DBDCT初步毒代动力学、神经毒性作用及其机制研究
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摘要
目的：二-（4-氯苯甲酰异羟肟酸）二正丁基合锡（DBDCT）是一种典型的R2SnL2型有机锡类化合物，大量资料表明，此类有机锡化合物可致中枢神经系统损伤，但具体机制不明，有待进一步研究。本实验第一部分拟建立生物样品中锡含量的检测方法，确定DBDCT毒代动力学参数，确定大鼠暴露于毒剂量DBDCT的组织分布，并证明DBDCT可以透过血脑屏障，从而对神经系统产生影响；第二部分及第三部分拟通过动物在体实验和神经细胞体外培养两条途径研究DBDCT引起神经毒性的作用，并对可能机制进行初步探讨。
方法：（1）建立原子荧光光谱法（AFS）检测血浆及组织匀浆中锡含量的方法，并采用AFS测定大鼠单次毒剂量（15mg/kg）静脉注射DBDCT后的毒代动力学参数及组织分布，初步判断DBDCT是否可以通过血脑屏障产生神经系统影响；（2）采用紫外分光光度法测定大鼠多次静脉注射DBDCT后的血清及脑组织生化指标；（3）观察大鼠多次静脉注射DBDCT前后体重的变化，并用HE染色检测主要组织脏器的病理学改变，确定主要毒性靶器官和毒性产生的可能原因；（4）通过TUNEL和Westernblot技术，研究大鼠多次静脉注射DBDCT后脑组织凋亡及凋亡相关蛋白的表达情况，初步明确DBDCT产生神经毒性的机制；（5）以PC12细胞为体外神经毒性研究对象，采用MTT法测定染毒后细胞的增殖抑制率，通过光镜、荧光染色和电镜等方法观察细胞核形态的变化，以PI/AnnexinV-FITC双染检测细胞染毒后的凋亡率，DNALadder方法检测细胞染毒后凋亡的特异性条带，用RT-PCR法检测凋亡相关基因的表达情况，从而证实DBDCT通过诱导细胞凋亡产生神经毒性；（6）采用紫外分光光度法测定PC12细胞染毒前后caspase-3和caspase-9活性的变化；以流式细胞术测定线粒体跨膜电位（ΔΨm）及活性氧（ROS）的变化，通过Westernblot分析Bax、Bcl-2、Cyt-c、caspase-3、caspase-9、p-JNK及p-p38等蛋白表达，进一步确证DBDCT通过多个信号转导通路诱导凋亡，产生神经毒性。
结果：（1）建立了定量准确，精密度高，操作方便的检测血浆及组织匀浆中锡含量的AFS；测定了大鼠单次毒剂量静脉注射DBDCT后毒代动力学参数：分布半衰期t1/2α为49.977min、消除半衰期t1/2β为1.260min、表观分布容积Vc为8.201(μg/mL)/(mg/kg)、曲线下面积AUC为56.073(mg/kg)min、清除率Cl为0.297μg/mL/min/(mg/kg)；大鼠单次毒剂量静脉注射后DBDCT可迅速分布到各组织，但锡浓度维持时间较短，肾上腺中锡浓度最高，其余组织中锡浓度相似，脑组织中能检测到少量锡元素，注射后两小时内维持0.10μg/g以上水平；（2）大鼠多次静脉注射DBDCT后，血清中AST、ALT、ALP、GGT、STB、BUN及CRE均显著升高（p<0.01），脑组织中SOD及GSH-Px显著降低（p<0.01），而MDA显著增高（p<0.01）；（3）大鼠多次静脉注射DBDCT后，前三周体重虽有增加，但增长缓慢，最后一周称重时体重不增反降，HE染色后光学显微镜下观察发现，染毒组动物肝脏均被膜增厚，部分出现肝细胞嗜酸性变，核固缩等病理改变，部分脑组织也出现神经细胞结节状增生及皮质部分神经细胞变性等病理改变；（4）大鼠多次静脉注射DBDCT后对脑组织进行TUNEL染色，光学显微镜下可见染毒组大鼠大脑皮质中的细胞核大量呈现圆形和不规则形，棕染且着色深，凋亡指数AI极显著增高，从8.26±1.25%增加到30.3±1.94%（p<0.01），Westernblot实验结果显示染毒组蛋白Bax表达增加，蛋白Bcl-2的表达显著减少，