环境汞污染对大鼠脑即刻早期基因c-fos和c-jun表达的影响研究
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摘要
本论文通过应用RT-PCR 与免疫组织化学两种方法,在转录与翻译水平上检测大鼠暴露甲基汞后大鼠脑即刻早期基因c-jun、c-fos mRNA表达和C-JUN、C-FOS 蛋白表达的变化。研究发现甲基汞的神经毒性存在一个信息传递过程,结合本课题组其他两位同学的研究成果,初步确定IEG可以作为汞神经毒性早期预报指标。
在对典型汞污染地区汞污染现状调查基础上,本论文应用汞污染地区实验田粮食对大鼠进行暴露,尝试应用即刻早期基因c-jun、c-fos 的表达特征对典型汞污染地区汞污染状况进行预报和评价的可行性。同时发现汞的不同形态诱导IEG 表达的强度不同,MMC 比HgCl2更容易诱导IEG 的表达; 硒—汞拮抗作用不仅体现在生物体中器官的吸收,同样体现在IEG的表达,即硒可抑制汞诱导IEG 的表达。
本论文最后把基因芯片引入环境科学领域,探索应用基因芯片筛选甲基汞神经毒性的差异表达基因,初步得出应用基因表达谱芯片能够筛选出甲基汞神经毒性敏感基因。
Mercury (Hg),as one of the priority pollutant and hot topic in the front of environmental research in many countries, has been paid higher attention in the world since the middle of last century. China is one of countries with the highest mercury production in the world. And 70% of the total is produced in Guizhou province. Due to the long time in exploration and smelting, abundant mercury around a mining of the province are accumulated, which has threatened on the local ecosystem.
Another source of Hg in environment was discharged from a local chemical industries where Hg is used as a catalyst for the production of acetaldehyde and other organic compounds, which has heavily contaminated around this area. It is found from the detection of the local samples and the data collection that the mercury content in the most media of aquatics, soil and atmosphere and in the biomass of corn, plant and animas, is higher than the national standard or the data from unpolluted area. It is the reason for this dissertation to search the influence and the assessment of the pollution above on the healthy of local citizen.
The c-jun/ c-fos proto-oncogene are the member of the immediate early genes(IEGs). IEGs including c-jun/c-fos in neurons are easily induced by a variety of extracellular stimuli. They are considered to link such acute stimuli with subsequent changes in gene expression and hence to act as third messengers during signal transduction. In the neuronal cells, the basal level of c-jun/c-fos expression is low generally. By the stimuli or disturbing on some linked to neuron from outside, the mRNA expression of c-jun/c-fos and their protein could be induced instantaneously. The c-fos encodes a DNA-binding protein (FOS) which functions as a component of the transcriptional factor,
AP-1. Fos family proteins are shown to form stable heterodimers with the members of the Jun family proteins to regulate transcription of other genes by binding to the specific nucleotide sequence, AP-1 sites (TGACTCA).More recently, the expression of the JUN/FOS protein product of the immediate early gene, c-jun/c-fos, has been used as a functional marker for activation of neurons. Objective (1) To apply the expression changes of immediate early genes (IEG) c-fos/c-jun in brain of rats to early predict the neurotoxicity of MMC .by means of the study on the effect of chloro methylmercury (MMC) on the expression of IEGs c-fos and c-jun in brain, and on the role of IEGs c-fos and c-jun in the neurotoxic mechanism of methylmercury chloride and the signal transduction mechanism in molecular level. (2) To look for the possibility to apply the expression changes of IEG c-fos and c-jun in rat brain to early predict the neurotoxicity of MMC and to search for the correlations between mercury and selenium by means of the test rats exposure with the two kinds of rice, unpolluted and polluted by Hg mining and chemical factory in Guizhou. (3) To look for the possibility of the device using the cDNA microarray to screen the sensitive genes in the expression of the neuotoxicity by MMC by means of the comparison of the differential expression genes between the control and the exposed groups. Methods: Sprague-Dawley(SD) rats were exposed with and without MMC and Hg-polluted rices respectively. The expressed intensity of IEG c-fos and c-jun in rat brain was detected in the courses of different doses and time. The indexes were determined as followed. (1) The Hg accumulation in rat brain was detected by means of AMA-254 liquid/solid mercury analyzer. (2) The expression of c-jun mRNA and c-fos mRNA was observed by means of RT-PCR device. (3) The expression of C-JUN protein and C-FOS protein in hippocampus and cortex and ependyma was observed by using immunocytochemical method. (4) The differential expression genes between the control group and the exposed group were screened by means of the cDNA microarray.
