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PubMed2006

Tributyltin-induced cell death is mediated by calpain in PC12 cells.

Tributyltin, an endocrine-disrupting chemical, has been used as a heat stabilizer, agricultural pesticide and component of antifouling paints. In this study, we investigated whether calpain is involved in tributyltin toxicity in undifferentiated PC12 cells. Tributyltin (2 microM) induced an increase of lactate dehydrogenase release, a marker of cytotoxicity, in PC12 cells in a time-dependent manner. It also induced calpain activation in a dose-dependent manner, and a calpain inhibitor, MDL28170 (40 microM), decreased the cellular toxicity, suggesting that calpain is involved in tributyltin toxicity in PC12 cells. Because calpain is a calcium-dependent protease, we examined the effect of EGTA, an extracellular Ca(2+) chelator and BAPTA-AM, an intracellular Ca(2+) chelator. Calpain activation induced by tributyltin was decreased by BAPTA-AM (50 microM), but not by EGTA (1 mM), suggesting that calpain activation is associated with calcium release from intracellular Ca(2+) stores. Further, we investigated the relationship between caspase-3 and calpain. Inhibition of caspase-3 reduced calpain activity induced by tributyltin. In conclusion, we have demonstrated that tributyltin induced cell death through calpain activation, and that intracellular Ca(2+) increase and caspase-3 activation are required for calpain activation by tributyltin.

Analysis of Variance↗
PubMed2006

In utero exposure to tributyltin chloride differentially alters male and female fetal gonad morphology and gene expression profiles in the Sprague-Dawley rat.

Tributyltin (TBT) is an environmental contaminant commonly used in anti-fouling agents for boats, as well as a by-product from several industrial processes. It has been shown to accumulate in organisms living in areas with heavy maritime traffic thereby entering the food chain. Here, we determined the consequences of in utero exposure to TBT on the developing fetal gonads in the Sprague-Dawley rat. Timed pregnant rats were gavaged either with vehicle or TBT (0.25, 2.5, 10 or 20 mg/kg) from days 0 to 19 or 8 to 19 of gestation. On gestational day 20, dams were sacrificed; fetal testes and ovaries were processed for light (LM) or electron microscopic (EM) evaluation and RNA was prepared for gene expression profiling. At the highest doses of TBT the number of Sertoli cells and gonocytes was reduced, there were large intracellular spaces between Sertoli cells and gonocytes and there was an increased abundance of lipid droplets in the Sertoli cells; EM studies revealed abnormally dilated endoplasmic reticulum in Sertoli cells and gonocytes. In the intertubular region between adjacent interstitial cells, immunostaining for the gap junctional protein connexin 43 was strong in controls, whereas it was reduced or completely absent in treated rats. In the ovaries, TBT (20 mg/kg, days 0-19; 10 mg/kg, days 8-19) reduced the number of germ cells by 44% and 46%, respectively. On examining gene expression profiles in the testis, 40 genes out of 1176 tested were upregulated more than two-fold over control. While no genes were upregulated in the TBT exposed fetal ovary, eight genes were downregulated. In conclusion, in utero exposure to TBT resulted in gender-specific alterations in gonadal development and gene expression profiles suggesting that there may be different adaptive changes to toxicity in developing male and female rats.

Abnormalities, Drug-Induced↗
PubMed2006

Histopathological evidence of antagonistic effects of tributyltin on benzo[a]pyrene toxicity in the Arctic charr (Salvelinus alpinus).

We previously reported that long-term (54 days), repeated intraperitoneal exposure to low doses of tributyltin (TBT; 0.3 mg/kg) inhibited the metabolic activation of co-administered benzo[a]pyrene (BaP; 3 mg/kg) in the Arctic charr (Salvelinus alpinus); BaP, in turn, stimulated the metabolism and/or excretion of TBT. Here, we report the results of histopathological examinations of liver, kidney and pseudobranch tissue samples originating from these same fish. The results revealed higher lesion incidences at all sampling time points (Days 8, 32 and 56) among BaP-exposed fish compared with fish exposed to either TBT alone or combined with BaP. The severity of lesions like necrosis was also higher in BaP-exposed fish. Moreover, hepatic basophilic foci were observed exclusively in fish exposed to BaP alone. Together, these results provide new evidences that TBT can antagonize BaP toxicity in fish exposed to both pollutants under controlled laboratory conditions. In contrast, BaP does not appear to provide protection against TBT toxicity.

