镉对大鼠大脑皮质神经细胞毒性损伤的机制
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摘要
镉是具有很强毒性的重金属,常见于工业场所、食品污染物和烟草中。低浓度镉就具有毒性,因为其在体内的半衰期长达10～30年,易在体内蓄积,可对包括肺脏、肝脏、’肾脏、睾丸、脑和胎盘在内的多个器官产生严重损害。镉可进入脑实质和神经元导致人和动物模型的神经学上的改变,引起注意力低下、痛觉敏感性高、嗅觉异常和记忆力下降。些以神经元和神经胶质细胞为模型的体外研究表明,μM级的镉就具有神经毒性,且这种细胞毒性与诱导凋亡有一定的相关性,并得出镉致皮质神经细胞凋亡是引起中枢神经系统异常及导致记忆减退、智力发育低下的主要原因,但镉致神经细胞凋亡的机制尚未阐明。本研究用孕18～19d Sprague Dawley (SD)大鼠的胎鼠建立体外培养的大鼠大脑皮质神经细胞模型,通过体外试验探讨了镉对大鼠大脑皮质神经细胞的毒性损伤效应及其凋亡可能的作用机理,为进一步认识镉的神经毒性作用提供理论依据。
1、镉诱导大鼠大脑皮质神经细胞凋亡的线粒体途径
为从线粒体途径研究镉致大鼠大脑皮质神经细胞凋亡的机制。本研究在建立体外原代大鼠大脑皮质神经细胞培养的基础上,以不同浓度(0、5、10、20μmol/L)醋酸镉染毒12h,Hoechst33258荧光染色观察细胞凋亡的形态变化；流式细胞术检测细胞内活性氧(ROS)水平和线粒体膜电位(△Ψm);实时荧光定量PCR检钡Caspase-3mRNA转录水平。以10μmol/L醋酸镉染毒大鼠大脑皮质神经细胞0、12、24和48h,免疫印迹检测Caspase-9活化和PARP裂解情况。结果表明：经免疫组化染色鉴定,所培养的原代细胞为神经元特异性烯醇化酶(NSE)阳性,呈现典型神经细胞特征。与对照组相比,各染毒组细胞表现核皱缩、染色质致密浓染、核碎裂等典型的凋亡特征,ROS水平显著或极显著升高(P<0.05或P<0.01),△Ψm显著或极显著降低(P<0.05或P<0.01),Caspase-3mRNA转录水平极显著升高(P<0.01),同时经10μmol/L镉处理皮质神经细胞12h后开始检测至Caspase-9活化及PARP裂解大片段。说明镉诱导大鼠大脑皮质神经细胞凋亡可能通过线粒体途径。
2、钙稳态失衡在镉致大鼠大脑皮质神经细胞凋亡中的作用
为研究钙稳态失衡在镉致大鼠大脑皮质神经细胞凋亡中的作用,并探讨内质网钙库释放在镉致神经细胞钙稳态失衡机制中的作用。本研究用不同浓度(0、5、10、20μmol/L)醋酸镉和细胞内钙离子螯合剂BAPTA-AM[1,2-二(2-氨基苯氧基)乙烷-N,N,N',N'-四乙酸-四乙酰氧甲基酯,1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-tetraacetoxymethyl ester (10μmol/L)]以及三磷酸肌醇受体(IP3R)特异性阻断剂2-APB [2-氨基乙氧基二苯基硼酸盐,2-aminoethoxydiphenyl borate (50μmol/L)]单独或联合作用于大鼠大脑皮质神经细胞12h。Hoechst33258荧光染色观察细胞凋亡的形态变化,流式细胞术检测细胞内[Ca2+]i,ATPase酶试剂盒测定Na+-K+-ATPase和Ca2+-Mg2+-ATPase活性的变化,实时荧光定量PCR测定钙调蛋白(CaM) mRNA转录水平。结果表明,与对照组相比,染毒后的神经细胞经Hoechst33258染色呈现典型的凋亡特征,各镉染毒组细胞内[Ca2+]i极显著升高(P<0.01),Na+-K+-ATPase和Ca2+-Mg2+-ATPase活性显著或极显著降低<0.05或P<0.01),20μmol/L组CaM mRNA转录水平极显著降低(P<0.01)。与相应镉染毒组相比,BAPTA-AM联合组凋亡细胞减少,BAPTA-AM联合组和2-APB联合组细胞内[Ca2+]i显著或极显著降低(P<0.05或P<0.01)。说明镉可能通过影响CaM mRNA转录水平与维持钙稳态相关酶(Na+-K+-ATPase和Ca2+-Mg2+-ATPase)的活性以及胞内内质网Ca2+库的释放,从而干扰神经细胞内钙稳态,而细胞内钙稳态失衡在镉诱导大鼠大脑皮质神经细胞凋亡中起着重要作用。
3、镉对大鼠大脑皮质神经细胞MAPK言号通路的影响
为探讨不同浓度、不同时间染镉对体外培养的原代大鼠大脑皮质神经细胞中细胞外信号调节蛋白激酶(ERK1/2)、c-Jun氨基末端激酶(JNK)和p38MAPK磷酸化的影响,大鼠大脑皮质神经细胞用不同浓度(0、5、10、20μmol/L)醋酸镉染毒3h及10μmol/L醋酸镉染毒不同时间(0、1、2、3、4、5、6h),免疫印迹法测定样品ERK1/2、JNK和p38MAPK总蛋白的表达及磷酸化水平。结果表明,5、10、20μmol/L镉处理细胞3h后,除5μmol/L镉处理组ERK1/2磷酸化水平未升高外,其余所有浓度镉处理组的ERK1/2、JNK1和p38MAPK磷酸化水平均升高,而染镉后ERK1/2、JNK和p38MAPK,总量无明显变化；10μmol/L醋酸镉染毒后,ERK1/2磷酸化水平于2h便开始升高,一直维持到6h; JNK和p38MAPK磷酸化水平于试验后1h开始升高,3h达到高峰,之后逐渐下降,但6h内仍高于对照组,ERK1/2、JNK和p38MAPK、总量无明显变化。说明镉可引起MAPK信号通路关键蛋白的活化。
4、镉对大鼠大脑皮质神经细胞线粒体氧化损伤的影响
