7.5 mg/kg TMT gradually returned to control values over the next 2 to 3 weeks while those rats receiving 10 mg/kg never recovered. Rats receiving 3, 4.25, and 5.6 mg/kg TET showed a decrease in the percentage of reinforced responses immediately after receiving TET. The behavior of those rats receiving 3 mg/kg returned to control values in 24 hr. Following 4.25 mg/kg TET, the health of the rats deteriorated rapidly. They were kept alive through heroic measures, but then were killed after testing on the 12th day following TET due to their failing health. At 5.6 mg/kg, the rats were killed on the 4th day due to failing health. These results indicate that TMT and TET differ with respect to potency and time course. The behavioral deficits produced by TET parallel the time course of general toxicity while the behavioral effects of acute TMT administration can persist in time long after the general appearance of the rats has returned to normal.

Animals↗
PubMed1985

Effects of trimethyltin on homecage behavior of rats.

Diurnal patterns of feeding, drinking, locomotor activity, and rearing in male Fischer-344 rats were examined for 2 weeks after a single oral dose of trimethyltin chloride (TMT) at 0, 3, 5, or 7 mg/kg. Body weights and feeding and drinking efficiency ratios (ratios of amount of food or water consumed per unit effort) were also determined daily. TMT caused a dose- and time-related drop in body weight; two of five rats in the 7 mg/kg group were killed moribund on 15 days after dosing. Feed consumption fell to 25% of control within 5 days after 7 mg/kg TMT, and to 50% of control for Days 2 and 3 after 5 mg/kg TMT. Water consumption doubled within 2 days after 7 mg/kg TMT and remained elevated for 2 weeks. Feeding efficiency dropped to 40% of control after 7 mg/kg, but drinking efficiency was unchanged. The diurnal patterns of drinking and of rearing were disrupted at all doses of TMT; a normal peak in rearing activity, occurring immediately prior to light onset, was markedly attenuated after all doses on Day 3, and at 5 and 7 mg/kg on Days 5 and 7 post-TMT. These results suggest (1) that the regulation of feed and water intake is severely compromised after a high dose of TMT, and (2) that the rat's cyclical patterns of homecage behavior are sensitive to TMT doses as low as 3 mg/kg.

Animals↗
PubMed1986

Inhibition of protein synthesis by trimethyltin.

The effects of trimethyltin chloride (TMT) on protein synthesis, measured as the incorporation of [3H]valine into trichloroacetic acid-precipitable material, were investigated in mice. One hour after intraperitoneal administration of a 3.0 mg/kg dose, TMT decreased brain protein synthesis by 47% and also caused a significant decrease (4.2 degrees C) in body temperature. When hypothermia was prevented by maintaining the animals at 35 degrees C, TMT decreased protein synthesis by 20%. Twenty-four hours following administration of TMT, protein synthesis was decreased in brain and liver; however, only a reduction of brain protein synthesis was observed at 48 hr. No hypothermia was present at either time point. A regional study in brain showed that at 24 and 48 hr after TMT administration, protein synthesis was decreased by 18-23% in cerebral cortex and hippocampus but not in cerebellum. TMT also inhibited protein synthesis in vitro in mouse brain homogenates with an IC50 of about 100 microM. Neither SnCl2, nor dimethyltin or monomethyltin had any effect on protein synthesis in vitro. These results suggest that, as for other neurotoxicants such as methyl mercury or acrylamide, inhibition of protein synthesis might be involved in TMT neurotoxicity.

Animals↗
PubMed1986

Diurnal patterns in homecage behavior of rats after acute exposure to triethyltin.