Animals↗
PubMed2005

Sex difference in the principal cytochrome P-450 for tributyltin metabolism in rats.

Tributyltin is metabolized by cytochrome P-450 (CYP) system enzymes, and its metabolic fate may contribute to the toxicity of the chemical. In the present study, it is examined whether sex differences in the metabolism of tributyltin exist in rats. In addition, the in vivo and in vitro metabolism of tributyltin was investigated using rat hepatic CYP systems to confirm the principal CYP involved. A significant sex difference in metabolism occurred both in vivo and in vitro, suggesting that one of the CYPs responsible for tributyltin metabolism in rats is male specific or predominant at least. Eight cDNA-expressed rat CYPs, including typical phenobarbital (PB)-inducible forms and members of the CYP2C subfamily, were tested to determine their capability for tributyltin metabolism. Among the enzymes studied, a statistically significant dealkylation of tributyltin was mediated by CYP2C6 and 2C11. Furthermore, the sex difference in metabolism disappeared in vitro after anti-rat CYP2C11 antibody pretreatment because CYP2C11 is a major male-specific form in rats. These results indicate that CYP2C6 is the principal CYP for tributyltin metabolism in female rats, whereas CYP2C11 as well as 2C6 is involved in tributyltin metabolism in male rats, and it is suggested that CYP2C11 is responsible for the significant sex difference in the metabolism of tributyltin observed in rats.

Animals↗
PubMed2004

Tri-n-butyltin-induced cytotoxicity on rat thymocytes in presence and absence of serum.

Influence of fetal bovine serum (FBS) on cytotoxicity induced by tri-n-butyltin (TBT), an environmental pollutant, on rat thymocytes was examined to reveal how FBS modifies TBT cytotoxicity. As the medium FBS concentration was increased from 0 to 10%, the cytotoxicity of TBT was dose-dependently reduced when the cells were incubated with 1 microM TBT for 3 h. Almost complete inhibitions of TBT-induced changes in cell viability and population of cells with exposed phosphatidylserine (cells undergoing apoptosis) were observed when the FBS concentration was 10%. Thus, the cytotoxicity induced by 3 h incubation with TBT in FBS-free medium may be different from that in medium containing 10% FBS. However, even in presence of 10% FBS, TBT at concentrations ranging from 10 to 300 nM exerted cytotoxic action on rat thymocytes when the cells were incubated with TBT for 24 h. TBT dose-dependently increased the population of shrunken cells, of which more than 30% were stained with propidium. TBT at 30 nM or more significantly increased the population of cells with hypodiploid DNA, indicating TBT-induced apoptotic cell death. Thus, in the presence of 10% FBS, the prolonged incubation (24 h) of rat thymocytes with TBT at nanomolar concentrations induced apoptosis rather than necrosis.

Animals↗
PubMed2004

Tributyltin exposure causes decreased granzyme B and perforin levels in human natural killer cells.

Natural Killer (NK) cells are a subset of lymphocytes that are capable of killing tumor cells, virally infected cells and antibody coated cells. Tributyltin (TBT) is a toxic chemical used for various industrial purposes such as: slime control in paper mills, disinfection of circulating industrial cooling waters, anti-fouling agents in shower curtains and the preservation of wood. TBT can be found in edible items such as dairy products and fish. This study investigates the mechanism by which TBT exposure decreases the immune function of human NK cells, in vitro. Cytotoxic function, the expression of the cytotoxic proteins (granzyme B and perforin), and cAMP response element binding protein (CREB) phosphorylation were examined. NK cells exposed to 300 nM TBT for 1 h showed no significant decrease in cytotoxic function, levels of granzyme B and perforin, or phosphorylation of CREB. However, mRNA levels for the cytotoxic proteins were significantly decreased. A 24 h exposure to 200 nM TBT caused significant decreases in cytotoxic function, levels of granzyme B and perforin, and levels of granzyme B and perforin mRNA. When NK cells were exposed to 300 nM TBT for 1h followed by a 24 h period in TBT-free media, again there were significant decreases in NK cell cytotoxic function, levels of granzyme B and perforin and their mRNA. A 1h exposure to 300 nM TBT followed by a 48 h period in TBT-free media showed similar changes in cytotoxic function and levels of granzyme B and perforin as seen after 24 h in TBT-free media. Additionally, both of these exposures showed significant decreases in phosphorylation of CREB. These results indicate that TBT exposures can disrupt the transcription of granzyme B and perforin and that this disruption cannot be entirely accounted for by a decrease in phosphorylated CREB (phosphoCREB) levels.