为研究镉对大鼠大脑皮质神经细胞线粒体的氧化损伤,用不同浓度(0、5、10、20μmol/L)醋酸镉染毒大鼠大脑皮质神经细胞6h,透射电子显微镜观察线粒体超微结构的变化,比色法测定MDA含量,实时荧光定量PCR从转录水平检测线粒体细胞色素氧化酶亚基COX I、COX Ⅱ COX Ⅲ表达的变化。结果表明：与对照组相比,各染毒组细胞超微结构变化明显,表现线粒体肿胀,嵴断裂、部分或完全消失,MDA含量均极显著升高(P<0.01), COX Ⅰ、COX Ⅱ基因表达量均显著或极显著降低(P<0.05或P<0.01),10和20μmol/L染毒组COX Ⅲ基因表达量极显著降低(P<0.01)。说明镉可引起线粒体损伤,COX Ⅰ、 COX Ⅱ、COX Ⅲ基因表达量显著下降可能与镉暴露导致的线粒体脂质过氧化损伤有关。
5、镉对大鼠大脑皮质神经细胞Bcl-2和Bax表达的影响
为研究镉对大鼠大脑皮质神经细胞凋亡相关基因Bcl-2和Bax表达的影响,用不同浓度(0、5、10、20μmol/L)醋酸镉染毒大鼠大脑皮质神经细胞12h,实时荧光定量PCR检测Bcl-2和Bax mRNA转录水平,并计算Bcl-2/Bax的比值,免疫印迹检测Bcl-2和Bax蛋白表达情况。结果表明：与对照组相比,各染毒组细胞Bax mRNA转录水平均极显著升高(P<0.01),而Bcl-2mRNA转录水平均显著降低(P<0.05),Bcl-2/Bax的比值均极显著降低(P<0.01)。此外,免疫印迹的结果也显示,随镉浓度的增加,Bcl-2蛋白表达水平下降,Bax蛋白表达水平升高。提示镉能通过调节凋亡相关基因Bcl-2和Bax mRNA转录和蛋白表达,从而促进细胞凋亡
6、镉对大鼠大脑皮质神经细胞一氧化氮合酶基因mRNA转录的影响
为研究镉对大鼠大脑皮质神经细胞一氧化氮合酶基因mRNA转录的影响,用不同浓度(0、5、10、20μmol/L)醋酸镉染毒大鼠大脑皮质神经细胞12h,实时荧光定量PCR检测神经型一氧化氮合酶(nNOS)、诱导型一氧化氮合酶(iNOS) mRNA转录水平。结果表明：与对照组相比,5、10μmol/L组nNOS mRNA转录水平显著和极显著升高(P<0.05和P<0.01);20μmol/L组iNOS mRNA转录水平极显著升高(P<0.01)。说明镉可诱导调节nNOS和iNOS mRNA的转录。
Cadmium (Cd) is an extremely toxic metal commonly found in industrial workplaces, food contaminants and cigarette smoke. It is toxic even at low doses since the metal accumulates and has a long biological half-life in humans (10-30years). Cd has been shown to cause severe damage to a variety of organs, including the lung, liver, kidney, testis, brain and even to the placenta. Cd can enter into the brain parenchyma and neurons causing neurological alterations in humans and animal models, leading to lower attention, hypeociception, olfactory dysfunction and memory deficits. Moreover, there are studies showing the neurotoxicity of Cd at μM range on cell culture models like neurons and glial cells, and the Cd-mediated toxicity is thought to involve, at least in part, the induction of apoptosis. Furthermore, previous study demonstrated that apoptosis of cortical neurons caused by Cd is the main reason of abnormality in central nervous system, leading to memory deficits and mental retardation. However, the mechanisms of Cd-induced apoptosis have not been well elucidated. In the current experiment, the model of cerebral cortical neurons cultured in vitro was used, which were obtained from foetal Sprague-Dawley rats at18-19days of gestation, and the potential mechanism of Cd-induced cytotoxicity and apoptosis in rat's cerebral cortical neurons was investigated, which will offer theoretic evidences for future exploring the mechanism in neurotoxicity of Cd.
