Toxicity Of Organotin Compounds Research Articles

Recent Studies on the Trimethyltin Actions in Central Nervous Systems

Trimethyltin (TMT) is a toxic organotin compound that produces injury to the central nervous systems of mammals. Recently, high-dose TMT (2.8 mg/kg) has been shown to produce neurodegeneration and subsequent neurogenesis specifically in the hippocampal dentate gyrus of mice, indicating that mice injected with TMT serve as a useful in vivo model to study neurogenesis as well as neurodegeneration in this brain region. In addition, gene-engineered mice have allowed research to focuse on the mechanisms of TMT toxicity. These studies have revealed the involvement of stannin, nuclear factor kappa B (NF-kappaB), presenilin-1, apolipoprotein E, and pituitary adenylyl cyclase-activating polypeptide (PACAP) in TMT toxicity and suggested the relationship between genetic mutations and neuronal susceptibility to degeneration. In this review, we briefly summarize the previous studies and discuss the current status of research on TMT.

Tributyltin chloride interactions with fatty acids composition and degradation ability of the filamentous fungus Cunninghamella elegans

Abstract Toxic organotin compounds are widely present in the environment. Tributyltin chloride (TBT), an organotin, is degraded by a filamentous fungus Cunninghamella elegans. The major fatty acids of this fungus were: palmitate (16:0), stearate (18:0), oleate (18:1n9), linoleate (18:2n6) and γ-linolenate (18:3n6). We show that the fatty acid unsaturation index was decreased and the conversion of stearic acid (18:0) in oleic acid (18:1n9) was significantly inhibited in the presence of TBT. Changes in fatty acid compositions during TBT degradation at 10 mg l−1 in C. elegans revealed that the degree of saturation was correlated with biotransformation of the xenobiotic to less toxic compounds: dibutyltin and monobutyltin. Our results suggest that the high TBT resistance in C. elegans is associated with the modulation of the fatty acids composition and the biocide degradation.

Structure, Dynamics, and Membrane Topology of Stannin: A Mediator of Neuronal Cell Apoptosis Induced by Trimethyltin Chloride

Organotin compounds or alkyltins are ubiquitous environmental toxins that have been implicated in cellular death. Unlike other xenobiotic compounds, such as organomercurials and organoleads, alkyltins activate apoptotic cascades at low concentrations. Trimethyltin (TMT) chloride is amongst the most toxic organotin compounds, and is known to selectively inflict injury to specific regions of the brain. Stannin (SNN), an 88-residue mitochondrial membrane protein, has been identified as the specific marker for neuronal cell apoptosis induced by TMT intoxication. This high specificity of TMT makes SNN an ideal model system for understanding the mechanism of organotin neurotoxicity at a molecular level. Here, we report the three-dimensional structure and dynamics of SNN in detergent micelles, and its topological orientation in lipid bilayers as determined by solution and solid-state NMR spectroscopy. We found that SNN is a monotopic membrane protein composed of three domains: a single transmembrane helix (residues 10-33) that transverses the lipid bilayer at approximately a 20 degrees angle with respect to the membrane normal; a 28 residue unstructured linker, which includes a conserved CXC metal-binding motif and a putative 14-3-3zeta binding domain; and a distorted cytoplasmic helix (residues 61-79) that is partially absorbed into the plane of the lipid bilayer with a tilt angle of approximately 80 degrees from the membrane normal. The structure and architecture of SNN within the lipid environment provides insight about how this protein transmits toxic insults caused by TMT across the membrane.

The ion channel of F-ATP synthase is the target of toxic organotin compounds.

