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PubMed1993

Studies on the mechanism of oxidative phosphorylation. ATP synthesis by submitochondrial particles inhibited at F0 by venturicidin and organotin compounds.

Oligomycin,N,N'-dicyclohexylcarbodiimide (DCCD), venturicidin, and tetracoordinate organotin compounds (R3SnX) are potent inhibitors of the mitochondrial ATP synthase complex, all acting on the membrane sector, F0. Oligomycin and DCCD inhibit proton translocation through F0 and energy transfer between F0 and the catalytic sector, F1, of the ATP synthase complex. Our results have shown that venturicidin and organotin compounds (tributyltin and triphenyltin chloride were used) greatly attenuate these processes, but do not cause complete inhibition. As a result, bovine submitochondrial particles (SMP) treated with venturicidin or tributyltin chloride were shown to be capable of ATP hydrolysis and synthesis, albeit at very slow rates. We had shown previously that in ATP synthesis Vmax and apparent Km for ADP and Pi increase or decrease, respectively, as the steady-state membrane potential is elevated or lowered (Matsuno-Yagi, A., and Hatefi, Y. (1986) J. Biol. Chem. 261, 14031-14038). These changes occurred at constant Vmax/Km, suggesting that the apparent Km changes were due mainly to kcat changes. Results presented here show that, in respiring SMP treated with venturicidin or organotin compounds, the membrane potential is near the static-head level, but the slow rate of ATP synthesis takes place with a low KmADP value of 2-3 microM. In agreement with our previous conclusions, these results indicate that it is not the membrane potential per se that affects KmADP during ATP synthesis, but rather it is the rate of energy transfer from F0 to F1 that influences both Vmax and KmADP. Further conclusions from the above studies have been discussed in relation to the possible mechanism of energy transfer between F0 and F1 and the manner in which venturicidin and organotin compounds might attenuate this process.

Adenosine Triphosphate↗
PubMed2002

[Distribution of tributyltin between water and liposome].

Distribution of the tributyltin (TBT) between egg-phosphatidylcholine membranes (liposome) and water under different pH and a comparison between the partition of TBT into lipid membranes and into octanol were studied. The distribution of this compound into both lipid membranes and octanol increased with pH. The major difference was that at lower pH, where ionized TBT dominated distribution was greater into lipid membranes compared to that of octanol. At high pH, where TBT predominates as neutral species, the distribution ratios were very similar in the octanol and the liposome-water system. These differences can be attributed to the properties of the biomembrane. The results indicated that the liposome-water partition model appears to be a better molecular descriptor for ionogenic organic compounds.

Hydrogen-Ion Concentration↗
PubMed2005

Simultaneous multi-species determination of trimethyllead, monomethylmercury and three butyltin compounds by species-specific isotope dilution GC-ICP-MS in biological samples.

An accurate and sensitive multi-species species-specific isotope dilution GC-ICP-MS method was developed for the simultaneous determination of trimethyllead (Me3Pb+), monomethylmercury (MeHg+) and the three butyltin species Bu3Sn+, Bu2Sn2+, and BuSn3+ in biological samples. The method was validated by three biological reference materials (CRM 477, mussel tissue certified for butyltins; CRM 463, tuna fish certified for MeHg+; DORM 2, dogfish muscle certified for MeHg+). Under certain conditions, and with minor modifications of the sample pretreatment procedure, this method could also be transferred to environmental samples such as sediments, as demonstrated by analyzing sediment reference material BCR 646 (freshwater sediment, certified for butyltins). The detection limits of the multi-species GC-ICP-IDMS method for biological samples were 1.4 ng g(-1) for MeHg+, 0.06 ng g(-1) for Me3Pb+, 0.3 ng g(-1) for BuSn3+ and Bu3Sn+, and 1.2 ng g(-1) for Bu2Sn2+. Because of the high relevance of these heavy metal alkyl species to the quality assurance of seafood, the method was also applied to corresponding samples purchased from a supermarket. The methylated lead fraction in these samples, correlated to total lead, varied over a broad range (from 0.01% to 7.6%). On the other hand, the MeHg+ fraction was much higher, normally in the range of 80-100%. Considering that we may expect tighter legislative limitations on MeHg+ levels in seafood in the future, we found the highest methylmercury contents (up to 10.6 microg g(-1)) in two shark samples, an animal which is at the end of the marine food chain, whereas MeHg+ contents of less than 0.2 microg g(-1) were found in most other seafood samples; these results correlate with the idea that MeHg+ is usually of biological origin in the marine environment. The concentration of butyltins and the fraction of the total tin content that is from butyltins strongly depend on possible contamination, due to the exclusively anthropogenic character of these compounds. A broad variation in the butylated tin fraction (in the range of <0.3-49%) was therefore observed in different seafood samples. Corresponding isotope-labeled spike compounds (except for trimethyllead) are commercially available for all of these compounds, and since these can be used in the multi-species species-specific GC-ICP-IDMS method developed here, this technique shows great potential for routine analysis in the future.