Bax/Bcl-2比值从0.767上升至2.842，且蛋白caspase-3及caspase-9均出现显著地剪切条带；（5）MTT法测定DBDCT暴露24h后PC12细胞IC50值为4.110μmol/L，通过光镜、荧光染色和电镜观察到DBDCT染毒后PC12细胞呈现凋亡细胞所特有的形态学特征，PI/AnnexinV-FITC双染显示随DBDCT染毒剂量的增大和暴露时间的延长，PC12细胞的凋亡率显著增加（p<0.05），琼脂糖凝胶电泳中可见凋亡特征性改变的DNA梯形带，RT-PCR实验可见凋亡相关基因caspase-3、caspase-8、caspase-9、NF-κB、Fas、Fas-L及Cty-c的表达均发生显著变化（p<0.05，p<0.01）；（6）PC12细胞暴露于不同染毒剂量DBDCT不同时间后，caspase-3和caspase-9的活性显著增加（p<0.05，p<0.01），随着DBDCT染毒剂量的增加和暴露时间的延长，△Ψm显著下降，ROS的生成明显增多，蛋白Bcl-2的表达下凋，蛋白Bax表达上调，线粒体内蛋白Cyt-c含量显著下降，胞质中蛋白Cyt-c含量明显增加，蛋白caspase-3及caspase-9均出现越来越显著地剪切条带，p-JNK和p-p38的表达逐渐增加，且均有明显量效和时效关系（p<0.01）。
结论：（1）AFS适用于测定血液及组织样品中锡的含量，大鼠单次静脉注射DBDCT后血中锡浓度随时间变化符合二室模型，分布迅速，锡浓度维持时间较短，在主要组织器官中不易蓄积，DBDCT可以透过血脑屏障，因此可能对神经系统产生影响；（2）DBDCT影响大鼠体重增长和一般生长发育，改变大鼠血清中多种生化指标，表现出显著地肝脏及肾脏毒性；（3）DBDCT降低大鼠脑组织中抗氧化系统的活性，增强脑组织脂质过氧化反应，一定程度上通过诱导细胞凋亡对大鼠脑组织神经系统造成损害；（4）DBDCT能够诱导体外培养的PC12细胞株发生凋亡，作用机制可能是氧化应激及DNA损伤；Bcl-2家族、线粒体凋亡途径及MAPK信号转导通路均参与到DBDCT诱导的PC12细胞凋亡中，揭示DBDCT通过多途径诱导神经细胞凋亡从而产生神经毒性。
Objective:DBDCT is a typical R2SnL2type organotin compound synthesized by our group. The central nervous system is the major toxic target organ of the organotin compounds, but the exact mechanism of their neurotoxicity still remains unclear. In the first part of this experiment, the detection method of tin in biological samples was established, the toxicokinetic parameters and the tissue distribution of DBDCT in a toxic dose were determined. And it was confirmed that DBDCT could penetrate through the blood-brain barrier and influence the central nerve system.The neurological effects in rats in vivo and the possible mechanisms of neurotoxicity of DBDCT in vitro were studied in the second and the third part of the experiment.