ATP is the universal energy currency of living cells, and the majority of it is synthesized by the F1F0 ATP synthase. Inhibitors of this enzyme are therefore potentially detrimental for all life forms. Tributyltin chloride (TBT-Cl) inhibits ATP hydrolysis by the Na(+)-translocating ATP synthase of Ilyobacter tartaricus or the H(+)-translocating counterpart of Escherichia coli with apparent Ki of 200 nM. To target the site of this inhibition, we synthesized a tritium-labeled derivative of TBT-Cl in which one of the butyl groups was replaced by a photoactivatable aryldiazirine residue. Upon illumination, subunit a of the ATP synthase becomes specifically modified, and this labeling is suppressed in the presence of the original inhibitor. In case of the Na+ ATP synthase, labeling is also suppressed in the presence of Na+ ions, suggesting an interference in Na+ or TBT-Cl binding to subunit a. This interference is corroborated by the protection of ATP hydrolysis from TBT-Cl inhibition by 105 mM Na+. TBT-Cl strongly inhibits Na+ exchange by the reconstituted I. tartaricus ATP synthase. Taken together these results indicate that the subunit a ion channel is the target site for ATPase inhibition by toxic organotin compounds. An inhibitor interacting specifically with this site has not been reported previously.

Effect of tributyltin on trout blood cells: changes in mitochondrial morphology and functionality

The aquatic environment is the largest sink for the highly toxic organotin compounds, particularly as one of the main sources is the direct release of organotins from marine antifouling paints. The aim of this study was to investigate the mitochondrial toxicity and proapoptotic activity of tributyltin chloride (TBTC) in teleost leukocytes and nucleated erythrocytes, by means of electron microscopy investigation and mitochondrial membrane potential evaluation, in order to provide an early indicator of aquatic environmental pollution. Erythrocytes and leukocytes were obtained from an inbred strain of rainbow trout ( Oncorhynchus mykiss). Transmission electronic micrographs of trout red blood cells (RBC) incubated in the presence of TBTC at 1 and 5 μM for 60 min showed remarkable mitochondrial morphological changes. TBTC-mediated toxicity involved alteration of the cristae ultrastructure and mitochondrial swelling, in a dose-dependent manner. Both erythrocytes and leukocytes displayed a consistent drop in mitochondrial membrane potential following TBTC exposure at concentrations >1 μM. The proapoptotic effect of TBTC on fish blood cells, and involvement of mitochondrial pathways was also investigated by verifying the release of cytochrome c, activation of caspase-3 and the presence of “DNA laddering”. Although mitochondrial activity was much more strongly affected in erythrocytes, leukocytes incubated in the presence of TBTC showed the characteristic features of apoptosis after only 1 h of incubation. Longer exposures, up to 12 h, were required to trigger an apoptotic response in erythrocytes.

Review: Biodegradation of tributyltins (organotins) by marine bacteria

AbstractMany marine bacterial strains have an inherent capability to degrade toxic organotin compounds, especially tributyltins (TBTs), that enter into the environment in the form of insecticides, fungicides and antifouling paints as a result of anthropogenic and industrial activities. Significant degradation of these compounds in the ambient environment may take several years, and it is necessary to consider methods or strategies that can accelerate the degradation process. There have been few demonstrations of biological degradation of these organotin biocides exclusively in laboratory‐scale experiments. Compared with the few bench‐scale degradation processes, there are no reports of field‐scale processes for TBT bioremediation, in spite of its serious environmental threat to non‐target organisms in the aquatic environment. Implementation of field‐scale biodegradation of TBT requires inputs from biology, hydrology, geology, chemistry and civil engineering. A framework is emerging that can be adapted to develop new processes for bioremediation of toxic environmental wastes. In the case of TBT bioremediation, this framework incorporates screening and identification of natural bacterial strains, determination of optimal conditions for growth of isolates and TBT degradation, establishment of new metabolic pathways involved in TBT degradation, identification, localization and cloning of genes involved in degradation and in TBT resistance, development of suitable microbial strains using genetic manipulation techniques for practical applications and optimization of practical engineering processes for bioremediation of organotin‐contaminated sites. The present review mainly addresses the aspect of TBT biodegradation with special reference to environmental sources of TBT, chemical structure and biological activity, resistant and degrading bacterial strains, possible mechanisms of resistance and degradation and the genetic and biochemical basis of TBT degradation and resistance. It also evaluates the feasibility and potential of natural and genetically modified TBT‐degrading bacterial strains in field‐scale experiments to bioremediate TBT‐contaminated marine sites, and makes recommendations for more intensive and focused research in the area of TBT bioremediation mediated by marine bacterial strains. Copyright © 2002 John Wiley & Sons, Ltd.