1. Mitochondrial pathway in cadmium-induced apoptosis of rat's primary cultured cerebral cortical neurons
To explore the mechamism of Cd-induced apoptosis in rat's cerebral cortical neurons from mitochondrial pathway, the model of rat's primary cerebral cortical neurons in vitro was established successfully. The neurons were exposured to cadmium acetate of different concentrations (0,5,10,20μmol/L) for12h. Then, the morphological changes of apoptosis in neurons with Cd treatment was observed by Hoechst33258staining, and the level of reactive oxygen species (ROS), mitochondrial membrane potential (AΨm) were detected by flow cytometry, meanwhile, the transcriptional level of Caspase-3mRNA was detected by real-time fluorescent quantitative PCR. In addition, the neurons were exposured to10μmol/L cadmium acetate for0,12,24,48h. Then, the Cleaved Caspase-9and Cleaved PARP were detected by immunoblot at each time-point. With immunocytochemical detection, the cultured cells were affirmed as neurons, which are positive to neurons specific enolase (NSE) antibody and represent classical features of neurons. After Cd exposure, in comparison with the control group, the cells in Cd-treated groups showed typical morphological changes of apoptosis with nucleus crimpled and chromatin condensedation, even nucleus disintegratation, on the other hand, ROS level were increased significantly (P<0.05or P<0.01), ΔΨm were decreased significantly (P<0.05or P<0.01), and the transcriptional level of Caspase-3mRNA increased significantly (P<0.01). Caspase-9was activated early at12h after treatment of10μmol/L Cd and PARP was cleaved subsequently. It was suggested that Cd-induced apoptosis involves mitochondrial pathway in rat's cerebral cortical neurons.
2. Effect of the disequilibrium of calcium homeostasis on the apoptosis in rat's primary cultured cerebral cortical neurons induced by cadmium
To investigate the effect of the disequilibrium of calcium homeostasis on the apoptosis in rat's cerebral cortical neurons induced by Cd and ER-released calcium on the disequilibrium of calcium homeostasis induced by Cd, the neurons were exposured to cadmium acetate of different concentrations (0,5,10,20μmol/L), in the absence or the presence of10μmol/L BAPTA-AM [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-tetraacetoxymethyl ester], a specific intracellular Ca2+chelator and the inositol1,4,5tri-sphosphate receptor (IP3R) inhibitor,50μmol/L2-APB (2-aminoethoxydiphenyl borate) for12h. Then, the morphological changes of apoptosis in neurons with Cd treatment were observed by Hoechst33258staining and the intracellular [Ca+]i was detected by flow cytometry. Meanwhile, the activities of Na+-K+-ATPase as well as Ca2+-Mg2+-ATPase were measured by ATPase test kits, and the transcriptional level of CaM mRNA was detected by real-time fluorescent quantitative PCR. In comparison with the control group, the results showed that typical morphological changes of apoptosis were observed in cerebral cortical neurons with Hoechst33258staining after Cd treatment, intracellular [Ca2+]iwas increased significantly (P<0.01), in contrast, the activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase were decreased significantly (P<0.05or P<0.01) in the Cd-treated groups, and the transcriptional level of CaM mRNA was decreased significantly (P<0.01) in20μmol/L Cd group. Compared to the poisoning groups, apoptosis induced by cadmium can be efficiently prevented by BAPTA-AM, furthermore, the intracelluar [Ca2+]i were decreased significantly (P<0.05or P<0.01) in the presence of BAPTA-AM and2-APB groups. It was suggested that Cd could disturb intracellular Ca2+homeostasis by affecting the transcriptional level of CaM mRNA as well as the activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase and ER-released calcium, the disequilibrium of calcium homeostasis played a vital role in the Cd-induced apoptosis of rat's cerebral cortical neurons.