Diurnal patterns of eating, drinking, locomotor activity, and rearing in male Fischer-344 rats were examined for 11 days after a single oral dose of triethyltin bromide (TET) at 0, 1.5, 3, or 5 mg/kg. The 5 mg/kg group exhibited a time-related drop in food consumption and body weight until 3 of 10 rats were sacrificed moribund 11 days after dosing. Doses of 1.5 and 3 mg/kg TET did not reduce body weight or consumption of food and water. In contrast, food consumption was significantly increased 7 and 11 days after 3 mg/kg TET, and diurnal patterns of eating and drinking were disrupted 7 days after 3 and 5 mg/kg TET. A phase shift in licking patterns was induced by the high dose. Unlike trimethyltin (TMT), TET did not affect efficiency of eating. Diurnal patterns of both horizontal and vertical activity were disrupted at all dose levels on Day 2 after dosing; by 16 days after dosing, recovery was evident in all rats including those surviving 5 mg/kg TET. These results show that a near-lethal dose of TET produced a reversible syndrome of hypoactivity, aphagia, and weight loss similar to that seen after acute TMT; in the absence of the above signs, diurnal patterns of behavior revealed effects of TET at doses as low as 1.5 mg/kg; the magnitude of the effect depended on the time of day at which the response was measured; and TET did not produce the same effects on ingestive behaviors (polydipsia and reduced feeding efficiency) that were previously observed after acute TMT.

Animals↗
PubMed1986

Trimethyltin exposure produces an unusual form of toxic auditory damage in rats.

A single injection of trimethyltin chloride (TMT; 2, 4, or 6 mg/kg) is shown to produce a frequency-specific, dose-dependent auditory impairment, as well as to decrease the amplitude of the acoustically elicited startle response, in exposed rats. This finding stands in contrast to data presented earlier on the effects of triethyltin bromide (TET), which produces changes in startle response without affecting auditory acuity. Animals intoxicated with TMT at moderate doses appear to recover their auditory acuity over the course of several weeks. This slow recovery of auditory function, which is uncharacteristic for chemical ototoxicity, suggests that TMT may be a useful model agent for studying ototoxic mechanisms.

Acoustic Stimulation↗
PubMed1988

Effects of tributyltin on biomembranes: alteration of flow cytometric parameters and inhibition of Na+, K+-ATPase two-dimensional crystallization.

Carboxyfluorescein diacetate (CFDA) is a lipophilic nonfluorescent molecule that readily crosses the cell membrane. In the cytoplasm, it is hydrolyzed by nonspecific esterases to carboxyfluorescein (CF), a negatively charged fluorescent molecule, which is retained incompletely by cells with an intact plasma membrane. Exposure (4 hr) of the murine erythroleukemic cell (MELC) to micromolar quantities (0.1 to 5.0 microM) of tributyltin (TBT) results in increased cellular CF fluorescence. The increase occurs within a range below a critical value of the product (CPV) of the concentration (C) of TBT X duration (T) of exposure to TBT. Fluorescence increase is a sensitive indicator of the interaction of TBT with the cell: it is observed following exposure to 0.1 microM TBT for 4 hr at 37 degrees C. In the range above the CPV, cellular CF fluorescence is reduced apparently resulting from perturbation of membrane structure. For example, exposure of MELC to 2.5 microM TBT for 4 hr at 37 degrees C produces resistance to detergent-mediated cytolysis and inhibition of vanadate-mediated two-dimensional crystallization of Na+, K+-ATPase molecules in porcine renal microsomal membrane preparations, a process requiring molecular mobility within the membrane. Taken together, the increased cellular CF fluorescence and resistance of the MELC to cytolysis along with the inhibition of Na+, K+-ATPase crystallization in the microsomal membrane preparations suggest fixation (protein denaturation, cross-linking, etc.) at the level of the plasma membrane as a mode of toxic action of TBT.

Animals↗
PubMed1988

Alkyltin inhibition of ATPase activities in tissue homogenates and subcellular fractions from adult and neonatal rats.