Adult↗
PubMed2005

Tributyltin-induced effects on MAP kinases p38 and p44/42 in human natural killer cells.

NK cells form a class of lymphocytes that are able to kill tumor cells, virally infected cells and antibody-coated cells without prior sensitization. Tributyltin (TBT) is a toxic chemical that was used in large scale in wood preservation, marine antifouling paints, and slime control in paper mills. TBT has been detected in human foods such as dairy products, meat and fish and detectable levels have been found in human blood. The role of TBT in immunosuppression has been reported and its specific inhibition of the human NK-cell cytotoxic function has also been described. The current studies examined the role of mitogen-activated protein kinases (MAPKs) p38 and p44/42 during TBT-induced inhibition of NK cytotoxic function. Continuous in vitro exposure to 300 nM TBT for 1h decreased the NK cell cytotoxic function with concomitant increases in phosphorylated forms of both p38 and p44/42 but not the total levels of either of these enzymes. Similar results were obtained with 500 nM TBT treatment. A 1 h exposure to 300 nM TBT followed by 24 h in TBT-free media resulted in a further decrease in the cytotoxic function with an accompanying increase in the phosphorylated forms of p38 and p44/42 MAPKs as compared to controls (approximately 50%). However, after 48 h in TBT-free media, the phosphorylation levels of both p44/42 and p38 MAPKs decreased by about 50 and 30%, respectively. NK cell cytotoxic function also continued to decrease with time in TBT-free media. A 24h exposure to 200 nM TBT decreased cytotoxic function of NK cells (>90%) but produced donor-dependent effects on the phosphorylated p38 and p44/42 MAPK levels. These data indicated that in vitro exposures to TBT induced changes in the phosphorylation (activation) states of p38 and p44/42 but not in their overall levels of expression in human NK cells.

Adult↗
PubMed2006

Alteration of an essential NK cell signaling pathway by low doses of tributyltin in human natural killer cells.

Tributyltin (TBT), a toxic and widespread environmental contaminant, has been shown to inhibit natural killer (NK) cell cytotoxic function significantly. Inhibition of NK cell cytotoxic function has the potential to increase viral infections and tumor growth. Upon NK cell binding to lysis-sensitive tumor cells, an intracellular pathway is activated, which generally begins with activation of non-receptor protein tyrosine kinases (PTKs) and ends with mitogen-activated protein kinase (MAPK)-mediated release of lytic granules toward the contacted target cell. In the current studies, we used a cytotoxicity assay to examine how low doses (200nM or lower) of TBT affect cytotoxic function. Additionally, we investigated how low doses of TBT modulate the signaling pathway that dictates lytic granule exocytosis. A 1h exposure to 200, 100, 50 and 25nM TBT significantly decreased cytotoxic function 6d later. We also saw significant activation of p38 and p44/42 by as low as 50nM TBT within ten minutes of exposure. The observed activation of MAPKs, p38 and p44/42, implicated their upstream activators MAPK kinases (MAP2Ks). On examining MAP2Ks, MKK3/6 and MEK1/2, activation was seen within ten minutes. However, when the most upstream signaling molecules in this pathway, non-receptor protein tyrosine kinases (PTKs) such as Syk, ZAP-70, Pyk2 and Src were examined, no significant activation was seen. These data imply that upstream activators of MAP2Ks, MAP2K kinases (MAP3Ks), are activated by TBT exposures and/or that MAP2K phosphatases are being inhibited by TBT. Taken together, these data suggest that TBT-induced activation of MAPKs, p38 and p44/42, is caused by their upstream activators MAP2Ks, MKK3/6 and MEK1/2, respectively.

