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PubMedDate not supplied

Effects of interleukins 2 and 12 on TBT-induced alterations of MAP kinases p38 and p44/42 in human natural killer cells.

NK cells are lymphocytes in the non-adaptive immune system that protect the body against intracellular pathogens and eliminate tumor cells. Tributyltin (TBT) is a toxic chemical that has been detected in human foods as well as in human blood. The role of TBT in immunosuppression has been described, including inhibition of the human NK-cell cytotoxic function. Previous studies indicated that exposure of NK cells to TBT for 1 h induced progressive and irreversible inhibition of cytotoxic function. However, it was found that if NK cells were incubated in TBT-free media with either IL-2 or IL-12, loss of cytotoxic function was prevented/reversed within 24 h. Molecular studies established that loss of cytotoxic function is accompanied by alteration of MAP kinases (MAPKs) p38 and p44/42 phosphorylation. This study examined whether interleukin-mediated recovery of cytotoxicity involved reversal of tributyltin-altered p38 and p44/42 phosphorylation. The results indicated that there was no substantial IL-2 prevention/reversal of the TBT-induced alteration of phosphorylation of either p38 or p44/42 after either a 24 or 48 h recovery period. Additionally, IL-12 caused no substantial prevention/reversal of the TBT-induced alteration of phosphorylation of the MAPKs seen after either 24 or 48 h. These data suggest that IL-2 and/or IL-12-mediated recovery of NK cytotoxic function is not a result of prevention/reversal of TBT-induced phosphorylation of p38 and p44/42 MAPKs at the 24 or 48 h time points.

Adult↗
PubMed1981

Male characteristics on female mud snails caused by antifouling bottom paints.

This study continues an investigation of an anatomical abnormality, named 'imposex', which consists of a superimposition of male characteristics on to a functionally normal female reproductive anatomy of the dioecious snail Nassarius obsoletus Say. Imposex is prevalent in natural populations living near yacht basins and rarely found distant from them. In the current study caged snails were transferred between a yacht basin and a distant 'clean' locality where the natural population of snails was normal. Imposex was induced in some normal snails kept at the marina and suppressed, but not lost in abnormal snails kept at the clean locality. A similar positive result was obtained in the laboratory by exposing normal snails to organotin-containing antifouling paints and abnormal snails to clean sea water. Results were negative in parallel tests of various marina-associated materials which did not contain organotin. The laboratory studies have thus identified a causative factor for the anatomical abnormalities common near yacht basins in the natural environment. They also provide a rare, if not unique, example of a chemical agent which causes the appearance of superfluous anatomical features in an animal.

Animals↗
PubMed1981

Electroencephalographic and evoked response correlates of trimethyltin induced neuronal damage in the rat hippocampus.

Trimethyltin produces localized neuronal damage in the rat hippocampus, amygdala and pyriform cortex when given systemically. In the present study the behavioural, electroencephalographic and auditory evoked responses of conscious rats were followed over an 11 day period after oral administration of trimethyltin. An early increase in hippocampal and, to a lesser extent, neocortical evoked response was seen, this preceding the behavioural symptoms. Development of symptoms (hyperactivity, tremor and fear) was accompanied by an increase in the incidence of theta rhythm in the electroencephalogram (EEG). Finally a fall in hippocampal evoked response and theta incidence was seen. It is suggested that a phase of neuronal excitability precedes neuronal damage, and that this is more pronounced in the hippocampus than in areas not developing subsequent neuronal loss.

Animals↗
PubMed1984

The neurotoxicity of trimethyltin chloride in hamsters, gerbils and marmosets.

Trimethyltin chloride (TMT) was given to Syrian hamsters, gerbils and marmosets, and the changes in the brain were studied 1 day to 7 weeks later by light and electron microscopy. Within the marmoset brain, TMT was found to be uniformly distributed, similar to that in the rat. In all three species, signs of poisoning included whole-body tremors and prostration, while death might occur in 3-4 days; in marmosets ataxia, agitation, aggression and occasional fits were also observed. Bilateral symmetrical neuronal necrosis and chromatolysis were seen in the majority, which involved the hippocampus, pyriform cortex, amygdaloid nucleus, neocortex, various brain stem nuclei and in marmosets the retina. The probably lethal dose of TMT in all three species is approximately 3 mg kg-1, while the LD50 for the rat is 12.6 mg kg-1. The lower figure is probably related to lack of binding to haemoglobin in contrast to the binding in the rat. TMT does not bind to human haemoglobin and thus the predicted lethal dose for humans may be about 3 mg kg-1 (15.1 mumol kg-1), while the dose required to produce neuronal damage could well be less.