Tin concentrations in river / bay sediments of Tokyo in 1984 and 2000

To analyze in greater detail the fate and behavior of toxic organotin compounds in the environment, total tin (Sn) concentrations were determined for sediments of the Arakawa River, the Sumida River, and Tokyo Bay by using a graphite furnace atomic absorption spectrophotometer (GFAAS). Sn concentrations in 2000 were compared with those of 1984 (8 years before the regulation on tributyltin-based antifouling paint) as well as with other heavy metals (Cu, Ni, Pb, and Zn). The Sn concentrations ranged from 1.04 to 4.43 mg kg−1 for sediments sampled in 2000. Although the average concentration of Sn in the sediments was low compared with that of 1984, the concentration tended to increase at several sites in 2000. Moreover, the Sn concentration showed significant correlations with the Cu, Ni, Pb, and Zn concentrations. These results suggest that a significant proportion of the overall Sn content in these sediments was probably introduced from the sources other than antifouling paint. The metals extracted from air-dried sediments with 0.1 m HCl showed that the mobility and bioavailability of Sn was low compared with those of other heavy metals.

Toxicity of organotin compounds in primary cultures of rat cortical astrocytes.

The neurotoxic organotin compounds trimethyl (TMT) and triethyltin (TET) are known to induce astrogliosis in vivo, which is indicated by an increased synthesis of glial fibrillary acidic protein (GFAP) in astrocytes. In contrast, tributyltin (TBT) does not induce astrogliosis. The aim of this study was to investigate whether trialkyltin derivatives can induce an increased GFAP synthesis in astrocyte cultures in the absence of neurons and whether differences between the action of TMT, TET, and TBT can be detected. Primary cultures of rat cortical astrocytes from 2-day-old rats were grown in 96-well plates until confluency and then exposed to various concentrations of TMT, TET, and TBT for 40 h. Effects on basal cell functions were measured by colorimetric determination of cell protein contents and by assessment of viability by means of the MTT assay. An indirect sandwich ELISA for 96-well plates was used for quantitative measurements of the GFAP content of the cells. All three compounds induced a concentration-dependent cytotoxicity indicated by parallel decreases of protein contents and MTT reduction. Half-maximum cytotoxic concentrations were 3 micromol/L (TBT), 30 micromol/L (TET), and 800 micromol/L (TMT). Cellular GFAP contents were reduced in parallel to cytotoxic action but no increase in GFAP expression at subcytotoxic concentrations could be observed. Thus, the astrocytes were not able to respond to TMT or TET exposure by an increased synthesis of GFAP in the absence of neuronal signals.

Dynamic Sorptive Behavior of Tributyltin on Quartz Sand at Low Concentration Levels: Effect of pH, Flow Rate, and Monovalent Cations

The highly toxic organotin compounds which have been used as biocides in ship antifouling paints have been introduced into aquatic ecosystems. Among them, tributyltin (TBT) is the most important organotin compound which has been produced on the largest scale. Understanding its fate in the environment is therefore of primary importance to prevent its migration. TBT sorption from aqueous solutions was studied at much lower concentrations (10 nM to 2 μM) than those used in previous studies. Experiments were performed using column reactors filled with a quartz sand. The influence of physicochemical parameters on TBT partitioning, i.e. ionic strength, pH, and nature of electrolyte cation was investigated. Equilibrium times were short as TBT retention appeared to be independent of the mean pore velocity. TBT sorption was affected strongly by the pH and slightly by the ionic strength of the solution. Competitions with monovalent alkaline cations showed a small influence of Li+, Na+, K+, Rb+, with respect to Cs+ ...