Animals↗
PubMed1988

Dibutyltin and tributyltin compounds induce thymus atrophy in rats due to a selective action on thymic lymphoblasts.

Di-n-butyltin dichloride (DBTC) or tri-n-butyltin chloride (TBTC) given in the diets of rats have previously been shown to cause atrophy of the thymus and subsequently suppression of the T-cell-dependent immune responses. To study the mechanism of the immunotoxic effects, the dose-effect relationships and the kinetics of the thymus atrophy caused by DBTC and TBTC were investigated in detail. A single oral dose of DBTC or TBTC to rats induced a dose-related reduction of relative thymus weight, which was maximal 4 days after intubation. The log dose-effect relationships for both compounds were linear and ran parallel over a dose range of 5-60 mg/kg. Dose levels calculated to cause 50% reduction of relative thymus weight were 18 mg DBTC and 29 mg TBTC per kg body wt. A single oral dose of mono-n-butyltin trichloride (MBTC), however, did not cause thymus atrophy at dose levels up to 180 mg/kg. The kinetics of the dibutyltin- and tributyltin-induced thymus atrophy in rats were investigated by measuring thymus weight, total thymic cell count, number of small, intermediate and large cells and the incorporation of DNA, RNA and protein precursors into isolated thymocytes during a period of 9 days after a single oral dose. DBTC and TBTC caused atrophy of the thymus due to a selective reduction in the number of rapidly proliferating lymphoblasts in the first 2 days after dosing. As a consequence the large pool of small lymphocytes declined in the following 2 days. On the fourth day, when atrophy was most pronounced, the frequency of the lymphoblasts increased above the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed2004

Structure-activity comparison of organotin species: dibutyltin is a developmental neurotoxicant in vitro and in vivo.

Human exposure to the organotins can occur due to their use as polyvinyl chloride heat stabilizers and as marine biocides. The consequences of this exposure for human health are unknown. We initially compared the toxicity of monomethyltin, dimethyltin, and dibutyltin to the known neurotoxicant trimethyltin using an in vitro model of neuronal development in PC12 cells. Dibutyltin, a compound traditionally thought to target the immune system, was the most potent neurotoxicant. Dibutyltin significantly inhibited neurite outgrowth and caused cell death at concentrations approximately 40-fold lower than the lowest toxic concentrations of trimethyltin. Dimethyltin was less potent than trimethyltin and monomethyltin was not toxic at any concentration examined. These results suggested the importance of prioritizing in vivo neurotoxicity testing with dibutyltin. To accomplish this, pregnant rats were dosed orally with low levels of dibutyltin from gestational day 6 through weaning. In response to developmental dibutyltin exposure, the incidence of apoptotic cell death, measured by DNA fragmentation and TUNEL staining, was increased in the neocortex and hippocampus of postnatal day 38 offspring. No effect was observed at other ages examined.

Age Factors↗
PubMed2002

Organotin-induced apoptosis occurs in small CD4(+)CD8(+) thymocytes and is accompanied by an increase in RNA synthesis.

The organotin compounds di-n-butyltin dichloride (DBTC) and tri-n-butyltin chloride (TBTC) induce thymus atrophy in rats. At low doses they inhibit immature thymocyte proliferation, whereas at higher doses in particular TBTC induces apoptotic cell death. In vitro, a similar concentration-effect relationship was observed, i.e. low concentrations inhibit DNA and protein synthesis and higher concentrations induce apoptosis. The mechanism of apoptosis by organotins has been partly investigated, but their capacity to inhibit protein synthesis seems to contradict with the idea that macromolecular synthesis is required for organotin-induced apoptosis. Therefore, we aimed to evaluate the relation between apoptosis and the synthesis of RNA and proteins, with a focus on the apoptosis-sensitive thymocyte subset. Results showed that DBTC increases RNA synthesis in particular in the subset of small CD4(+)CD8(+) thymocytes, which normally shows a high incidence of DNA fragmentation. Moreover, the RNA synthesis inhibitor actinomycin D or the protein synthesis inhibitor cycloheximide protected cells from apoptosis by DBTC or TBTC. Although organotin compounds increase synthesis of the heat shock protein HSC73/HSP72, heat shock treatment did not initiate apoptosis in thymocytes, neither antagonized organotin-induced apoptosis. This indicates that synthesis of heat shock proteins is not related to organotin-induced increase of RNA synthesis, and that other RNA-molecules are probably involved.

Animals↗
PubMed2000

Organotins induce apoptosis by disturbance of [Ca(2+)](i) and mitochondrial activity, causing oxidative stress and activation of caspases in rat thymocytes.