Blotting, Western↗
PubMed2006

Apoptotic related biochemical changes in human amnion cells induced by tributyltin.

Tributyltin (TBT) is one of the environmental pollutants, which is mostly accumulated in marine animals. The toxic effects of TBT have been extensively documented in several types of cells, but the molecular mechanisms responsible for TBT-induced cell damage are still not fully elucidated. The present study was undertaken to evaluate the apoptotic related biochemical changes in human amnion cells induced by TBT. After cells were exposed to TBT at the concentrations of 1-4 microM for 2h, the results suggested that TBT could induce an early and typical apoptosis, moreover caspase-3, the modifications of cytoskeletal structure and the Bcl-2 family were involved in this process. The results will deepen our understanding about the toxic mechanism of TBT on human amnion cells.

Amnion↗
PubMed2006

Characterization of tributyltin in shipyard waters and removal through laboratory and full-scale treatment.

Characterization and treatment studies were conducted in an effort to evaluate treatment options capable of removing tributyltin (TBT) in shipyard waters from above 1,000,000 ng/L to effluent concentrations below 50 ng/L. Laboratory studies and operation of a full-scale treatment plant were used to examine treatment options for TBT removal and included physicochemical treatment processes of coagulation-clarification, filtration, and granular activated carbon (GAC) adsorption. Significant variability was observed in TBT-containing shipyard waters (generated from different ships) in terms of their particulate solids, conductivity, and TBT and dissolved organic carbon concentrations. Laboratory tests with aluminum sulfate and ferric sulfate showed that on average 90% of TBT in shipyard waters could be removed by coagulation-flocculation-clarification under optimum conditions. No statistically significant difference was found in TBT removal capabilities between the two metal salts when compared at equivalent metal doses and coagulation pH. Much lower removals were observed for the coagulation-flocculation-clarification portion of the full-scale plant while the complete full-scale treatment plant averaged 99.8% TBT removal over a period of 3 years. While relatively high % removals were achieved, the total treatment process did not consistently remove TBT to levels that would meet the regulatory requirements proposed (50 ng/L) at the time the study was conducted. Based on the results from limited efforts to characterize the dissolved and particulate TBT fractions in the full-scale treatment plant effluent, particulate TBT was observed to be the dominant component of the effluent TBT from the full-scale plant and may be associated with polymer carry through.

Adsorption↗
PubMed2001

Effect of tributyltin chloride on the release of calcium ion from intracellular calcium stores in rat hepatocytes.

The effects of tri-n-butyltin chloride (TBT), an environmental pollutant, on the release of Ca(2+) from intracellular stores were investigated in isolated rat hepatocytes. Isolated hepatocytes permeabilized with digitonin were suspended in solution, and the concentration of extracellular Ca(2+) was measured, using a fluorescent Ca(2+) dye, fura-2. In the solution containing permeabilized hepatocytes that had been preincubated with 4.0 microM TBT for 30 min, the extracellular Ca(2+) concentration was high, but the inositol 1,4,5-trisphosphate (InsP(3))-induced increase in Ca(2+) concentration was suppressed, suggesting that the extracellular release of Ca(2+) in response to TBT treatment was from intracellular stores. Images of the Ca(2+) concentration in the intracellular stores of primary cultured hepatocytes loaded with fura-2 were obtained after digitonin-permeabilization, using digitalized fluorescence microscopy. The permeabilized hepatocytes that had been preincubated with 4.0 microM TBT for 30 min had a very low fura-2 fluorescence ratio (340/380 nm), suggesting that stored Ca(2+) was released. When the hepatocytes were treated with 4.0 microM TBT after digitonin-permeabilization, the decrease in the fura-2 fluorescence ratio was very small. However, when the permeabilized hepatocytes were incubated with 4.0 microM TBT and 2.0 microM NADPH, the decrease was enhanced, raising the possibility that TBT might be metabolized to the active form(s), thus releasing Ca(2+) from intracellular stores. When the hepatocytes were preincubated with 0.1 microM TBT for 30 min and then were permeabilized, the fura-2 fluorescence ratio was almost the same as that in the control permeabilized hepatocytes. However, the InsP(3)-induced decrease in the fluorescence ratio was suppressed significantly in the permeabilized hepatocytes. These results suggest that TBT released Ca(2+) from the intracellular stores at high concentrations, and suppressed the InsP(3)-induced Ca(2+) release at non-toxic low concentrations. It is probable that the latter effect was responsible for the previously reported suppression of Ca(2+) response induced by hormonal stimulations (Kawanish et al., Toxicol Appl Pharmacol 1999;155:54-61).