Methods:(1) The atomic fluorescence spectrometry (AFS) assay was established to detect the concentration of tin in plasma or in tissue homogenates in rats. And the toxicokinetic parameters and tissue distributions of tin after single intravenous15mg/kg DBDCT in rats were detected using the AFS assay. These detections were used to preliminarily judge the possibility of DBDCT penetrating through the blood-brain barrier and influencing the central nerve system.(2) A series of biochemical indicators in serum and in brain tissues in rats after repeatedly intravenous injection of DBDCT were determined by UV spectrophotometric assay.(3) The changes of the rats' body weights were observed during the exposure period of DBDCT, and the HE staining was used to observe the pathological changes in main organs after repeatedly intravenous injection of DBDCT. These detections were used to determine the main toxic target organ and possible causes of toxicity after exposure to DBDCT in vivo.(4) The apoptosis indexes (AI) and the expressions of apoptosis-related proteins in rats' brains were detected after repeatedly intravenous injection of DBDCT using TUNEL and Western blot techniques, which were expected to explain the possible neurotoxic mechanism after exposure to DBDCT in vivo.(5) The PC12cell line was selected to study the neurotoxicity of DBDCT in vitro. Growth inhibitions of the PC12cells were analyzed by MTT method. Hoechst33258 and AO/EB staining, light and electron microscope were used to examine the nuclear changes after exposure to DBDCT. The apoptosis ratios were determined by PI/Annexin V-FITC double staining, and the specific DNA ladder-shaped strips were studied by agarose gel electrophoresis. The expression changes of apoptosis-related genes such as caspase-3, caspase-8, caspase-9, NF-κB, Fas, Fas-L and Cty-c were detected by RT-PCR. All the detection methods were used to confirm that the cytotoxicity and neurotoxicity exposure to DBDCT were caused by inducing apoptosis.(6) The changes of enzymatic activities of caspase-3and caspase-9in PC12cells before and after exposure to DBDCT were evaluated using UV spectrophotometric method. The changes of mitochondria transmembrane potential variance (ΔΨm) and reactive oxygen species (ROS) were measured using flow cytometry. Meanwhile, the protein expressions of Bax, Bcl-2, Cyt-c, caspase-3, caspase-9, p-JNK and p-p38were analyzed by western blot method to further confirm that the neuronal apoptosis induced by DBDCT was resulted through multiple signal transduction pathways.
Results:(1) An AFS assay was established which was proved to be accurate quantitative, high precision, operated easily to detect the concentration of tin in plasma or in tissue homogenates in rats. After single intravenous injection of toxic dose to rats, the toxicokinetic parameters of DBDCT were showed below, the distribution half life t1/2α and the elimination half life t1/2β were49.977min and1.260min separately, the apparent volume of distribution Vc was8.201(μg/mL)/(mg/kg), the area under the curve was56.073(mg/kg)min, and the clearance rate Cl was0.297μg/mL/min/(mg/kg). After single intravenous injection of toxic dose to rats, DBDCT could be distributed quickly. The concentration of tin in adrenal gland was the highest, and the concentrations of tin in the rest tissues were similar. The tin concentrations in rats'brain were determined not less than0.10μg/g within the first two hours after intravenous injection.