Concentration and distribution of butyltin compounds in a heavy tanker route in the strait of Malacca and in Tokyo Bay

The distribution of butyltins was investigated in seawater at 20 stations (n=69) along the tanker route in the Strait of Malacca and in Tokyo Bay, areas of potential release of toxic organotin compounds to the aquatic environment from large vessels coated with antifouling paints containing tributyltin (TBT) compounds. Relatively high concentrations of butyltins were observed along the Strait of Malacca and Tokyo Bay, high enough to cause deleterious effects on aquatic organisms, such as imposex in gastropods. The high ratio of TBT/dibutyltin (DBT) observed in the Strait of Malacca suggests that recent inputs of TBT have occurred there. Lower ratios were observed in Tokyo Bay. The present study suggested that the release of TBT from large vessels is the major source of butyltins in seawater.

Response of fish immune cells to in vitro organotin exposures

The presence of contaminants in aquatic environments may compromise the health and survival of fish. Many of these compounds are known immunotoxins in mammals; however, relatively little information is available on the immunotoxic responses of fish to these pollutants. Organotins are examples of widespread industrial and agricultural compounds which persist in aquatic environments. In this study, we investigate the effects of tributyltin (TBT) and its dealkylated metabolite dibutyltin (DBT) on fish immune responses. Immune cells were isolated from the spleen and head kidney of juvenile rainbow trout ( Oncorhynchus mykiss) and exposed to 0, 2.5, 50 and 500 ppb of either TBT or DBT. Mitogenesis was quantified by tritiated thymidine incorporation into cells cultured with the mitogens concanavalin A (Con A) or lipopolysaccharide (LPS). No changes in immune function occurred at the lowest organotin dose of 2.5 ppb. Con A-stimulated mitogenesis was significantly suppressed by 85% in spleen cells on exposure to 50 ppb DBT. LPS-stimulated mitogenesis was significantly suppressed by 96% in spleen cells and by 58% in head kidney cells with 50 ppb DBT. The highest concentration of 500 ppb of TBT and DBT inhibited both Con A- and LPS-stimulated mitogenesis by more than 95% in both head kidney and spleen cells. Flow cytometric analysis revealed dose-dependent changes in the cell population profile which correlated with the inhibition of mitogen-stimulated lymphoproliferation. In contrast, natural cytotoxic cell activity was not inhibited by in vitro exposure to either compound, as determined by the lysis of chromium-51-labelled K562 human erythroleukaemia cells and P815 mouse mastocytoma cells. These results show that organotins have both functional and tissue-specific effects on the fish immune system, i.e. spleen ⪢ head kidney tissue and, in general. LPS-responsive ⪢ Con A-responsive leukocytes. In aquatic systems, TBT is considered to be the most toxic organotin compound, and this toxicity decreases with progressive dealkylation to diand mono-organotins. However, our results indicate that DBT is a more potent immunotoxin than TBT, and suggest a need for the reassessment of the potential toxicity of DBT to aquatic organisms.

Toxicity of Organotin Compounds on Embryos of a Marine Invertebrate (Styela plicata;Tunicata)

In order to clarify the interaction mechanism between organotin compounds and organisms, the effects of these compounds on the development of a benthonic filter-feeding invertebrate were studied. Embryos of the ascidianStyela plicatawere obtained in laboratory by cross-fertilization and their development was followedin vivoafter incubation with 0.1, 1, and 10 μMorganotin compounds for various exposure times. Moreover, embryos selected at opportune stages after incubation with 10 μMtributyltin (TBT) or triphenyltin (TPT) for 1 hr were observed at the electron microscope to recognize cell alterations. Results indicate that organotins significantly affect all stages of ascidian development in a dose- and time-dependent manner and the most sensitive stages are gastrula and neurula. These compounds are able to block development, giving rise to anomalous embryos with irreversible effects. The order of inhibition appears to be strongly dependent on the organotin liposolubility: TBT > dibutyltin (DBT) > monobutyltin (MBT) and TPT gt; tricyclohexyltin (TCHT). The mitosis block of blastomeres in the early stages may be related to an inhibition of the microtubule polymerization. Observations with light and electron microscopes reveal globe-shaped blastomeres with large intercellular spaces in the morula and gastrula stages, suggesting a toxic damage with alteration of the cytoskeleton. Moreover, the occurence of electron-dense precipitates of organotins in the inner membrane of mitochondria and morphological changes of their cristae suggest an inhibitory effect on oxidative phosphorylation which is conspicuous in the gastrula stage. In this stage, the size of the electron-dense aggregates grow from 50–70 to 110–170 nm, while at the same time the alteration of the cristae increases.

