摘要
镉(cadmium)是一种有毒的重金属元素,易在体内蓄积,镉在人体内的半衰期长达20-30年,镉对机体毒性效应十分复杂。镉毒性作用的靶器官包括肺脏、肝脏、肾脏、骨骼、心血管系统和免疫系统,镉能够诱导这些器官的细胞死亡并导致相关功能丧失。肝脏是镉损伤的主要靶器官之一,目前对镉致肝细胞损伤研究较多,但其作用机制目前还不完全清楚。本研究以体外培养的人肝癌细胞株SMMC-7721为模型,在对数生长期用不同的镉浓度进行染毒,无血清培养不同时间,采用细胞生物学、分子生物学和比较蛋白质组学方法评价镉对肝细胞的毒性效应及机制。研究内容如下：
1.镉对肝癌细胞SMMC7721的毒性损伤
0-80μmo1/L醋酸镉分别作用SMMC7721细胞6、12、24h,采用MTT法测定了细胞相对存活率；1、2.5、5、10、20μmol/L醋酸镉分别作用细胞6、12、24h并测定培养上清中LDH活性、细胞凋亡率；观察了镉染毒24h对细胞形态、超微结构以及DNA损伤的影响。结果表明,随着镉浓度的增大,肝癌细胞的存活率逐渐降低,12h和24h时各剂量染镉组细胞存活率均极显著低于对照组(P<0.01)；随着镉剂量的增加和作用时间的延长,细胞变圆,脱落,急剧变形,坏死细胞增多,超微结构观察可见细胞核染色质边集,内容物皱缩空泡化或最终崩解。LDH释放量随剂量升高而增加,部分剂量组与对照组比较差异显著或极显著(P<0.05或P<0.01)。与对照组比较,镉染毒12h,仅20μmol/LCd组凋亡率显著升高,24h各组凋亡率均显著升高(P<0.05或P<0.01),并以10μmol/LCd组最高。Hoechst33258染色可以观察到凋亡细胞发生了核碎裂。表明镉对肝癌细胞的损伤呈剂量—时间—效应,5-20μmol/L镉即可引起肝癌细胞凋亡和坏死,其中10μmol/LCd所致的凋亡率最高。
2.氧化应激在镉致肝癌细胞SMMC7721损伤中的作用
5、10、20μmol/L醋酸镉处理SMMC7721细胞,测定了不同时间肝癌细胞内ROS、GSH及MDA含量；同时检测了NAC对镉致肝癌细胞凋亡及LDH释放的影响。结果表明,ROS升高主要发生在染毒后2h,显著或极显著高于对照组(P<0.05或P<0.01)；染毒12h时,10和20μmol/L染毒组细胞内GSH含量极显著低于对照组(P<0.01)；20μmol/L剂量组MDA含量显著高于对照组(P<0.05)。染毒24h时,GSH随镉浓度增高而降低,显著或极显著低于对照组(P<0.05或P<0.01)；MDA含量则随镉染毒浓度升高而升高,并极显著高于对照组(P<0.01)。与染毒组比较,在镉染毒同时添加NAC能显著降低细胞上清中LDH活性,减少凋亡细胞比例。表明氧化应激在镉致肝癌细胞损伤过程中发挥了重要作用。
3.镉对肝癌细胞SMMC7721线粒体的影响
1、2.5、5、10、20μmol/L醋酸镉处理SMMC7721细胞,测定了染毒12h和24h后线粒体膜电位的变化,观察了染毒24h线粒体超微结构,同时对线粒体损伤相关基因Bcl-2、Bax、CytC、Caspase-9、Caspse-3的mRNA相对表达水平及蛋白表达水平的变化进行了测定。结果表明,染毒12h线粒体膜电位变化不显著,染毒24h5μmol/L以上组线粒体膜电位显著或极显著低于对照组(P<0.05或P<0.01)。超微结构显示,随着镉染毒浓度的增加线粒体出现嵴断裂,空泡化,严重时发生崩解。Bcl-2mRNA目对表达量随染毒浓度增加而降低,bax表达变化与之相反,Western blot结果呈现同样的变化规律；细胞免疫组织化学检测Cyt-c表达随染毒浓度升高表达量增加,(?)Vestern blot检测无差异；Caspase-9mRNA相对表达量随染毒浓度升高而增加,并显著高于对照组(P<0.01)。10μmol/LCd组Caspse-3mRNA相对表达量显著低于对照组(P<0.05),其余染毒组与对照组比较无显著差异(P>0.05)。表明线粒体凋亡途径参与了镉致肝癌细胞的损伤。
4.镉致肝癌细胞SMMC7721损伤的蛋白质组学研究
选择10μmol/LCd染毒24h建立镉致肝癌细胞损伤模型,通过提取细胞总蛋白和双向凝胶电泳对蛋白质进行分离,共有24个蛋白点出现显著的差异表达,包括7个新增点,11个上调点,6个下调点。采用MALDI-TOF-MS质谱法对24个差异表达蛋白点进行质谱分析,结果成功鉴定了23个蛋白点,对应23种蛋白质。它们是肽酰-脯氨酰-顺反式异构酶FKBP4、角蛋白8、热休克蛋白27、蛋白酶激活复合物亚基2、60S酸性核糖体P0蛋白、热休克蛋白70蛋白6、甘氨酰-tRNA合成酶异构体CRA a、半乳糖凝集素-1、线粒体细胞色素b-c1复合体亚单位1、60KD热休克蛋白、围脂滴蛋白-3、角蛋白细胞骨架Ⅰ-18、角蛋白/细胞支架Ⅰ-17、钙腔蛋白亚基5、酪氨酸3-monooxygenasea/tryptophan5单加氧酶激活蛋白ζ、角蛋白10、蛋白S100-A4、Ran特异性GTP酶活化蛋白、真核翻译起始因子5A-1、Ran特异性GTP酶活化蛋白、β-链微管蛋白2C、膜联蛋白A5、GDP解离抑制因子。通过数据库查询和生物信息学分析,证实这些已知的差异蛋白中与细胞骨架相关蛋白占21.7%,应激相关蛋白占21.7%,细胞凋亡相关蛋白占8.7%,信号传导相关蛋白占21.7%,核酸结合相关蛋白占8.7%,其他占21.7%。在此基础上结合现有的文献报道,对这些差异蛋白质的功能与镉损伤相关机制等方面进行分析讨论。结果表明镉破坏了细胞骨架系统,诱导了氧化应激,并且发现硫氧还蛋白、酸性磷酸化P0蛋白等可能参与了镉诱导肝癌细胞凋亡的调节。