(2) The levels of AST, ALT, ALP, GGT, STB, BUN and CRE in serum after repeatedly intravenous injection of DBDCT were all elevated extremely obviously (p<0.01). The activities of SOD and GSH-Px in brain homogenate were increased, on the other hand, the MDA levels were decreased notably (p<0.01).(3) Although the body weights increased in the first three weeks, they dropped at the last week after repeatedly intravenous injection of DBDCT. After HE staining, the thickened liver capsules, eosinophilic change and karyopyknosis of liver cells were observed in liver, nodular hyperplasia of nerve cells and cell degenerations in cerebral cortex were also observed in brain.(4) After repeatedly intravenous injection of DBDCT, the nucleus of the neurons in the cerebral cortex appeared irregular shaped and were stained brown by TUNEL staining. The apoptosis index (AI) was significantly increased from8.26±1.25%to30.3±1.94%(p<0.01). After western blot assay, the protein expression of Bax increased, on the contrary, the protein expression of Bcl-2decreased, the ratio of Bax/Bcl-2increased from0.767to2.842. The cleaved caspase-3and cleaved caspase-9were detected.(5) The IC50of DBDCT in24h was4.110μmol/L. The classic nuclear morphology characteristics were observed in PC12cells exposed with DBDCT using fluorescent staining, light and electron microscope. The apoptosis rates determined by PI/Annexin V-FITC double staining method in PC12cells exposed with DBDCT for different period of time showed significant statistics difference (p<0.05) compared with the control group. In the agarose gel electrophoresis, DNA ladder-shaped strips were also clearly observed. The results of RT-PCR indicated that the mRNA expresses of apoptosis-related genes such as caspase-3, caspase-8, caspase-9, NF-κB, Fas, Fas-L and Cty-c in the PC12cells exposed with DBDCT were obviously changed (p<0.05, p<0.01) compared with the normal PC12cells.(6) The enzymatic activities of caspase-3and caspase-9of PC12cells exposed with different concentrations of DBDCT for different period of time increased significantly (p<0.05,P<0.01). The ΔΨm strikingly decreased which was detected by JC-1, and the generation of ROS increased exposed with different concentrations of DBDCT for different period of time. The results of western blot analysis showed the down-regulation of bcl-2and the up-regulation of Bax. The expression of Cyt-c decreased in mitochondria and elevated in the cytosol. The cleaved caspase-3and cleaved caspase-9were detected. The expressions of p-JNK and p-p38also increased. All the changes of protein expressions were dose-and time-dependent (p<0.05).
Conclusions:(1) The AFS applied to the determination of the tin concentrations in the blood and tissue samples. The concentration changes of tin in blood over time met the two-compartment model. DBDCT distributed rapidly, but was not easy to accumulate in the major tissues and organs. It could penetrate through the blood-brain barrier, which indicates it may have neurotoxic effect.(2) DBDCT affected the increase of the body weights and the general growth and development of rats. The changes of a series of biochemical indicators in blood and in brain tissues in rats revealed that DBDCT had significant liver toxicity and kidney toxicity.(3) DBDCT reduced the activity of the antioxidant system and enhanced the lipid peroxidation in the brain tissue of rats, and to some extent, caused damage in central nerve system by inducing neuron apoptosis in vivo.(4) DBDCT was able to induce apoptosis in the PC12cells cultured in vitro, the mechanism of which might be oxidative stress and DNA damage. The Bcl-2family, mitochondrial apoptosis pathway and MAPK signal transduction pathway were all involved in the apoptosis in the PC12cells induced by DBDCT, which revealed that DBDCT could cause neurotoxicity by inducing apoptosis in neuron on multi-pathways.