Animals↗
PubMed1991

Immunotoxicity of tri-n-butyltin oxide (TBTO) and tri-n-butyltin chloride (TBTC) in the rat.

In a 1-month feeding trial, pure and commercial tri-n-butyltin oxide (TBTO) and tri-n-butyltin chloride (TBTC) were fed to rats at concentrations of 5 ppm and 25 ppm. At all times, the mean body weight gain and the food consumption was significantly less in rats treated with 25 ppm pure TBTO or pure TBTC as compared to control rats or rats receiving commercial TBTO. Histological examination of the thymus of rats treated for 7 days with TBTO showed atrophy with severe lymphocytic depletion in the cortex. After 28 days of exposure, most of the lesions reversed and the thymus became markedly smaller than in control rats, both in absolute terms and in relation to body weight. Seven days of exposure to TBTO increased liver weight but this change was reversed during a further 3-week exposure. Tin concentrations were the highest in livers and kidneys. Concentrations in the thymus were less than one-fifth of hepatic values. Changes in the rats treated with the commercial TBTO were very similar. Rats treated with TBTC showed lower tin levels and less immunotoxicity as compared to those treated with TBTO.

Animals↗
PubMed1991

Triorganotin inhibition of rat cardiac adenosine triphosphatases and catecholamine binding.

Triorganotins have been reported to affect heme metabolism as well as the cardiovascular system. Our recent studies indicated that these organotins inhibit cardiac sarcoplasmic reticulum Ca(2+)-transport and cAMP-stimulated phosphorylation of specific proteins involved in Ca2+ transport, suggesting their interference with cardiac adrenergic function. The present study determines the effect of three organotins--tributyltin bromide (TBT), triethyltin bromide (TET) and trimethyltin chloride (TMT)--on rat cardiac ATPases and catecholamine binding, since these phenomena are involved in cardiac function. Cardiac membrane fraction was prepared from heart ventricles of male Sprague-Dawley rats. All three organotins inhibited cardiac Na+,K(+)-ATPase, [3H]ouabain binding, K(+)-activated p-nitrophenyl phosphatase (K(+)-PNPPase) and oligomycin-sensitive (OS) and oligomycin-insensitive (OI) Mg(2+)-ATPase in a concentration-dependent manner. K(+)-PNPPase was less sensitive to these triorganotins when compared to Na+K(+)-ATPase, suggesting that triorganotins affect the Na(+)-pump activity by acting on the Na(+)-dependent phosphorylation process. OS Mg(2+)-ATPase was more sensitive to these organotins when compared to OI Mg(2+)-ATPase, confirming their potent effect on the enzymes of oxidative phosphorylation. The order of potency is TBT greater than TET greater than TMT. TET and TMT, but not TBT, inhibited [3H]norepinephrine and [3H]dopamine binding to cardiac membranes in a concentration-dependent manner, the effect being more with TET. These results suggest that triorganotins inhibit sodium pump activity as well as ATP synthesis. Since Na+,K(+)-ATPase is involved in the active transport of catecholamines, triorganotins not only inhibited the catecholamine transport but also to some extent affected catecholamine binding, thus interfering with cardiac function.

Adenosine Triphosphatases↗
PubMed1986

Tricyclohexyltin hydroxide effects on cationic and substrate activation kinetics of beta-adrenergic-stimulated cardiac Ca2+-ATPase.