Inhibition of ATPase activities by triethyltin (TET), diethyltin (DET), monoethyltin (MET), and trimethyltin (TMT) was studied in homogenates of brain and liver from adult and neonatal rats. In the adult, sensitivities were as follows: mitochondrial ATPase of liver much greater than Na+, K+-ATPase of brain approximately equal to mitochondrial ATPase of brain greater than nonspecific ATPase of brain and liver. MET did not produce significant inhibition. ATPase activities in brain and liver homogenates from TET-treated adult rats did not differ from controls. Mitochondrial ATPase in brain homogenates from 5-day-old rats was two orders of magnitude more sensitive to TET than brain homogenates from adult rats (IC50 of 2.5 microM in the 5-day-old neonate vs 260 microM in the adult). By contrast, isolated mitochondria and synaptosomal fractions from adult and neonatal brains were equally sensitive to TET (IC50 = 1-3 microM). At 10 days of age, following the onset of myelination, the IC50 for TET inhibition of brain mitochondrial ATPase increased to 71 microM. Myelin added directly to isolated mitochondria also reduced TET-induced inhibition. It is concluded that in vivo brain tin concentrations in 5-day-old rats following a neurotoxic dose of TET are sufficient to inhibit brain mitochondrial ATPase, whereas in adults, tin concentrations are insufficient for inhibition. In the adult rat, TET binding to myelin appears to prevent inhibition of brain mitochondrial ATPase, and the target of toxic action may be myelin. In the neonateal rat, TET may inhibit oxidative phosphorylation in unmyelinated brain tissue, leading to neuronal cell death.

Adenosine Triphosphatases↗
PubMed1989

Prenatal or postnatal exposure to bis(tri-n-butyltin)oxide in the rat: postnatal evaluation of teratology and behavior.

The results of a series of screening tests to determine the potential teratogenicity and neurotoxicity of developmental exposure to TBTO in rats are presented in this paper. For prenatal exposure, pregnant Long Evans rats were intubated with 0-16 mg/kg/day bis(tri-n-butyltin)oxide TBTO from Days 6 to 20 of gestation (GD 6-20). For postnatal exposure, rat pups were intubated with 0-60 mg/kg TBTO on Postnatal Day 5 (PND 5). Following prenatal exposure, dams were allowed to litter and pups were evaluated using a postnatal teratology screen. Postnatal evaluation for both exposures included motor activity (PND 13-64), the acoustic startle response (PND 22-78), growth, and brain weight. The maximally tolerated dose (MTD) in pregnant rats was 5 mg/kg/day, which is one-third the MTD in nonpregnant rats. There were decreased numbers of live births, and decreased growth and viability at dosages greater than or equal to 10 mg/kg/day. Cleft palate was found in 3% of the 12 mg/kg/day group. There was mortality following postnatal exposure to 60 mg/kg and all prenatal dosages greater than or equal to 10 mg/kg/day. Preweaning body weight was significantly decreased for all postnatal dosages, and all prenatal dosages greater than 2.5 mg/kg/day. Body weight reductions persisted to the postweaning period only in the high dose groups (10 mg/kg/day and 60 mg/kg). Behavioral evaluation demonstrated transient alterations in motor activity development (prenatal exposure only) and the acoustic startle response (postnatal exposure only). Persistent behavioral effects were observed only at dosages that produced overt maternal toxicity and/or postnatal mortality. The demonstration of the teratogenic and neurotoxic potential of TBTO in rats is confounded by associated maternal toxicity and/or pup mortality.

Abnormalities, Drug-Induced↗
PubMed1990

Trimethyltin effects on auditory function and cochlear morphology.

Trimethyltin (TMT) is a neurotoxicant known to alter auditory function. The present study was designed to compare TMT-induced auditory dysfunction using behavioral, electrophysiological, and anatomical techniques. Adult male Long-Evans hooded rats (n = 9-12/group) were acutely exposed to saline, 3, 5, or 7 mg/kg TMT. Auditory thresholds were determined 11 weeks postdosing for 5- and 40-kHz tones using reflex modification of the auditory startle response (ASR). Brainstem auditory evoked response (BAER) thresholds were determined for 5-, 40-, and 80-kHz tonal stimuli 9 weeks postdosing. Cochlear histology was assessed at 13 weeks postdosing. Functional endpoints demonstrated a high-frequency hearing loss. ASR thresholds for 40-kHz tones were elevated 25-35 dB in all dosage groups. BAER thresholds for 40- and 80-kHz tones were elevated 30-50 dB in the 5 and 7 mg/kg groups. Organ of Corti surface preparations revealed a pattern of damage suggesting classical ototoxicity. That is, outer hair cells died preferentially in regions associated with high-frequency hearing, in a dosage-dependent manner from base to apex. These data demonstrate the utility of the ASR and BAER in detecting functional alterations in audition and indicate that TMT-induced high-frequency hearing loss is associated with cochlear damage.