Speciation and genotoxicity of butyltin compounds

The northern part of the Elbe river in Germany is one of the most highly polluted rivers in Europe, in particular with toxic organotin compounds. Two major anthropogenic sources are the Hamburg harbour area with intensive docking activities and a chemical plant in Bitterfeld close to the Mulde river in eastern Germany. Tributyltin is leached from the antifouling paints and enters the water phase. Thus, the Hamburg harbour area is highly contaminated with tributyltin and its degradation products, di- and mono-butyltin. Untreated run-off waters of an organotin plant in Bitterfeld contaminate the Mulde, a tributary of the Elbe, extensively. The Mulde sediments contain butyltin compounds of the order of mg of Sn per kilogram of dry mass. In Raguhun sediments, concentrations of tetrabutyltin and tributyltin were 1.8 ± 0.4 mg of Sn per kilogram of dry mass and 1.1 ± 0.2 mg of Sn per kilogram of dry mass, respectively. Remobilization of the sediments during high water periods transports the contaminants along the Mulde river into the Elbe river. Tetrabutyltin can be detected in the Elbe river as far as Cuxhaven and its estuary. To evaluate the ecological impact, fish tissues were analysed for their butyltin content and the data were correlated with the butyltin content in the surrounding water. The analysis of different fish tissues: liver, kidney, gills and the edible tissue, shows a clear enrichment of the tributyltin species. In the liver, tributyltin concentrations of up to 200 ng of Sn per gram of wet tissue were found. Bioconcentration factors were calculated to be of the order of 4500–9000. Tetrabutyltin could not be found in all the tissues, whereas it is present in water. The low bioavailability of tetrabutyltin is presumably caused by the low amount of tetrabutyltin in the dissolved constituents of water. Up to 99% of the tetrabutyltin content in water is bonded to particulate matter. The butyl groups influence the toxic behaviour of the butyltins. Although the toxic effects of butyltins on different organisms are well investigated, the genotoxic potential of the butyltins has received much less attention. The SOS-Chromotest was used to evaluate their genotoxicity. All the butyltins were found to be genotoxic; dibutyltin was the most genotoxic (10–40 µg of Sn per litre) followed by tri-, tetra- and mono-butyltin. An enhancement of the genotoxicity of all butyltins was observed using spiked lake water instead of distilled water. For the analysis of the butyltin compounds sodium tetraethylborate was used as in situ ethylating agent in the buffered samples. No pre-extraction steps with complexing agents are necessary. The extraction yields of all butyltin compounds are in the range of 82–94% for water; 76–88% for suspended particulate matter, sediment and soil; 80–94% for organisms; and 76–97% for air samples. The limit of detection of GC–AAS is 25 ± 5 pg of Sn per microlitre injected volume (3σ of the baseline noise).

有機スズ化合物の生物毒性

有機スズ化合物の生物毒性

The Gender Toxicity of Select Organotin Compounds

The work reported here indicates that male Long Evans rats have a greater sensitivity to organotin compound (OTC) than female rats over the 8-day toxic period used in this study, but little discernible difference was observed during the first 72 h following a single oral dose of an organotin compound. No distinct gender difference in the toxicity of organotin compounds was observed for tri- n-butyltin chloride, Di- n-butyltin dichloride, and di- n-octyltin dilaurate during the first 3 days subsequent to administering a dose equal to 75% of the LD 50 for the compounds. Both sexes of the animals were severely affected. After 3 days exposure. the normal acute toxicity observation time for OTC, the females rapidly recover, whereas males continue to languish as evident from the reduced food and water intake, weight loss, continued male deaths, and severe organ damage upon necropsy.