Previous studies from this laboratory have indicated that tricyclohexyltin hydroxide (Plictran) is a potent inhibitor of both basal- and isoproterenol-stimulated cardiac sarcoplasmic reticulum (SR) Ca2+-ATPase, with an estimated IC-50 of 2.5 X 10(-8) M. The present studies were initiated to evaluate the mechanism of inhibition of Ca2+-ATPase by Plictran. Data on substrate and cationic activation kinetics of Ca2+-ATPase indicated alteration of Vmax and Km by Plictran (1 and 5 X 10(-8) M), suggesting a mixed type of inhibition. The beta-adrenergic agonist isoproterenol increased Vmax of both ATP- and Ca2+-dependent enzyme activities. However, the Km of enzyme was decreased only for Ca2+. Plictran inhibited isoproterenol-stimulated Ca2+-ATPase activity by altering both Vmax and Km of ATP as well as Ca2+-dependent enzyme activities, suggesting that after binding to a single independent site, Plictran inhibits enzyme catalysis by decreasing the affinity of enzyme for ATP as well as for Ca2+. Preincubation of enzyme with 15 microM cAMP or the addition of 2mM ATP to the reaction mixture resulted in slight activation of Plictran-inhibited enzyme. Pretreatment of SR with 5 X 10(-7) M propranolol and 5 X 10(-8) M Plictran resulted in inhibition of basal activity in addition to the loss of stimulated activity. Preincubation of heart SR preparation with 5 X 10(-5) M coenzyme A in combination with 5 X 10(-8) M Plictran partly restored the beta-adrenergic stimulation. These results suggest that some critical sites common to both basal- and beta-adrenergic-stimulated Ca2+-ATPase are sensitive to binding by Plictran, and the resultant conformational change may lead to inhibition of beta-adrenergic stimulation.

Adenosine Triphosphate↗
PubMed1988

Membrane potential of primitive red cells from chick embryo is a proton potential.

The membrane potential of primitive red cells from 4- and 6-day old chick embryos has been determined using the fluorescent dye Dis-C3-(5). At day 4 the membrane potential Em was -44 mV for pH 7.4 and 20 degrees C and -36 mV at day 6. Both values are far removed from the equilibrium potential for chloride, which is about -14 mV at day 6. Changes in the external potassium, sodium or chloride concentration were without effect on the membrane potential, except at very high potassium concentrations, where a small but significant depolarization was observed at day 6. The measurements gave the same results in the absence or presence of the anion exchange blocking agent DIDS. Three pieces of evidence indicate that the membrane potential of primitive red cells is primarily caused by an electrogenic H+ conductance: 1) The measured membrane potential of -36 mV at day 6 is close to the previously determined proton equilibrium potential (Baumann and Haller, 1983) EH + of -36 mV. 2) Addition of the electrosilent Cl-/OH- exchanger tributyltin causes a significant depolarization of about 20 mV at day 4 and about 14 mV at day 6. 3) Measurement of hydrogen ion fluxes demonstrate a potential dependent proton conductance, which increases with depolarization. These results indicate that large qualitative differences exist with regard to the mechanisms involved in the generation of membrane potential and hydrogen distribution between red cell and plasma of embryonic and adult chicken.

Animals↗
PubMed2004

Modulation of adenyl cyclase activity in the gills of Tapes philippinarum.

Adenyl cyclase (AC) plays a pivotal role in cell signaling. The AC system of bivalves has received little attention so far, and our study has been addressed to the characterization of AC properties in the gills of T. philippinarum. The enzyme showed a Km value of 0.77 mM for ATP in the presence of 5 mM Mg2+; in the absence of agonists, it was poorly affected by GTP, while it was stimulated by GTPgammaS and GppNHp up to 14-fold and 4-fold, respectively. Similarly to other invertebrates, the enzyme activity was scarcely stimulated by forskolin. The receptor agonist serotonin (5-HT) significantly stimulated the AC activity, and the pharmacological profile of the 5-HT receptor/s was as follows: (+)butaclamol > dihydroergocryptine > methysergide > prazosin > yohimbine. The AC activity was assessed in vitro in the presence of tributyltin chloride and HgCl2, which reduced the AC activity only at the highest dose tested (10-100 microM). Our data indicate the presence of a membrane-bound AC in gill membranes of T. philippinarum, coupled to Gs proteins and to a specific class of 5-HT receptors. Such receptors show a pharmacological profile slightly different from that reported for 5-HT invertebrate receptors cloned so far.

Adenylyl Cyclases↗
PubMed2007

In utero exposure to tributyltin alters the expression of E-cadherin and localization of claudin-1 in intercellular junctions of the rat ventral prostate.