All of the results were calculated statistically asx±S,n=5 .and the comparison among the groups were conducted by using t test. Results and Conclusions: (1) After the exposure with 0.5mg/kg MMC for 20min and with 0.05mg/kg MMC for 60min, MMC with the high affinity was easily to be arrived to the target of the central nervous system through the barrier of blood and brain and accumulated in brain. The course of the accumulation in the organs is a dynamic process with the peak at 240min and the decrease after 1440min. (2) The expression of c-jun mRNA and the expression of C-JUN /C-FOS protein in hippocampus, cortex and ependyma in the rat brain is prior to the accumulation of Hg in the rat brain. Namely the expression of c-jun mRNA and of C-JUN /C-FOS protein has been induced before the Hg land in brain. It is proved that the neuotoxicity of MMC includes a course of signal transduction, which assume the possibility of IEGs as an efficiency early warning index to detect and assess neurotoxicity by MMC. (3) Compared the expression intensity of C-JUN /C-FOS protein among the different regions of hippocampus and cortex as well as ependyma, it could be concluded that more sensitive expression is occurred in hippocampus and cortex but ependyma, which is the demonstration of hippocampus and cortex as the selected regions for the early warning on MMC toxicity. (4) The accumulation quantity of mercury in the rat brain exposed by Hg-polluted rice for 20days and 30days was significantly increased compared to that in control group and the data from the group exposed for 30days was significantly increased than those for 20days. The Hg content in the rat brain in simulated group was also increased significantly compared to that in control group. The accumulation is relative to the Hg species and the accumulation course in the groups exposed by Hg-polluted rice is slower than those by MMC. The uptake of MeHg by brain is easier than that of HgCl2, which is, probably, due to the higher affinity of MeHg; Selenium(Se) shows an effect on the accumulation and ionic Se can reduce the Hg uptake. The expression of C-JUN /C-FOS protein in different regions of rat brain, hippocampus and cortex as well as ependyma, were induced by the mercury polluted rice. The expression of c-jun /c-fos mRNA and the expression of C-JUN /C-FOS protein in hippocampus and cortex as well as ependyma of rats exposed by using the mercury polluted rice for 20days and 30days was more significantly increased than which
exposed by unpolluted rice. And the expression could keep a long time. This phenomena suggests that it should be cautious for human being to eat any kind of food Hg-polluted. In a world the expression changes of IEG c-fos、c-jun in brain of rats is possible to apply as the early warnning for the neuotoxicity of mercury. (5) The expression of c-jun /c-fos mRNA and of C-JUN /C-FOS protein in hippocampus,cortex and ependyma of rats in the group exposed with normal rice and MMC was higher than that exposed with normal rice and HgCl2. This proves again that the expression of mRNA and of the protein is relative to Hg species. Like above, the expression of c-jun /c-fos mRNA and of C-JUN /C-FOS protein in hippocampus and cortex of rats exposed with the normal rice and Se-Hg was significantly decreased than that exposed with normal rice and MMC. This demonstrated the antagonisis between selenium and mercury on the expression of c-jun /c-fos mRNA and of C-JUN /C-FOS protein in hippocampus and cortex of rats. (6) Combined with animal model, gene chip could be used to analyze gene expression patterns in the neuotoxicity of MMC, as well to screen the sensitive expressed genes, between normal group and exposed group in large and high-speed and high sensitivity and reliability . So genechip technology can play an important role in exploring the neuotoxicity of MMC mechanism at genetic level.
在对典型汞污染地区汞污染现状调查基础上,本论文应用汞污染地区实验田粮食对大鼠进行暴露,尝试应用即刻早期基因c-jun、c-fos 的表达特征对典型汞污染地区汞污染状况进行预报和评价的可行性。同时发现汞的不同形态诱导IEG 表达的强度不同,MMC 比HgCl2更容易诱导IEG 的表达; 硒—汞拮抗作用不仅体现在生物体中器官的吸收,同样体现在IEG的表达,即硒可抑制汞诱导IEG 的表达。
本论文最后把基因芯片引入环境科学领域,探索应用基因芯片筛选甲基汞神经毒性的差异表达基因,初步得出应用基因表达谱芯片能够筛选出甲基汞神经毒性敏感基因。
Mercury (Hg),as one of the priority pollutant and hot topic in the front of environmental research in many countries, has been paid higher attention in the world since the middle of last century. China is one of countries with the highest mercury production in the world. And 70% of the total is produced in Guizhou province. Due to the long time in exploration and smelting, abundant mercury around a mining of the province are accumulated, which has threatened on the local ecosystem.