3. Influence of cadmium on MAPK signaling pathway in rat's primary cultured cerebral cortical neurons.
To observe the effect of Cd on the levels of the phosphorylation of extracellular signal regulated kinase1/2(ERK1/2), c-Jun NH2-terminal kinases(JNK), p38mitogen-activated protein kinases (p38MAPK) in rat's primary cultured cerebral cortical neurons, the neurons were exposured to cadmium acetate of different concentrations (0,5,10,20μmol/L) for3h and10μmol/L cadmium acetate for different time points (0,1,2,3,4,5,6h). The total and phosphorylated protein of ERK1/2, JNK and p38MAPK were assayed by immunoblots. The result showed that after treatment of5,10,20μmol/L Cd for3h the phosphorylation of ERK1/2, JNK1and p38MAPK was increased in all other Cd-treated groups with the exception of ERK1/2in5μmol/L Cd-treated group, while the total protein had no obvious changes. Following the treatment of10μmol/L Cd, the phosphorylation of ERKl/2begin to increase from2h and keeps to6h, at the same time, the phosphorylation of JNK and p38MAPK begin to be activated from1h with a peak at3h and decreased gradually. However, the phosphorylation of JNK and p38MAPK was also higher than that in the control within6h. The total expression of ERK1/2, JNK and p38MAPK had no obvious changes with the Cd exposure. It was suggested that cadmium can activate the key proteins in the MAPK signaling pathway.
4. Effect of cadmium on the oxidative damage of mitochondria in rat's primary cultured cerebral cortical neurons
To investigate the oxidative damage of mitochondria in rat's cerebral cortical neurons caused by Cd. The neurons were exposured to cadmium acetate of different concentrations (0,5,10,20μmol/L) for6h. Then, changes in ultrastructure of mitochondria were detected by transmission electron-microscope and the contents of malon-dialdehyde (MDA) were detected by colorimetric method. In addition, the relative gene expression levels of cytochrome oxidase submits (COX Ⅰ/Ⅱ/Ⅲ) were quantified by real-time fluorescent quantitative PCR. In comparison with the control group, the results showed that the changes of ultrastructure in the Cd-treated groups are obvious, the most ultrastructural modifications involved mitochondrial swelling, fragmentation and disappearance of mitochondrial cristae. The contents of MDA were significantly increased in the poisoning groups (P<0.01). The relative expression levels of COX Ⅰ and COX Ⅱ in the three exposed groups were significantly decreased (P<0.05or P<0.01), the relative expression levels of COX Ⅲ were also significantly decreased (P<0.01) in10,20μmol/L groups. Therefore, the damage of mitochondria may be medicated by cadmium. Moreover, the decreased expression levels of COX Ⅰ, COX Ⅱ, COX Ⅲ may be related to the mitochondrial lipid peroxidation.
5. Influence of cadmium on Bcl-2and Bax expression in rat's primary cultured cerebral cortical neurons.
To investigate the effects of Cd on the expressions of apoptosis-related genes Bcl-2, Bax in rat's primary cerebral cortical neurons, the neurons were exposured to Cd of different concentrations (0,5,10,20μmol/L) for12h. Real-time quantitative PCR was used to detect the mRNA transcriptional levels of Bcl-2and Bax. Furthermore, the protein expressions of Bcl-2and Bax were also detected by immunoblots. In comparison with the control group, the results showed that transcriptional levels of Bax mRNA in Cd-treated groups increased significantly (P<0.01). On the contrary, the transcriptional levels of Bcl-2mRNA and the ratios of Bcl-2/Bax decreased significantly (P<0.05or P<0.01). Correspondingly, the decreased Bcl-2and increased Bax protein expression levels were obtained by immunoblots detection with the increasing concentration of Cd. These results together indicating that cadmium can promote apoptosis by regulating the transcription and protein expression of apoptosis-related genes, including Bcl-2and Bax.