Tributyltin (TBT) is an environmental contaminant, exhibiting well-established toxicity to reproductive systems in aquatic organisms. Little information exists regarding the effects of TBT on mammalian reproduction. Cellular junctions are crucial for sperm development and maturation. Intercellular tight junctions are formed by transmembrane proteins such as claudins (Cldns), while the formation of tight junctions involves signaling components of adhering junctions, comprised of cadherins. The objectives of this study were to determine the effects of in utero exposure to TBT on the rat ventral prostate. Pregnant Sprague-Dawley rats were given doses of TBT (2.5, 10, or 20 mg/kg) throughout gestation and sacrificed at Day 91. Ventral prostate weights of TBT-treated rats were decreased in all treatment groups. Results of gene expression macro-array analysis indicated that numerous genes related to cellular adhesion and cell polarity were affected. Cldn-1 mRNA levels decreased after exposure to TBT. Cldn-1 was immunolocalized to the apical lateral margins of adjacent prostatic epithelial cells in controls, but was increasingly dispersed along the lateral plasma membrane with increasing TBT dose, suggesting that the targeting of Cldn-1 or its localization to tight junctions was altered as a result of fetal TBT exposure. E-cadherin mRNA levels and immunolocalization were decreased in a dose-dependent manner. These data indicate that in utero TBT exposure results in permanent alterations in ventral prostate and that these are associated with alterations in the expression and distribution of cell adhesion and tight junctional proteins.

Animals↗
PubMed2004

Development of a biosensor for the detection of tributyltin.

A biosensor (LUMISENS I), based on the inducible bioluminescence of the Escherichia coli strain TBT3 (Ec::luxAB TBT3), was developed for the detection of the biocide tributyltin. LUMISENS I was set up with a minibioreactor and additional equipment for growth monitoring and light acquisition. The 100-mL minibioreactor has allowed us to establish a stable and reproducible environment for the bacteria (regulation of the growth rate, temperature, pH, and oxygenation), as well as for in situ contact with the xenobiotic. The optical components of the transducer were chosen according to the spectral emission of the strain being studied using a highly sensitive spectrophotometer that was initially devoted to Raman scattering. LUMISENS I was patented according to the in situ, automatic, and simultaneous measurement of the cell density and bioluminescence in the bioreactor. The first results showed that cells cultivated in a synthetic glucose medium provided a better detection limit than did those cultivated in a complex Luria-Bertani (LB) medium (0.02 and 1.5 microM of tributyltin, respectively). Cells maintained at a high growth rate (0.9 h(-1)) led to maximum bioluminescence. Moreover, air bubbling was efficient enough to provide suitable quantities of oxygen for both growth and light emission. When the TBT3 strain used the luxAB genes on its own, decanal, a long-chain aldehyde, had to be added to obtain the bioluminescence reaction. We found that the continuous addition of decanal was the most effective means of obtaining this reaction. The monitoring of the bioluminescence after tributyltin induction showed that the aldehyde was not toxic up to 300 microM during a 7-day experiment. Measurement of tributyltin with LUMISENS I was performed, which showed significant response up to 0.125 microM without any effect on optical density. Even though optimization of the performance of LUMISENS I is still under development, because of its original design, this biosensor is already in use as a warning system for the online monitoring of tributyltin.

Biosensing Techniques↗
PubMed2004

Xenobiotic substances such as PCB mixtures (Aroclor 1254) and TBT can influence swimming behavior and biotransformation activity (GST) of carp (Cyprinus carpio).