Animals↗
PubMed1990

Auditory dysfunction and cochlear vascular injury following trimethyltin exposure in the guinea pig.

Trimethyltin chloride (TMT) produces an auditory impairment in the rat due, presumably, to cochlear injury. The loss is unusual in that it persists for several weeks, but ultimately resolves at least at low to middle frequencies. Recovery of high frequency auditory loss is less predictable. Given this pattern of injury and recovery plus the known ability of TMT to impair oxidative phosphorylation, it was hypothesized that TMT would damage the stria vascularis which is the most metabolically active area and a structure containing one of the primary vascular networks in the cochlea. Trimethyltin chloride ototoxicity was evaluated in guinea pigs treated with the toxicant and then subjected to weekly tests of the auditory brainstem response evoked by tonal stimuli. A high frequency impairment was found which tended to improve within the first 2 weeks after exposure. Subjects were euthanized 6 weeks after TMT for histopathological study of the cochlea. At that time point most subjects showed full functional recovery. Subjects showed significant changes both in the number of outer hair cells and in the condition of the stria vascularis. Outer hair cell loss was observed in a restricted portion of the most basal turn of the cochlea which is responsible for encoding high frequency sound despite recovery of function in some animals. A very marked increase in the diameter of the vessels of the stria vascularis was observed along with signs of atrophy in the stria vascularis. Enlarged vessel diameters were particularly apparent in the apical and middle turns of the cochlea, which did not show significant hair cell loss. The data confirm that TMT does produce both hair cell damage and vascular pathology in the cochlea.

Animals↗
PubMed1990

Immunotoxicity of bis(tri-n-butyltin)oxide in the rat: effects on thymus-dependent immunity and on nonspecific resistance following long-term exposure in young versus aged rats.

To investigate whether immune function suppression observed in an earlier study after short-term bis(tri-n-butyltin)oxide (TBTO) exposure also occurred after long-term treatment, function studies for specific and nonspecific resistance were performed after exposure of weaned male rats to diets containing 0, 0.5, 5, or 50 mg TBTO/kg for 4-6 and 15-17 months. Treatment for 4.5 months had no effect on body weight but reduced thymus weight at 50 mg/kg. Regarding the thymus-dependent immunity, delayed-type hypersensitivity reactions to ovalbumin and tuberculin were not depressed, in contrast to the results of the short-term study. The resistance to the nematode Trichinella spiralis was dose-relatedly suppressed at the 5 and 50 mg/kg levels, in both experiments (5.5 and 16.5 months exposure), as shown by increased counts of muscle larvae and depressed serum IgE titers. Also the inflammatory reaction around cysts in parasitized musculature was reduced. No significant reduction was found in IgM and IgG titers to T. spiralis, ovalbumin, and sheep red blood cells as determined by enzyme-linked immunosorbent assay. TBTO exposure at 50 mg/kg for 4.5 months significantly reduced thymus weight, but the response of thymocytes to T-cell mitogens was unaltered. TBTO treatment for 4.5 or 16 months did not influence the response of spleen cells to T-and B-cell mitogens and neither influenced spleen weight. A dose-related shift was observed in T- and B- cell numbers in mesenteric lymph nodes as shown by flow cytometry using monoclonal antibodies: treatment for 6 and 18 months reduced the relative count of T-lymphocytes and consequently increased the percentage of B-lymphocytes. As a result, the T:B ratio was reduced in the 5 and 50 mg/kg groups. Concerning the nonspecific resistance, TBTO exposure for 5 and 17 months reduced macrophage function at 50 mg/kg as shown by impaired splenic clearance of Listeria monocytogenes bacteria. Natural cell-mediated cytotoxicity of spleen and peritoneal cells was investigated in a 51Cr-release assay with YAC-lymphoma target cells. TBTO treatment significantly suppressed natural killer (NK) activity in spleen cells. Significant suppression was noted in all treatment groups following 16 months TBTO exposure; in contrast to treatment for 4.5 months. No significant alterations were observed in the spontaneous cytotoxicity of nonadherent and adherent peritoneal cells following 4.5 months treatment. Treatment of aged (i.e., 1-year-old) male rats for 5 months with the 50 mg/kg diet reduced thymus weight but had no effect on body or spleen weight.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