6. Effect of cadmium on mRNA transcription of nitric oxide synthase in rat's primary cultured cerebral cortical neurons
To study the impact of Cd on mRNA transcriptional levels of nitric oxide synthase in rat's primary cultured cerebral cortical neurons, the neurons were exposured to Cd of different concentrations (0,5,10,20μmol/L) for12h. Then, transcriptional levels of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) mRNA were detected by real-time quantitative PCR. In comparison with the control group, the results showed that the transcriptional levels of nNOS mRNA increased significantly (P<0.05and P<0.01) in5,10μmol/L groups and transcriptional levels of iNOS mRNA increased significantly (P<0.01) in20μmol/L group. It was concluded that cadmium can regulate the transcription of nNOS and iNOS.
1、镉诱导大鼠大脑皮质神经细胞凋亡的线粒体途径
为从线粒体途径研究镉致大鼠大脑皮质神经细胞凋亡的机制。本研究在建立体外原代大鼠大脑皮质神经细胞培养的基础上,以不同浓度(0、5、10、20μmol/L)醋酸镉染毒12h,Hoechst33258荧光染色观察细胞凋亡的形态变化；流式细胞术检测细胞内活性氧(ROS)水平和线粒体膜电位(△Ψm);实时荧光定量PCR检钡Caspase-3mRNA转录水平。以10μmol/L醋酸镉染毒大鼠大脑皮质神经细胞0、12、24和48h,免疫印迹检测Caspase-9活化和PARP裂解情况。结果表明：经免疫组化染色鉴定,所培养的原代细胞为神经元特异性烯醇化酶(NSE)阳性,呈现典型神经细胞特征。与对照组相比,各染毒组细胞表现核皱缩、染色质致密浓染、核碎裂等典型的凋亡特征,ROS水平显著或极显著升高(P<0.05或P<0.01),△Ψm显著或极显著降低(P<0.05或P<0.01),Caspase-3mRNA转录水平极显著升高(P<0.01),同时经10μmol/L镉处理皮质神经细胞12h后开始检测至Caspase-9活化及PARP裂解大片段。说明镉诱导大鼠大脑皮质神经细胞凋亡可能通过线粒体途径。
2、钙稳态失衡在镉致大鼠大脑皮质神经细胞凋亡中的作用
为研究钙稳态失衡在镉致大鼠大脑皮质神经细胞凋亡中的作用,并探讨内质网钙库释放在镉致神经细胞钙稳态失衡机制中的作用。本研究用不同浓度(0、5、10、20μmol/L)醋酸镉和细胞内钙离子螯合剂BAPTA-AM[1,2-二(2-氨基苯氧基)乙烷-N,N,N',N'-四乙酸-四乙酰氧甲基酯,1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-tetraacetoxymethyl ester (10μmol/L)]以及三磷酸肌醇受体(IP3R)特异性阻断剂2-APB [2-氨基乙氧基二苯基硼酸盐,2-aminoethoxydiphenyl borate (50μmol/L)]单独或联合作用于大鼠大脑皮质神经细胞12h。Hoechst33258荧光染色观察细胞凋亡的形态变化,流式细胞术检测细胞内[Ca2+]i,ATPase酶试剂盒测定Na+-K+-ATPase和Ca2+-Mg2+-ATPase活性的变化,实时荧光定量PCR测定钙调蛋白(CaM) mRNA转录水平。结果表明,与对照组相比,染毒后的神经细胞经Hoechst33258染色呈现典型的凋亡特征,各镉染毒组细胞内[Ca2+]i极显著升高(P<0.01),Na+-K+-ATPase和Ca2+-Mg2+-ATPase活性显著或极显著降低<0.05或P<0.01),20μmol/L组CaM mRNA转录水平极显著降低(P<0.01)。与相应镉染毒组相比,BAPTA-AM联合组凋亡细胞减少,BAPTA-AM联合组和2-APB联合组细胞内[Ca2+]i显著或极显著降低(P<0.05或P<0.01)。说明镉可能通过影响CaM mRNA转录水平与维持钙稳态相关酶(Na+-K+-ATPase和Ca2+-Mg2+-ATPase)的活性以及胞内内质网Ca2+库的释放,从而干扰神经细胞内钙稳态,而细胞内钙稳态失衡在镉诱导大鼠大脑皮质神经细胞凋亡中起着重要作用。
3、镉对大鼠大脑皮质神经细胞MAPK言号通路的影响
为探讨不同浓度、不同时间染镉对体外培养的原代大鼠大脑皮质神经细胞中细胞外信号调节蛋白激酶(ERK1/2)、c-Jun氨基末端激酶(JNK)和p38MAPK磷酸化的影响,大鼠大脑皮质神经细胞用不同浓度(0、5、10、20μmol/L)醋酸镉染毒3h及10μmol/L醋酸镉染毒不同时间(0、1、2、3、4、5、6h),免疫印迹法测定样品ERK1/2、JNK和p38MAPK总蛋白的表达及磷酸化水平。结果表明,5、10、20μmol/L镉处理细胞3h后,除5μmol/L镉处理组ERK1/2磷酸化水平未升高外,其余所有浓度镉处理组的ERK1/2、JNK1和p38MAPK磷酸化水平均升高,而染镉后ERK1/2、JNK和p38MAPK,总量无明显变化；10μmol/L醋酸镉染毒后,ERK1/2磷酸化水平于2h便开始升高,一直维持到6h; JNK和p38MAPK磷酸化水平于试验后1h开始升高,3h达到高峰,之后逐渐下降,但6h内仍高于对照组,ERK1/2、JNK和p38MAPK、总量无明显变化。说明镉可引起MAPK信号通路关键蛋白的活化。
