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Analysis on various toxic actions of organotins including tri-n-butyltin

三正丁基锡等有机锡的多种毒性作用分析

基本信息

批准号：
12680544
负责人：
OYAMA Yasuo
金额：
$ 2.3万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

(A) As tri-n-butyltin (TBT), one of environmental pollutants, is accumulated in wild animals, concern regarding the toxicity of TBT in both wildlife and humans is increasing. TBT has been reported to increase intracellular Ca2+ concentration in several types of cells. In order to examine how Ca2+ is involved in TBT-induced cell death, the effect of TBT on rat thymocytes has been compared with that of A23187, a calcium ionophore, under various concentrations of external Ca2+ using a flow cytometer and fluorescent probes. Although both TBT and A23187 were toxic to cells under normal Ca2+ condition, under external Ca2+-free condition the cytotoxic action of TBT was potentiated without changing the threshold concentration while that of A23187 was completely abolished. A23187 attenuated the TBT-induced descent in cell viability under normal Ca2+ concentration despite intracellular Ca2+ concentration was increased. As external Ca2+ concentration increased, the TBT-induced increase in number … More of dead cells gradually decreased whereas the number of cells in an early stage of apoptosis increased. Results suggest that Ca2+ has contradictory actions on the process of TBT-induced cell death in rat thymocytes.(B) The effects of tri-n-butyltin (TBT), an environmental pollutant, on membrane currents elicited by N-methyl-D-asparlate (NMDA) were examined in the neurons acutely dissociated from the dorsal motor nucleus of vagus of rats, using a nystatin-perforated patch recording mode under the voltage-clamp conditions, in order to predict a neurotoxic action of TBT on humans and wild animals. TBT at an environmentally-relevant concentration (l00 nM) greatly increased the amplitude of NMDA-induced outward current, but not that of NMDA-induced inward current. The reversal potential of the NMDA-induced outward current was close to the theoretical K+ equilibrium potential of -82 mV. The NMDA-induced outward current augmented by TBT was markedly inhibited by 5 mM tetraethylammonium chloride and 300 nM charybdotoxin. The outward current was abolished by removal of extracellular Ca2+, suggesting that the outward current was due to the activation of Ca2+-activated K+ channels by Ca2+ passing through NMDA channels. The NMDA-induced outward current was completely blocked by Cs+-internal solution. Under this condition, TBT had no effect on the NMDA-induced inward current. The present results suggest that TBT potentiates Ca2+-activated K+ current induced by NMDA without augmenting the NMDA-induced inward current. Less

(A)由于三丁基锡（TBT）是一种环境污染物，在野生动物体内积累，人们越来越关注TBT对野生动物和人类的毒性。据报告，三丁基锡化合物可增加几种细胞的细胞内钙离子浓度。为了研究Ca~（2+）是如何参与TBT诱导的细胞死亡的，我们用流式细胞仪和荧光探针，在不同浓度的外源Ca~（2+）作用下，比较了TBT和钙离子载体A23187对大鼠胸腺细胞的作用。TBT和A23187在正常Ca~（2+）条件下均对细胞有毒性作用，但在无Ca~（2+）条件下，TBT的细胞毒性作用增强，而A23187的细胞毒性作用完全消失。A23187减弱TBT诱导的细胞活力下降，在正常的Ca 2+浓度下，尽管细胞内Ca 2+浓度增加。随着外源Ca~（2+）浓度的增加， ...更多信息死亡细胞的数量逐渐减少，而处于凋亡早期的细胞数量增加。结果表明，Ca~（2+）在TBT诱导的大鼠胸腺细胞死亡过程中具有相互矛盾的作用。(B)在大鼠迷走神经背核（dorsal motor nucleus of vagus）急性分离的神经元上，应用制霉菌素穿孔膜片钳技术，观察了环境污染物三丁基锡（TBT）对N-甲基-D-谷氨酸（NMDA）诱发的膜电流的影响，以预测TBT对人和野生动物的神经毒性作用。TBT在环境相关浓度（100 nM）大大增加了NMDA诱导的外向电流的幅度，但不是NMDA诱导的内向电流。NMDA诱导的外向电流的反转电位接近理论K+平衡电位-82 mV。NMDA诱导的外向电流增强TBT显着抑制由5 mM四乙基氯化铵和300 nM的Charybdotoxin。清除细胞外Ca~（2+）后，外向电流消失，提示外向电流是由于Ca~（2+）通过NMDA通道激活Ca~（2+）激活的K~+通道所致。NMDA诱导的外向电流可被Cs+内溶液完全阻断。在此条件下，TBT对NMDA诱导的内向电流无影响。结果表明，TBT增强NMDA诱导的Ca~（2+）激活的K~+电流，但不增强NMDA诱导的内向电流。少