Di-n-butyltin dichloride (DBTC) and tri-n-butyltin chloride (TBTC) cause thymus atrophy in rodents. At low doses, antiproliferative modes of action have been shown to be involved, whereas at higher doses apoptosis seems to be the mechanism of thymotoxicity by these chemicals. In vitro, a similar concentration-dependency has been observed. The purpose of the present research was to investigate the mechanisms underlying DNA fragmentation induced by these organotin compounds in freshly isolated rat thymocytes. As previously shown for TBTC, DBTC is also able to significantly increase intracellular Ca(2+) level ([Ca(2+)](i)). The rise in [Ca(2+)](i), already evident 5 min after treatment, was followed by a dose- and time-dependent generation of reactive oxygen species (ROS) at the mitochondrial level. Simultaneously, organotins induced the release of cytochrome c from the mitochondrial membrane into the cytosol. ROS production and the release of cytochrome c were reduced by BAPTA, an intracellular Ca(2+) chelator, or rotenone, an inhibitor of the electron entry from complex I to ubiquinone, indicating the important role of Ca(2+) and mitochondria during these early intracellular events. Furthermore, we demonstrated that rotenone prevents apoptosis induced by 3 microM DBTC or TBTC and, in addition, that both BAPTA and Z-DEVD FMK (mainly a caspase-3 inhibitor) decreased apoptosis by DBTC (already shown for TBTC). Taken together these data show the apoptotic pathway followed by organotin compounds starts with an increase of [Ca(2+)](i), then continues with release of ROS and cytochrome c from mitochondria, activation of caspases, and finally results in DNA fragmentation.

Animals↗
PubMed2000

Analytical aspects of the gas chromatographic determination of tributyltin and metabolites in environmental samples.

Tributyltin and its metabolites were determined in environmental samples by gas chromatography using a flame photometric detection method. The analytical method involved the propylation of the organotins and the use of a recovery standard to correct for inefficient recovery. A detection limit of 5 ng Sn l(-1) for seawater, and 5 ng Sn g(-1) for sediments, was obtained when the detector was equipped with an optical filter; however, this concentration limit, which is higher than the environmental quality standard for TBT, could be improved by a factor of 100 on removing the filter. The limitations imposed by the choice of recovery and internal standards were discussed and it was shown that the possible presence of Sn(II) had no effect on the total extractable inorganic tin, as determined by the analytical protocol. The identification of unexpected mixed methylbutyltins in TBT-contaminated sediments was described, and the implications of the existence of such compounds were discussed.

Chromatography, Gas↗
PubMed1989

The effect of organotin compounds on chloride secretion by the in vitro perfused rectal gland of Squalus acanthias.

The effects of various organotins on membrane function and electrolyte transport were studied in the marine elasmobranch, Squalus acanthias. The isolated perfused rectal gland was used as a model of electrolyte transport. This gland can be stimulated to secrete chloride by atrial natriuretic peptide, veratrine, and vasoactive intestinal polypeptide although the mechanism of action of each secretagogue is different. By analysis of the inhibitory effect of an organotin in the presence of each secretagogue, the mechanism of inhibition can be inferred. Tributyltin (TBT) produced a reversible inhibition of epithelial transport at 10(-8) to 10(-7) M which resulted from inhibition of stimulus-secretion coupling in VIP-containing neurons within the gland. The transporting epithelial cells were unaffected at these concentrations. Trimethytin (TMT) produced inhibition at 10(-7) M which was not reversible and which affected primarily the transporting epithelial cells. Triethyltin and triphenyltin were without effect. The inhibitory effect of TBT and TMT was not affected by simultaneous administration of dithiothreitol. TBT also produced inhibition of oxygen consumption, Na+,K-ATPase, and proton ATPase in dispersed rectal gland cells. These results indicate that organotins are toxic to cell membrane functions which are intimately involved in the movement of electrolytes. This is the first evidence of toxicity to membrane transport functions in a marine species which is at risk from environmental exposure.

Animals↗
PubMed1995

Rapid toxicity assessment using an in vivo enzyme test for Brachionus plicatilis (Rotifera).

A 1-hr in vivo enzyme inhibition assay based on esterase activity has good potential for marine toxicity assessment. A test was developed for the rotifer Brachionus plicatilis based on the nonfluorescent substrate fluorescein diacetate (FDA), which is metabolized by esterases to a fluorescent product. Enzyme inhibition, as determined by reduced fluorescence, can be scored visually or quantified using a fluorometer. Quantification of fluorescence permits the calculation of NOEC, LOEC, chronic value, and IC20. The 1-hr esterase inhibition test has sensitivity comparable to that of 24-hr rotifer acute tests for several compounds. The toxicity of six compounds was examined using the quantified assay. The resulting IC20s were within a factor of 3 of the 24-hour LC50s. IC20 values ranged from 0.017 mg/l for tributyltin to 3.1 mg/l for zinc, with an average coefficient of variation of 17.8%. Electrophoretic analysis of rotifer homogenates suggested that a single C esterase (acetylesterase) was responsible for FDA metabolism in B. plicatilis. Several other aquatic species are capable of metabolizing FDA, including Brachionus calyciflorus, Mysidopsis bahia, Menidia beryllina, Pimephales promelas, Ceriodaphnia dubia, Daphnia pulex, Artemia salina, and Ophryotrocha sp. The esterase inhibition test is an attractive tool for assessing aquatic toxicity because of its speed, simplicity, sensitivity, and applicability to a broad range of aquatic species.

Animals↗