4、镉对大鼠大脑皮质神经细胞线粒体氧化损伤的影响
为研究镉对大鼠大脑皮质神经细胞线粒体的氧化损伤,用不同浓度(0、5、10、20μmol/L)醋酸镉染毒大鼠大脑皮质神经细胞6h,透射电子显微镜观察线粒体超微结构的变化,比色法测定MDA含量,实时荧光定量PCR从转录水平检测线粒体细胞色素氧化酶亚基COX I、COX Ⅱ COX Ⅲ表达的变化。结果表明：与对照组相比,各染毒组细胞超微结构变化明显,表现线粒体肿胀,嵴断裂、部分或完全消失,MDA含量均极显著升高(P<0.01), COX Ⅰ、COX Ⅱ基因表达量均显著或极显著降低(P<0.05或P<0.01),10和20μmol/L染毒组COX Ⅲ基因表达量极显著降低(P<0.01)。说明镉可引起线粒体损伤,COX Ⅰ、 COX Ⅱ、COX Ⅲ基因表达量显著下降可能与镉暴露导致的线粒体脂质过氧化损伤有关。
5、镉对大鼠大脑皮质神经细胞Bcl-2和Bax表达的影响
为研究镉对大鼠大脑皮质神经细胞凋亡相关基因Bcl-2和Bax表达的影响,用不同浓度(0、5、10、20μmol/L)醋酸镉染毒大鼠大脑皮质神经细胞12h,实时荧光定量PCR检测Bcl-2和Bax mRNA转录水平,并计算Bcl-2/Bax的比值,免疫印迹检测Bcl-2和Bax蛋白表达情况。结果表明：与对照组相比,各染毒组细胞Bax mRNA转录水平均极显著升高(P<0.01),而Bcl-2mRNA转录水平均显著降低(P<0.05),Bcl-2/Bax的比值均极显著降低(P<0.01)。此外,免疫印迹的结果也显示,随镉浓度的增加,Bcl-2蛋白表达水平下降,Bax蛋白表达水平升高。提示镉能通过调节凋亡相关基因Bcl-2和Bax mRNA转录和蛋白表达,从而促进细胞凋亡
6、镉对大鼠大脑皮质神经细胞一氧化氮合酶基因mRNA转录的影响
为研究镉对大鼠大脑皮质神经细胞一氧化氮合酶基因mRNA转录的影响,用不同浓度(0、5、10、20μmol/L)醋酸镉染毒大鼠大脑皮质神经细胞12h,实时荧光定量PCR检测神经型一氧化氮合酶(nNOS)、诱导型一氧化氮合酶(iNOS) mRNA转录水平。结果表明：与对照组相比,5、10μmol/L组nNOS mRNA转录水平显著和极显著升高(P<0.05和P<0.01);20μmol/L组iNOS mRNA转录水平极显著升高(P<0.01)。说明镉可诱导调节nNOS和iNOS mRNA的转录。
Cadmium (Cd) is an extremely toxic metal commonly found in industrial workplaces, food contaminants and cigarette smoke. It is toxic even at low doses since the metal accumulates and has a long biological half-life in humans (10-30years). Cd has been shown to cause severe damage to a variety of organs, including the lung, liver, kidney, testis, brain and even to the placenta. Cd can enter into the brain parenchyma and neurons causing neurological alterations in humans and animal models, leading to lower attention, hypeociception, olfactory dysfunction and memory deficits. Moreover, there are studies showing the neurotoxicity of Cd at μM range on cell culture models like neurons and glial cells, and the Cd-mediated toxicity is thought to involve, at least in part, the induction of apoptosis. Furthermore, previous study demonstrated that apoptosis of cortical neurons caused by Cd is the main reason of abnormality in central nervous system, leading to memory deficits and mental retardation. However, the mechanisms of Cd-induced apoptosis have not been well elucidated. In the current experiment, the model of cerebral cortical neurons cultured in vitro was used, which were obtained from foetal Sprague-Dawley rats at18-19days of gestation, and the potential mechanism of Cd-induced cytotoxicity and apoptosis in rat's cerebral cortical neurons was investigated, which will offer theoretic evidences for future exploring the mechanism in neurotoxicity of Cd.