Animals↗
PubMed1992

The reversibility of tributyltin-induced toxicity in vitro as a function of concentration and duration of exposure (C x T).

The toxicity exhibited by murine erythroleukemic cells (MELC) exposed to tributyltin (TBT) is a function of both concentration (C) and duration of exposure (T). At or above a critical C x T product value (CPV) (e.g., 0.5-1.0 microM TBT, 6 hr), exposed MELC exhibit severe, irreversible toxicity: decreased membrane integrity (viability, measured by propidium iodide [PI] exclusion), grossly perturbed cell-cycle distributions, and fixation of the plasma membrane/cytoplasm complex. Below the CPV, exposed cells exhibit retention of carboxyfluorescein (CF) fluorescence (indicative of decreased plasma membrane permeability) and decreased cell proliferation, a result of retardation of progression into, through, and out of the S (DNA synthetic) phase of the cell cycle. However, following washout and recovery, mean CF fluorescence, cell proliferative capacity, and cell-cycle kinetics return to control levels. These results suggest that the toxic changes induced by TBT exposure may be reversible if exposure conditions do not exceed the CPV. To assess whether the CPV has been exceeded, a multiparameter flow cytometric analysis of membrane integrity and cell-cycle kinetics is useful.

Animals↗
PubMed1998

Cytochrome c release and caspase activation in hydrogen peroxide- and tributyltin-induced apoptosis.

The ability of H2O2 and tributyltin (TBT) to trigger pro-caspase activation via export of cytochrome c from mitochondria to the cytoplasm was investigated. Treatment of Jurkat T lymphocytes with H2O2 resulted in the appearance of cytochrome c in the cytosol within 2 h. This was at least 1 h before caspase activation was observed. TBT caused cytochrome c release already after 5 min, followed by caspase activation within 1 h. Measurement of mitochondrial membrane potential (delta psi(m)) showed that both H2O2 and TBT dissipated delta psi(m), but with different time courses. TBT caused a concomitant loss of delta psi(m) and release of cytochrome c, whereas cytochrome c release and caspase activation preceded any apparent delta psi(m) loss in H2O2-treated cells. Thus, our results suggest that different mechanisms are involved in triggering cytochrome c release with these apoptosis-inducing agents.

Apoptosis↗
PubMed1981

Simultaneous determination of trialkyltin homologues in biological materials.

Taking advantage of the high sensitivity of an electron capture detector to alkyltin halides, an analytical method has been developed for the simultaneous determination of trialkyltin homologues in biological materials. Trialkyltins were purified as chlorides from tissues by simultaneous extraction with hydrochloric acid and ethyl acetate, replacement of the extraction solution with n-hexane and stepwise elution with n-hexane-ethyl acetate on a silica gel column. Alternatively, gas chromatographic analysis was carried out on 20% DEGS-HG at temperatures from 100 to 120 degrees C. Detection limits reached 1 x 10(-12) g for trialkyltin chlorides. The recoveries of trialkyltins added to various tissues at the 50-pmole level ranged from 97 to 106%. By in vivo studies, it was confirmed that this method is rapid, sensitive and applicable to biomaterials containing more than 1 ng trialkyltins per gram of tissue.

Animals↗