The metabolism and toxicity of some organotin compounds in isolated rat hepatocytes

The metabolism and toxicity of some ethyl-substituted organotin compounds in isolated rat hepatocytes were studied. Tetra- and triethyltin derivatives were metabolized by isolated rat hepatocytes to yield ethane and ethylene. Hydrocarbon formation from tetraethyltin was larger than that obtained with triethyltin bromide, and ethylene was the major product (95%) of tetraethyltin metabolism. At a triethyltin salt concentration of 100 μM, the major product formed by cells from untreated rats was ethane. Pretreatment in vivo by phenobarbital resulted in a marked increase in the overall rate of hydrocarbon production and a change in ethylene to ethane ratio; in this case ethylene was the predominant metabolite produced. 5,6-Benzoflavone pretreatment in vivo resulted in a small depression in overall hydrocarbon production. No metabolism of diethyltin dichloride (100 μM) by isolated rat heptocytes was detected. Triethyltin bromide (100 μM) was a potent inhibitor of both the Phase I (oxidation) and Phase II (conjugation) metabolism of biphenyl in isolated hepatocytes from phenobarbital-pretreated rats, whereas diethyltin dichloride was seen to affect particularly the Phase I metabolism of the aromatic hydrocarbon. Triethyl- and diethyltin salts reduced oxygen consumption and ATP levels in these cells. However, the triethyl derivative was more effective in this respect. Tetraethyltin was not appreciably toxic to hepatocytes. Trypan blue dye exclusion and lactate dehydrogenase loss by the cells isolated from phenobarbital-pretreated rats indicated that triethyltin bromide was more toxic than diethyltin dichloride. In contrast, the diethyl derivative was more potent in stimulating lipid peroxidation as indicated by formation of thiobarbituric acid-reactive products than was triethyltin.

Separation of Toxic Organotin Compounds from Aqueous Solution by Adsorption

Abstract The adsorption characteristics of organotin compound (tributyltin oxide) are established on activated carbons, polymeric adsorbent, and synthetic carbonaceous adsorbents. Maximum adsorptive capacity is obtained with activated carbon containing high percentage of macropores (100–500 A). For this carbon the adsorptive capacity (g organotin adsorbed/g of adsorbent) at breakpoint is 0.30 and the capacity at exhaustion (with 30 mg/L organotin solution) is 0.50.

Toxicity of organotin compounds: IV. Impairment of energy metabolism of rat thymocytes by various dialkyltin compounds

Isolated thymocytes were incubated with various carbohydrates in the presence of dimethyltindichloride (DMTC), diethyltindichloride (DETC), di- n-butyltindichloride (DBTC), and di- n-octyltindichloride (DOTC) and the substrate conversion, oxygen consumption, and cell viability were measured. All the dialkyltin compounds produced a dose-dependent stimulation of the glucose consumption, but at different concentrations. The most toxic homologs, DBTC and DETC, stimulated the glucose consumption maximally at levels of 5 and 10 μ m, respectively, whereas DMTC and DOTC were less active, inducing a maximum stimulation at 120 μ m. At higher exposure levels a sharp fall in the stimulation of the glucose consumption was noted together with a decrease of the oxygen consumption and viability of the thymocytes. The oxidative metabolism of glucose, lactate, and pyruvate by the TCA cycle was inhibited by dialkyltin compounds in a dose-related fashion. The glycolytic pathway was not affected, since under anaerobic conditions the glucose consumption was similar to that of the controls up to levels inducing a maximum stimulation of the glucose consumption under aerobic conditions. Probably the entrance of the glycolytic end products into the TCA cyle is disturbed by an inhibition of the pyruvate dehydrogenase system. Additional support for an interference with α-keto acid dehydrogenase complexes were obtained from mitochondrial incubations. DBTC inhibited the pyruvate and α-ketoglutarate conversion, oxygen consumption and ATP production of rat liver mitochondria in a dose-related fashion. Although in vitro the dialkyltin homologs display a comparable mode of action on the energy metabolism of rat thymocytes, in vivo especially DBTC and DOTC induce thymus involution whereas DMTC and DETC hardly decrease thymus weight. This discrepancy may be related with a different distribution pattern of the water-soluble lower homologs and the fat-soluble higher homologs. Therefore, we conclude that the inhibition of the energy metabolism of rat thymocytes by dialkyltins is related to their thymolytic effects in vivo.