Different groups of carp were treated with polychlorinated biphenyl (PCB) or tributyltin (TBT), and possible effects of the chemicals on the swimming behavior of the carp were examined using the BehavioQuant system. By evaluating quantitative behavioral parameters of the animals, it became evident that exposure to high concentrations of chemicals (organotin, 7 microg L(-1), or polychlorinated biphenyl, 22 microg L(-1)) severely affected the carp, causing a significant change in their swimming speed. TBT stress led to a rapid decrease in mean swimming activity. A decrease in the preferred swimming depth was observed in TBT- and PCB-exposed fish. Animals exposed to PCB reduced their mean daily activity and increased their mean swimming speed in the nighttime during the second week of exposure. Therefore, our findings imply that the fish were adapted to cope with the chemicals after the second week of exposure. Furthermore, our results showed that low concentrations (TBT, 0.3 and 2 microg L(-1), or PCB, 14 microg L(-1)) did not significantly alter any quantified parameters of swimming behavior. In addition, the direct effects of chemicals on enzyme activity (GST) were determined. Measurement of soluble glutathione-S-transferase activity of fish liver or gills showed a significant elevation after exposure to PCB (0.1 or 22 microg L(-1)) or TBT (0.8 or 7 microg L(-1)). We had to conclude that the two different end points tested generally are useful as biomarkers of exposure and for investigations of energy resources in organisms under the influence of toxic stress.

Animals↗
PubMed2006

Tributyltin induces DNA damage as well as oxidative damage in rats.

In this study, oxidative and DNA damage were measured synchronously after Sprague-Dawley rats were exposed to different dosages of tributyltin (TBT) for 3 and 7 consecutive days. Oxidative damage was measured by analyzing the production of hepatic reactive oxygen species (ROS), the activity of superoxide dismutase (SOD), and the content of malondialdehyde (MDA). DNA damage was measured by single-cell gel electrophoresis (comet assay). After 3 days of exposure, significant differences in ROS production could only be seen between the control and the highest dosage group (10 mg/kg BW d), although after 7 days of treatment, ROS production increased in a dose-dependent manner. SOD activity increased with dosage after 3 days of exposure and decreased with dosage after 7 days of exposure. TBT also induced significant production of MDA after 7 days of exposure. The changes in ROS, SOD, and MDA found in this study suggest that the antioxidative systems of rats were activated by TBT in the first 3 days of exposure but had become exhausted by 7 days of exposure. In the comet assay, the number of cells with damaged DNA in rats treated with TBT increased with dosage of TBT. The most likely mechanism of the DNA breakage induced by TBT is oxidative damage. It can be concluded that exposure of TBT can promote both oxidative and DNA damage in mammals in vivo.

Animals↗
PubMed2006

Tributyltin contamination of bivalves in coastal areas around northern Kyushu, Japan.

We determined tributyltin (TBT) concentrations in bivalve samples of blue mussel (Myitlus edulis), Manila clam (Ruditapes philippinarum) and pen shell (Atrina pectinata) collected from coastal areas around northern Kyushu in 1998 and 2001. TBT was detected in all bivalve samples collected, ranging in concentration from 0.008 to 0.135 microg/g wet wt. In Hakata Port, which is an industrial area, high TBT concentrations were detected in bivalves (blue mussel, maximum concentration of 0.135 microg/g wet wt). In the Ariake Sea, which is an important bivalve habitat, TBT concentrations in Manila clams ranged from 0.062 to 0.125 microg/g wet wt in 1998 and from 0.008 to 0.033 microg/g wet wt in 2001. In addition, concentrations of TBT in pen shells collected from the Ariake Sea in 2001 ranged from 0.009 to 0.095 microg/g wet wt. These results clearly demonstrate that, despite the regulation of TBT usage since 1990 in Japan, contamination of bivalves by TBT has persisted in coastal areas around northern Kyushu.

Animals↗
PubMed1994

Intracellular calcium and pH alterations induced by tri-n-butyltin chloride in isolated rainbow trout hepatocytes: a flow cytometric analysis.

The effects of tri-n-butyltin chloride (TBT) on ionic homeostasis on isolated trout hepatocytes were investigated by flow cytometry (FCM), using the Ca(2+)-sensitive and pH-sensitive fluorescent probes Indo-1 and SNARF-1, respectively. Cell viability was monitored concurrently. Treatment of hepatocytes with 1 and 5 microM TBT caused a rapid and sustained elevation of cytosolic free Ca2+ concentration [Ca2+]i and an important cytoplasmic acidification. These changes were dependent upon TBT concentration and were maintained over 60 min, the maximum exposure period investigated. At 0.5 microM TBT, there was a slight but not significant increase in [Ca2+]i and a significant reduction in intracellular pH (pHi) only after 60 min of exposure. A rise in [Ca2+]i and cytoplasmic acidification were observed before loss of viability was detectable. Experiments carried out in Ca(2+)-free medium suggest that TBT mainly mobilizes Ca2+ from intracellular stores in trout hepatocytes. The cytoplasmic acidification following TBT exposure seems to be caused by the combination of intracellular Ca2+ mobilization and by direct action of TBT. The present results suggest that ionic homeostasis perturbations could be early events in the mechanism of cell injury by TBT.