方法：（1）建立原子荧光光谱法（AFS）检测血浆及组织匀浆中锡含量的方法，并采用AFS测定大鼠单次毒剂量（15mg/kg）静脉注射DBDCT后的毒代动力学参数及组织分布，初步判断DBDCT是否可以通过血脑屏障产生神经系统影响；（2）采用紫外分光光度法测定大鼠多次静脉注射DBDCT后的血清及脑组织生化指标；（3）观察大鼠多次静脉注射DBDCT前后体重的变化，并用HE染色检测主要组织脏器的病理学改变，确定主要毒性靶器官和毒性产生的可能原因；（4）通过TUNEL和Westernblot技术，研究大鼠多次静脉注射DBDCT后脑组织凋亡及凋亡相关蛋白的表达情况，初步明确DBDCT产生神经毒性的机制；（5）以PC12细胞为体外神经毒性研究对象，采用MTT法测定染毒后细胞的增殖抑制率，通过光镜、荧光染色和电镜等方法观察细胞核形态的变化，以PI/AnnexinV-FITC双染检测细胞染毒后的凋亡率，DNALadder方法检测细胞染毒后凋亡的特异性条带，用RT-PCR法检测凋亡相关基因的表达情况，从而证实DBDCT通过诱导细胞凋亡产生神经毒性；（6）采用紫外分光光度法测定PC12细胞染毒前后caspase-3和caspase-9活性的变化；以流式细胞术测定线粒体跨膜电位（ΔΨm）及活性氧（ROS）的变化，通过Westernblot分析Bax、Bcl-2、Cyt-c、caspase-3、caspase-9、p-JNK及p-p38等蛋白表达，进一步确证DBDCT通过多个信号转导通路诱导凋亡，产生神经毒性。
结果：（1）建立了定量准确，精密度高，操作方便的检测血浆及组织匀浆中锡含量的AFS；测定了大鼠单次毒剂量静脉注射DBDCT后毒代动力学参数：分布半衰期t1/2α为49.977min、消除半衰期t1/2β为1.260min、表观分布容积Vc为8.201(μg/mL)/(mg/kg)、曲线下面积AUC为56.073(mg/kg)min、清除率Cl为0.297μg/mL/min/(mg/kg)；大鼠单次毒剂量静脉注射后DBDCT可迅速分布到各组织，但锡浓度维持时间较短，肾上腺中锡浓度最高，其余组织中锡浓度相似，脑组织中能检测到少量锡元素，注射后两小时内维持0.10μg/g以上水平；（2）大鼠多次静脉注射DBDCT后，血清中AST、ALT、ALP、GGT、STB、BUN及CRE均显著升高（p<0.01），脑组织中SOD及GSH-Px显著降低（p<0.01），而MDA显著增高（p<0.01）；（3）大鼠多次静脉注射DBDCT后，前三周体重虽有增加，但增长缓慢，最后一周称重时体重不增反降，HE染色后光学显微镜下观察发现，染毒组动物肝脏均被膜增厚，部分出现肝细胞嗜酸性变，核固缩等病理改变，部分脑组织也出现神经细胞结节状增生及皮质部分神经细胞变性等病理改变；（4）大鼠多次静脉注射DBDCT后对脑组织进行TUNEL染色，光学显微镜下可见染毒组大鼠大脑皮质中的细胞核大量呈现圆形和不规则形，棕染且着色深，凋亡指数AI极显著增高，从8.26±1.25%增加到30.3±1.94%（p<0.01），Westernblot实验结果显示染毒组蛋白Bax表达增加，蛋白Bcl-2的表达显著减少，Bax/Bcl-2比值从0.767上升至2.842，且蛋白caspase-3及caspase-9均出现显著地剪切条带；（5）MTT法测定DBDCT暴露24h后PC12细胞IC50值为4.110μmol/L，通过光镜、荧光染色和电镜观察到DBDCT染毒后PC12细胞呈现凋亡细胞所特有的形态学特征，PI/AnnexinV-FITC双染显示随DBDCT染毒剂量的增大和暴露时间的延长，PC12细胞的凋亡率显著增加（p<0.05），琼脂糖凝胶电泳中可见凋亡特征性改变的DNA梯形带，RT-PCR实验可见凋亡相关基因caspase-3、caspase-8、caspase-9、NF-κB、Fas、Fas-L及Cty-c的表达均发生显著变化（p<0.05，p<0.01）；（6）PC12细胞暴露于不同染毒剂量DBDCT不同时间后，caspase-3和caspase-9的活性显著增加（p<0.05，p<0.01），随着DBDCT染毒剂量的增加和暴露时间的延长，△Ψm显著下降，ROS的生成明显增多，蛋白Bcl-2的表达下凋，蛋白Bax表达上调，线粒体内蛋白Cyt-c含量显著下降，胞质中蛋白Cyt-c含量明显增加，蛋白caspase-3及caspase-9均出现越来越显著地剪切条带，p-JNK和p-p38的表达逐渐增加，且均有明显量效和时效关系（p<0.01）。
结论：（1）AFS适用于测定血液及组织样品中锡的含量，大鼠单次静脉注射DBDCT后血中锡浓度随时间变化符合二室模型，分布迅速，锡浓度维持时间较短，在主要组织器官中不易蓄积，DBDCT可以透过血脑屏障，因此可能对神经系统产生影响；（2）DBDCT影响大鼠体重增长和一般生长发育，改变大鼠血清中多种生化指标，表现出显著地肝脏及肾脏毒性；（3）DBDCT降低大鼠脑组织中抗氧化系统的活性，增强脑组织脂质过氧化反应，一定程度上通过诱导细胞凋亡对大鼠脑组织神经系统造成损害；（4）DBDCT能够诱导体外培养的PC12细胞株发生凋亡，作用机制可能是氧化应激及DNA损伤；Bcl-2家族、线粒体凋亡途径及MAPK信号转导通路均参与到DBDCT诱导的PC12细胞凋亡中，揭示DBDCT通过多途径诱导神经细胞凋亡从而产生神经毒性。
Objective:DBDCT is a typical R2SnL2type organotin compound synthesized by our group. The central nervous system is the major toxic target organ of the organotin compounds, but the exact mechanism of their neurotoxicity still remains unclear. In the first part of this experiment, the detection method of tin in biological samples was established, the toxicokinetic parameters and the tissue distribution of DBDCT in a toxic dose were determined. And it was confirmed that DBDCT could penetrate through the blood-brain barrier and influence the central nerve system.The neurological effects in rats in vivo and the possible mechanisms of neurotoxicity of DBDCT in vitro were studied in the second and the third part of the experiment.