Toxicity of organotin compounds. III. Suppression of thymus-dependent immunity in rats by di-n-butyltindichloride and di-n-octyltindichloride

To evaluate the functional significance of di-n-butyl (DBTC)- and di-n-octyltin dichloride (DOTC)-induced lymphoid depletion various immune function studies were carried out. The delayed type hypersensitivity reaction, a parameter of cell-mediated immunity was decreased in rats fed 50 or 150 ppm of DOTC for 6 weeks. This decrease was dose-related. Allograft rejection, another cellular immune response, was significantly delayed by DBTC and DOTC. The antibody response against E. coli LPS, probably a T cell-independent antigen, was not affected by DBTC. However, the humoral immune response against sheep red blood cells (SRBC), which needs the co-operation of T helper cells and B cells, was distinctly depressed by DBTC. Hemagglutination and hemolysin titers as well as the number of direct plaque-forming cells against SRBC per spleen were decreased in a dose-related manner by DBTC. The phagocytic capacity of macrophages of rats was not affected by DOTC as was shown in the carbon clearance test. Altered immune functions were never found in mice or guinea pigs exposed to DBTC or DOTC. From this study it is concluded that both DBTC and DOTC induce immune suppression in rats by a selective inhibition of T-lymphocyte activity. Immune suppression was most pronounced in animals exposed to the chemicals during the developmental phase of the lymphoid system.

Toxicity of organotin compounds. II. Comparative in vivo and in vitro studies with various organotin and organolead compounds in different animal species with special emphasis on lymphocyte cytotoxicity

A series of organotin and organolead compounds were fed to male and female weanling rats for 2 weeks at dietary levels of 0, 50, or 150 ppm, in order to evaluate their toxic effects, with special emphasis on the thymus and peripheral lymphoid organs. A dose-related reduction in the weight of thymus, spleen, and popliteal lymph node, associated with lymphocyte depletion in the cortex of the thymus and the thymus-dependent areas in the peripheral lymphoid organs, was observed in animals fed di-n-octyltin dichloride (DOTC) and di-n-butyltin dichloride (DBTC). As shown previously, these effects were not related to stress. Similar, but less pronounced, lymphoid organ changes occurred in animals fed diets containing diethyltindichloride (DETC) and di-n-propyltindichloride. In contrast, other dialkyltin compounds (dimethyltindichloride; di-n-dodecyltindibromide; and di-n-octadecyltindibromide), as well as mono-n-octyltintrichloride (MOTC), tri-n-octyltinchloride, and tetraoctyltin did not cause atrophy of lymphoid organs. Of the dialkyllead compounds tested, di-n-butylleaddiacetate and di-n-hyxylleaddiacetate, the latter caused distinct lymphoid atrophy, but only when associated with severe growth retardation. A similar structure-activity relationship regarding thymus atrophy by dialkyltin compounds was observed after iv application. DOTC and DBTC were effective at a dose of 1 mg/kg. A dose-related reduction of thymus weight, cell count, and cell viability occurred in rats after a single iv injection of 0, 1, 2, 4, or 8 mg of DOTC/kg. The effect of DOTC was completely reversible. In contrast to rats, lymphoid atrophy did not occur in mice, guinea pigs, or Japanese quail fed DOTC or DBTC. In vitro incubation of thymocytes and bone marrow cells with DBTC and DOTC revealed the same selectivity regarding cell type and species origin of cells as was found in vivo. A dose-related decrease in the survival of rat thymocytes was observed, whereas rat bone marrow cells were not affected by DBTC and DOTC at levels up to 50 μg/ml. In contrast, the number and viability of mouse and guinea pig thymocytes exposed to DBTC were the same as the controls. As the survival of human thymocytes was markedly decreased by DBTC, it possibly acts in the same manner in man and rat. In agreement with in vivo results, the survival of rat thymocytes was not significantly decreased by dimethyltindichloride and diethyltindichloride.