Cadmium (Cd) is a toxic metal, targeting the lung, liver, kidney, and testes following acute intoxication, and causing nephrotoxicity, immunotoxicity, osteotoxicity and tumors after prolonged exposures. Liver plays a central role in toxicity of cadmium (Cd). Recently, there are lots of Studies reported on cadmium hepatotoxicity, but the specific mechanisms by which it produces its adverse effects have yet to be fully elucidated. In this study, hepatoma SMMC7721cells in the logarithmic phase were treated with cadmium by serum deprivation with different time to study the mechanism of cytotoxicity induced by Cd. The methods of cytobiology, molecular biology and comparative proteome methods were used to evaluate the mechanism of cytotoxicity in hepatocyte induced by cadmium. A series of tests were carried out:
1. Cadmium induced cytotoxicity in SMMC7721
SMMC7721cells were exposed to cadmium acetate (Cd(AC)2) atl,2.5,5,10,20,40and80μmol/L for a range of6,12and24h. Cell survival rates were measured with MTT assay. At the end of incubation, the leakage of lactate dehydrogenase (LDH) in cell-free medium was measured with spectro photometric assay; apoptosis rate were detectd with flow cytometry. The morphology, nucleus damage and ultrastructure of SMMC7721were also evaluated. The results showed that the inhibitory rate of SMMC7721cells increased significantly with the increasing dosage and time of exposure compared with control group (P<0.01). After24h treatment, hepatocytes showed sharp deformation and more dead cells in culture medium. Ultrastructurally, nucleoli damaged with crush and Chromatin margination and lots of vacuoles in cytoplasm, eventually collapse. After treated with Cd for12h or24h, the activity of LDH in cell free culture increased significantly(P<0.05or P<0.01)compared with control group. The apoptosis rate increased significantly compared with conrol group after24h exposed to Cd. Hoechst33258staining displayed nuclear fragmentation into2-3parts. In short, the injury induced by Cd shows does time effect.5-20μmol/L Cd could induce both necrosis and apoptosis. When treated with10μmol/LCd, we can receive relatively high apoptosis rate.