Methods:(1) The atomic fluorescence spectrometry (AFS) assay was established to detect the concentration of tin in plasma or in tissue homogenates in rats. And the toxicokinetic parameters and tissue distributions of tin after single intravenous15mg/kg DBDCT in rats were detected using the AFS assay. These detections were used to preliminarily judge the possibility of DBDCT penetrating through the blood-brain barrier and influencing the central nerve system.(2) A series of biochemical indicators in serum and in brain tissues in rats after repeatedly intravenous injection of DBDCT were determined by UV spectrophotometric assay.(3) The changes of the rats' body weights were observed during the exposure period of DBDCT, and the HE staining was used to observe the pathological changes in main organs after repeatedly intravenous injection of DBDCT. These detections were used to determine the main toxic target organ and possible causes of toxicity after exposure to DBDCT in vivo.(4) The apoptosis indexes (AI) and the expressions of apoptosis-related proteins in rats' brains were detected after repeatedly intravenous injection of DBDCT using TUNEL and Western blot techniques, which were expected to explain the possible neurotoxic mechanism after exposure to DBDCT in vivo.(5) The PC12cell line was selected to study the neurotoxicity of DBDCT in vitro. Growth inhibitions of the PC12cells were analyzed by MTT method. Hoechst33258 and AO/EB staining, light and electron microscope were used to examine the nuclear changes after exposure to DBDCT. The apoptosis ratios were determined by PI/Annexin V-FITC double staining, and the specific DNA ladder-shaped strips were studied by agarose gel electrophoresis. The expression changes of apoptosis-related genes such as caspase-3, caspase-8, caspase-9, NF-κB, Fas, Fas-L and Cty-c were detected by RT-PCR. All the detection methods were used to confirm that the cytotoxicity and neurotoxicity exposure to DBDCT were caused by inducing apoptosis.(6) The changes of enzymatic activities of caspase-3and caspase-9in PC12cells before and after exposure to DBDCT were evaluated using UV spectrophotometric method. The changes of mitochondria transmembrane potential variance (ΔΨm) and reactive oxygen species (ROS) were measured using flow cytometry. Meanwhile, the protein expressions of Bax, Bcl-2, Cyt-c, caspase-3, caspase-9, p-JNK and p-p38were analyzed by western blot method to further confirm that the neuronal apoptosis induced by DBDCT was resulted through multiple signal transduction pathways.