1. Mitochondrial pathway in cadmium-induced apoptosis of rat's primary cultured cerebral cortical neurons
To explore the mechamism of Cd-induced apoptosis in rat's cerebral cortical neurons from mitochondrial pathway, the model of rat's primary cerebral cortical neurons in vitro was established successfully. The neurons were exposured to cadmium acetate of different concentrations (0,5,10,20μmol/L) for12h. Then, the morphological changes of apoptosis in neurons with Cd treatment was observed by Hoechst33258staining, and the level of reactive oxygen species (ROS), mitochondrial membrane potential (AΨm) were detected by flow cytometry, meanwhile, the transcriptional level of Caspase-3mRNA was detected by real-time fluorescent quantitative PCR. In addition, the neurons were exposured to10μmol/L cadmium acetate for0,12,24,48h. Then, the Cleaved Caspase-9and Cleaved PARP were detected by immunoblot at each time-point. With immunocytochemical detection, the cultured cells were affirmed as neurons, which are positive to neurons specific enolase (NSE) antibody and represent classical features of neurons. After Cd exposure, in comparison with the control group, the cells in Cd-treated groups showed typical morphological changes of apoptosis with nucleus crimpled and chromatin condensedation, even nucleus disintegratation, on the other hand, ROS level were increased significantly (P<0.05or P<0.01), ΔΨm were decreased significantly (P<0.05or P<0.01), and the transcriptional level of Caspase-3mRNA increased significantly (P<0.01). Caspase-9was activated early at12h after treatment of10μmol/L Cd and PARP was cleaved subsequently. It was suggested that Cd-induced apoptosis involves mitochondrial pathway in rat's cerebral cortical neurons.
2. Effect of the disequilibrium of calcium homeostasis on the apoptosis in rat's primary cultured cerebral cortical neurons induced by cadmium
To investigate the effect of the disequilibrium of calcium homeostasis on the apoptosis in rat's cerebral cortical neurons induced by Cd and ER-released calcium on the disequilibrium of calcium homeostasis induced by Cd, the neurons were exposured to cadmium acetate of different concentrations (0,5,10,20μmol/L), in the absence or the presence of10μmol/L BAPTA-AM [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-tetraacetoxymethyl ester], a specific intracellular Ca2+chelator and the inositol1,4,5tri-sphosphate receptor (IP3R) inhibitor,50μmol/L2-APB (2-aminoethoxydiphenyl borate) for12h. Then, the morphological changes of apoptosis in neurons with Cd treatment were observed by Hoechst33258staining and the intracellular [Ca+]i was detected by flow cytometry. Meanwhile, the activities of Na+-K+-ATPase as well as Ca2+-Mg2+-ATPase were measured by ATPase test kits, and the transcriptional level of CaM mRNA was detected by real-time fluorescent quantitative PCR. In comparison with the control group, the results showed that typical morphological changes of apoptosis were observed in cerebral cortical neurons with Hoechst33258staining after Cd treatment, intracellular [Ca2+]iwas increased significantly (P<0.01), in contrast, the activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase were decreased significantly (P<0.05or P<0.01) in the Cd-treated groups, and the transcriptional level of CaM mRNA was decreased significantly (P<0.01) in20μmol/L Cd group. Compared to the poisoning groups, apoptosis induced by cadmium can be efficiently prevented by BAPTA-AM, furthermore, the intracelluar [Ca2+]i were decreased significantly (P<0.05or P<0.01) in the presence of BAPTA-AM and2-APB groups. It was suggested that Cd could disturb intracellular Ca2+homeostasis by affecting the transcriptional level of CaM mRNA as well as the activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase and ER-released calcium, the disequilibrium of calcium homeostasis played a vital role in the Cd-induced apoptosis of rat's cerebral cortical neurons.