Animals↗
PubMed1993

Cloning of gene responsible for tributyltin chloride (TBTC1) resistance in TBTC1-resistant marine bacterium, Alteromonas sp. M-1.

A genetic library of tributyltin chloride (TBTC1)-resistant marine bacterium, Alteromonas sp. M-1, was constructed using plasmid vector pUC 19. Three positive clones were obtained from E. coli JM 109 transformed with the plasmids by the method of replica plating to LB medium containing 1 mM TBTC1. These clones could grow in LB liquid medium containing 100 microM TBTC1. Plasmids harbouring genes of Alteromonas sp. M-1 were designated pTBT1, pTBT2 and pTBT3 which contain 1.8 kb Hind III-fragment, 4.8 kb Pst I-fragment and 7.8 kb Pst I-fragment, respectively. Nucleotide sequence of the shortest fragment, 1.8 kb Hind III-fragment was determined, revealing an open reading frame (ORF) was contained in the fragment. The ORF was 324 bp (108 amino acids). The 48.5% of the amino acids encoded was hydrophobic, suggesting that the product relating to TBTC1 resistance might be membrane related protein. Homology search in amino acids alignment indicated that the product has homology with transport proteins.

Amino Acid Sequence↗
PubMed2000

Diverse effect of tributyltin on apoptosis in PC12 cells.

It has not been fully elucidated how endocrine-disrupting chemicals disrupt hormone functions or how strong their effects are compared with natural hormones. There is little information concerning the effects of tributyltin (TBT), one of the endocrine disrupters on living organisms. Although TBT at high concentration induced apoptosis in PC12 cells, TBT at low concentration inhibited the DNA fragmentation in the cells cultured in serum-free medium or in medium containing 6-hydroxydopamine. The cell viability grown in both medium conditions increased after treatment with TBT. These findings suggest that TBT exerted a apoptosis-inducing and -inhibiting effect. These diverse effect of TBT on apoptosis would cause serious damages on cell differentiation.

Animals↗
PubMed2002

Tributyltin causes cytochrome C release from isolated mitochondria by two discrete mechanisms.

Using isolated liver mitochondria we show that low concentrations of TBT (0.5 microM) cause the release of mitochondrial cytochrome c, in the presence of Ca(2+). This is reflected in a rapid loss of membrane potential (DeltaPsi(m)), and a large-amplitude swelling characteristic of mitochondrial permeability transition (MPT). Despite this, the inclusion of cyclosporin A could not prevent the release of cytochrome c. Further, in the absence of Ca(2+), low concentrations of TBT (0.5 microM) resulted in a slow sub-maximal shift of DeltaPsi(m), not characteristic of MPT, which was still paralleled by a release of cytochrome c. Further experiments showed that the loss of DeltaPsi(m) in the absence of Ca(2+) was due to a combination of inhibition of respiration and a direct uncoupling effect on the respiratory chain. Under these conditions, rapid swelling of mitochondria could be demonstrated, due to chloride exchange over the inner mitochondrial membrane. Taken together these data suggest that TBT can induce the release of cytochrome c in intact cells by at least two mechanisms. The first and critical mechanism is initiated immediately the mitochondria sense the presence of TBT and involves a slow loss of DeltaPsi(m) and induction of swelling, which allows release of cytochrome c in a relatively non-specific manner and independently from a rise in [Ca(2+)](i). The second mechanism involves the induction of formal MPT as intracellular [Ca(2+)](i) increases. These data help to explain previous observations in intact lymphocytes demonstrating TBT-induced release of mitochondrial cytochrome c in the absence of a rise in [Ca(2+)](i) (Stridh, H., Gigliotti, D., Orrenius, S., and Cotgreave, I. A. (1999) Biochem. Biophys. Res. Commun. 266, 460-465).

Animals↗