Results:(1) An AFS assay was established which was proved to be accurate quantitative, high precision, operated easily to detect the concentration of tin in plasma or in tissue homogenates in rats. After single intravenous injection of toxic dose to rats, the toxicokinetic parameters of DBDCT were showed below, the distribution half life t1/2α and the elimination half life t1/2β were49.977min and1.260min separately, the apparent volume of distribution Vc was8.201(μg/mL)/(mg/kg), the area under the curve was56.073(mg/kg)min, and the clearance rate Cl was0.297μg/mL/min/(mg/kg). After single intravenous injection of toxic dose to rats, DBDCT could be distributed quickly. The concentration of tin in adrenal gland was the highest, and the concentrations of tin in the rest tissues were similar. The tin concentrations in rats'brain were determined not less than0.10μg/g within the first two hours after intravenous injection.(2) The levels of AST, ALT, ALP, GGT, STB, BUN and CRE in serum after repeatedly intravenous injection of DBDCT were all elevated extremely obviously (p<0.01). The activities of SOD and GSH-Px in brain homogenate were increased, on the other hand, the MDA levels were decreased notably (p<0.01).(3) Although the body weights increased in the first three weeks, they dropped at the last week after repeatedly intravenous injection of DBDCT. After HE staining, the thickened liver capsules, eosinophilic change and karyopyknosis of liver cells were observed in liver, nodular hyperplasia of nerve cells and cell degenerations in cerebral cortex were also observed in brain.(4) After repeatedly intravenous injection of DBDCT, the nucleus of the neurons in the cerebral cortex appeared irregular shaped and were stained brown by TUNEL staining. The apoptosis index (AI) was significantly increased from8.26±1.25%to30.3±1.94%(p<0.01). After western blot assay, the protein expression of Bax increased, on the contrary, the protein expression of Bcl-2decreased, the ratio of Bax/Bcl-2increased from0.767to2.842. The cleaved caspase-3and cleaved caspase-9were detected.(5) The IC50of DBDCT in24h was4.110μmol/L. The classic nuclear morphology characteristics were observed in PC12cells exposed with DBDCT using fluorescent staining, light and electron microscope. The apoptosis rates determined by PI/Annexin V-FITC double staining method in PC12cells exposed with DBDCT for different period of time showed significant statistics difference (p<0.05) compared with the control group. In the agarose gel electrophoresis, DNA ladder-shaped strips were also clearly observed. The results of RT-PCR indicated that the mRNA expresses of apoptosis-related genes such as caspase-3, caspase-8, caspase-9, NF-κB, Fas, Fas-L and Cty-c in the PC12cells exposed with DBDCT were obviously changed (p<0.05, p<0.01) compared with the normal PC12cells.(6) The enzymatic activities of caspase-3and caspase-9of PC12cells exposed with different concentrations of DBDCT for different period of time increased significantly (p<0.05,P<0.01). The ΔΨm strikingly decreased which was detected by JC-1, and the generation of ROS increased exposed with different concentrations of DBDCT for different period of time. The results of western blot analysis showed the down-regulation of bcl-2and the up-regulation of Bax. The expression of Cyt-c decreased in mitochondria and elevated in the cytosol. The cleaved caspase-3and cleaved caspase-9were detected. The expressions of p-JNK and p-p38also increased. All the changes of protein expressions were dose-and time-dependent (p<0.05).
Conclusions:(1) The AFS applied to the determination of the tin concentrations in the blood and tissue samples. The concentration changes of tin in blood over time met the two-compartment model. DBDCT distributed rapidly, but was not easy to accumulate in the major tissues and organs. It could penetrate through the blood-brain barrier, which indicates it may have neurotoxic effect.(2) DBDCT affected the increase of the body weights and the general growth and development of rats. The changes of a series of biochemical indicators in blood and in brain tissues in rats revealed that DBDCT had significant liver toxicity and kidney toxicity.(3) DBDCT reduced the activity of the antioxidant system and enhanced the lipid peroxidation in the brain tissue of rats, and to some extent, caused damage in central nerve system by inducing neuron apoptosis in vivo.(4) DBDCT was able to induce apoptosis in the PC12cells cultured in vitro, the mechanism of which might be oxidative stress and DNA damage. The Bcl-2family, mitochondrial apoptosis pathway and MAPK signal transduction pathway were all involved in the apoptosis in the PC12cells induced by DBDCT, which revealed that DBDCT could cause neurotoxicity by inducing apoptosis in neuron on multi-pathways.
引文
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