3. Influence of cadmium on MAPK signaling pathway in rat's primary cultured cerebral cortical neurons.
To observe the effect of Cd on the levels of the phosphorylation of extracellular signal regulated kinase1/2(ERK1/2), c-Jun NH2-terminal kinases(JNK), p38mitogen-activated protein kinases (p38MAPK) in rat's primary cultured cerebral cortical neurons, the neurons were exposured to cadmium acetate of different concentrations (0,5,10,20μmol/L) for3h and10μmol/L cadmium acetate for different time points (0,1,2,3,4,5,6h). The total and phosphorylated protein of ERK1/2, JNK and p38MAPK were assayed by immunoblots. The result showed that after treatment of5,10,20μmol/L Cd for3h the phosphorylation of ERK1/2, JNK1and p38MAPK was increased in all other Cd-treated groups with the exception of ERK1/2in5μmol/L Cd-treated group, while the total protein had no obvious changes. Following the treatment of10μmol/L Cd, the phosphorylation of ERKl/2begin to increase from2h and keeps to6h, at the same time, the phosphorylation of JNK and p38MAPK begin to be activated from1h with a peak at3h and decreased gradually. However, the phosphorylation of JNK and p38MAPK was also higher than that in the control within6h. The total expression of ERK1/2, JNK and p38MAPK had no obvious changes with the Cd exposure. It was suggested that cadmium can activate the key proteins in the MAPK signaling pathway.
4. Effect of cadmium on the oxidative damage of mitochondria in rat's primary cultured cerebral cortical neurons
To investigate the oxidative damage of mitochondria in rat's cerebral cortical neurons caused by Cd. The neurons were exposured to cadmium acetate of different concentrations (0,5,10,20μmol/L) for6h. Then, changes in ultrastructure of mitochondria were detected by transmission electron-microscope and the contents of malon-dialdehyde (MDA) were detected by colorimetric method. In addition, the relative gene expression levels of cytochrome oxidase submits (COX Ⅰ/Ⅱ/Ⅲ) were quantified by real-time fluorescent quantitative PCR. In comparison with the control group, the results showed that the changes of ultrastructure in the Cd-treated groups are obvious, the most ultrastructural modifications involved mitochondrial swelling, fragmentation and disappearance of mitochondrial cristae. The contents of MDA were significantly increased in the poisoning groups (P<0.01). The relative expression levels of COX Ⅰ and COX Ⅱ in the three exposed groups were significantly decreased (P<0.05or P<0.01), the relative expression levels of COX Ⅲ were also significantly decreased (P<0.01) in10,20μmol/L groups. Therefore, the damage of mitochondria may be medicated by cadmium. Moreover, the decreased expression levels of COX Ⅰ, COX Ⅱ, COX Ⅲ may be related to the mitochondrial lipid peroxidation.
5. Influence of cadmium on Bcl-2and Bax expression in rat's primary cultured cerebral cortical neurons.
To investigate the effects of Cd on the expressions of apoptosis-related genes Bcl-2, Bax in rat's primary cerebral cortical neurons, the neurons were exposured to Cd of different concentrations (0,5,10,20μmol/L) for12h. Real-time quantitative PCR was used to detect the mRNA transcriptional levels of Bcl-2and Bax. Furthermore, the protein expressions of Bcl-2and Bax were also detected by immunoblots. In comparison with the control group, the results showed that transcriptional levels of Bax mRNA in Cd-treated groups increased significantly (P<0.01). On the contrary, the transcriptional levels of Bcl-2mRNA and the ratios of Bcl-2/Bax decreased significantly (P<0.05or P<0.01). Correspondingly, the decreased Bcl-2and increased Bax protein expression levels were obtained by immunoblots detection with the increasing concentration of Cd. These results together indicating that cadmium can promote apoptosis by regulating the transcription and protein expression of apoptosis-related genes, including Bcl-2and Bax.
6. Effect of cadmium on mRNA transcription of nitric oxide synthase in rat's primary cultured cerebral cortical neurons
To study the impact of Cd on mRNA transcriptional levels of nitric oxide synthase in rat's primary cultured cerebral cortical neurons, the neurons were exposured to Cd of different concentrations (0,5,10,20μmol/L) for12h. Then, transcriptional levels of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) mRNA were detected by real-time quantitative PCR. In comparison with the control group, the results showed that the transcriptional levels of nNOS mRNA increased significantly (P<0.05and P<0.01) in5,10μmol/L groups and transcriptional levels of iNOS mRNA increased significantly (P<0.01) in20μmol/L group. It was concluded that cadmium can regulate the transcription of nNOS and iNOS.
引文
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