2. The role of oxidative stress in injury induced by cadmium in SMMC7721
The content of ROS, MDA and GSH in SMMC7721were detected after treated with Cd atl,2.5,5,10,20μmol/L. SMMC7721cells were treated with10μmol/L Cd in the presence or absence of NAC. The antagonistic effects of NAC on toxicity of Cd were evaluated. The results showed that the concentration of ROS increased significantly only after2h exposure, it decreased to nomal level after6h or longer. When exposed to Cd for12h, the concentration of GSH decreased significantly after treated with10μmol/L and20μmol/LCd compared with control group, while the concentration of MDA increased significantly with group20μmol/LCd. When exposed to Cd for24h, the concentration of GSH decreased significantly in all groups treated with Cd compared with control group, the concentration of MDA was on the contrary. Both apoptosis and necrosis induced by cadmium can be efficiently prevented by NAC. In conclusion, oxidative stress plays an important role in cytotoxicity induced by cadmium on SMMC7721.
3. Effects of cadmium on mitochondria of SMMC7721
The mitochondrial membrane potential (ΔΨm) was detected and ultramicrostructure of mitochondrial was observed after treated with Cd at5,10,20μmol/L for12h and (or)24h. At the same time the relative expression levels and/or protein expression level of gene Bcl-2, Bax, Cyt-c, Caspase-9and Caspse-3in SMMC7721were detected. The results showed that, after exposed to Cd for12h there was no significant difference on ΔΨm between control and groups (P>0.05); after expoused to Cd for24h, the ΔΨm of all groups exposed to Cd decreased significantly compared with control group(P<0.05or P<0.01). Ultrastructurally, mitochondria swelling and degeneration, mitochondrial cristae blurred, deformed or final collapse. The relative expression levels of Bcl-2decreased significantly in the groups treated with Cd at5,10μmol/L compared with control group, but increased significantly in (20μmol/LCd) group. The reverse change was detected with gene Bax. Western blot analysis showed the same tendency as above. The relative expression levels of Caspase-9increased significantly in group (Cd2.5,5,10,20μmol/L) compared to control group. Cd at10μmol/L decreased the relative expression levels of Caspase-3obviously compared with control, no significant difference was observed between the other groups and control. We can conclude that cytotoxicity induced by cadmium may through the mitochondrial path way in SMMC7721.
4. Proteomic study on SMMC7721induced by cadmium
We chose Cd at10μmol/L for24h to establish the damage model. The total protein of SMMC7721was extracted and separated with2-D gel electrophoresis. The results showed that24protein spots in total expressed differently during exposed to Cd including7new spots,11up-regulated spots and6down-regulated. With MALDI-TOF-MS,24protein spots representing23proteins were successfully identified, including peptidyl-prolyl cis-trans isomerase FKBP4, KRT8protein, heat shock protein27, proteasome activator complex subunit2,60S acidic ribosomal protein P0, heat shock70kDa protein6, glycyl-tRNA synthetase, isoformCRA_, calumenin isoform5, tyrosine3-monooxygenasea/tryptophan5-monooxygenase activation protein zeta, thioredoxin, Galectin-1, rho GDP-dissociation inhibitor1isoform a, ANNEXIN A5, Tubulin beta-2C chain keratin, type I cytoskeletal17, Eukaryotic translation initiation factor5A-1, Ran-specific GTPase-activating protein, KRT18protein, perilipin-3isoform3, heat shock60kDa protein1, Protein S100-A4, cytochrome b-c1complex subunit1mitochondrial, Keratin10. In addition, As confirmed by database query, these differential proteins were mainly associated with cell skeleton protein(21.7%), stress protein(21.7%), proliferation and apoptosis(8.7%), signal transduction(21.7%), nucleric acid binding protein(8.7%) and other proteins(21.7%). Based on the forthcoming research, we analyzed the function of these differential proteins as well as their relationship with mechanism of cytotoxicity induced by treated with Cd. In conclution, cytoskeleton was destroyed and oxidative stress was induced by Cd. Thioredoxin and60S acidic ribosomal protein PO may also participate in regulating apoptosis induced by Cd.
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