Another source of Hg in environment was discharged from a local chemical industries where Hg is used as a catalyst for the production of acetaldehyde and other organic compounds, which has heavily contaminated around this area. It is found from the detection of the local samples and the data collection that the mercury content in the most media of aquatics, soil and atmosphere and in the biomass of corn, plant and animas, is higher than the national standard or the data from unpolluted area. It is the reason for this dissertation to search the influence and the assessment of the pollution above on the healthy of local citizen.
The c-jun/ c-fos proto-oncogene are the member of the immediate early genes(IEGs). IEGs including c-jun/c-fos in neurons are easily induced by a variety of extracellular stimuli. They are considered to link such acute stimuli with subsequent changes in gene expression and hence to act as third messengers during signal transduction. In the neuronal cells, the basal level of c-jun/c-fos expression is low generally. By the stimuli or disturbing on some linked to neuron from outside, the mRNA expression of c-jun/c-fos and their protein could be induced instantaneously. The c-fos encodes a DNA-binding protein (FOS) which functions as a component of the transcriptional factor,
AP-1. Fos family proteins are shown to form stable heterodimers with the members of the Jun family proteins to regulate transcription of other genes by binding to the specific nucleotide sequence, AP-1 sites (TGACTCA).More recently, the expression of the JUN/FOS protein product of the immediate early gene, c-jun/c-fos, has been used as a functional marker for activation of neurons. Objective (1) To apply the expression changes of immediate early genes (IEG) c-fos/c-jun in brain of rats to early predict the neurotoxicity of MMC .by means of the study on the effect of chloro methylmercury (MMC) on the expression of IEGs c-fos and c-jun in brain, and on the role of IEGs c-fos and c-jun in the neurotoxic mechanism of methylmercury chloride and the signal transduction mechanism in molecular level. (2) To look for the possibility to apply the expression changes of IEG c-fos and c-jun in rat brain to early predict the neurotoxicity of MMC and to search for the correlations between mercury and selenium by means of the test rats exposure with the two kinds of rice, unpolluted and polluted by Hg mining and chemical factory in Guizhou. (3) To look for the possibility of the device using the cDNA microarray to screen the sensitive genes in the expression of the neuotoxicity by MMC by means of the comparison of the differential expression genes between the control and the exposed groups. Methods: Sprague-Dawley(SD) rats were exposed with and without MMC and Hg-polluted rices respectively. The expressed intensity of IEG c-fos and c-jun in rat brain was detected in the courses of different doses and time. The indexes were determined as followed. (1) The Hg accumulation in rat brain was detected by means of AMA-254 liquid/solid mercury analyzer. (2) The expression of c-jun mRNA and c-fos mRNA was observed by means of RT-PCR device. (3) The expression of C-JUN protein and C-FOS protein in hippocampus and cortex and ependyma was observed by using immunocytochemical method. (4) The differential expression genes between the control group and the exposed group were screened by means of the cDNA microarray.
All of the results were calculated statistically asx±S,n=5 .and the comparison among the groups were conducted by using t test. Results and Conclusions: (1) After the exposure with 0.5mg/kg MMC for 20min and with 0.05mg/kg MMC for 60min, MMC with the high affinity was easily to be arrived to the target of the central nervous system through the barrier of blood and brain and accumulated in brain. The course of the accumulation in the organs is a dynamic process with the peak at 240min and the decrease after 1440min. (2) The expression of c-jun mRNA and the expression of C-JUN /C-FOS protein in hippocampus, cortex and ependyma in the rat brain is prior to the accumulation of Hg in the rat brain. Namely the expression of c-jun mRNA and of C-JUN /C-FOS protein has been induced before the Hg land in brain. It is proved that the neuotoxicity of MMC includes a course of signal transduction, which assume the possibility of IEGs as an efficiency early warning index to detect and assess neurotoxicity by MMC. (3) Compared the expression intensity of C-JUN /C-FOS protein among the different regions of hippocampus and cortex as well as ependyma, it could be concluded that more sensitive expression is occurred in hippocampus and cortex but ependyma, which is the demonstration of hippocampus and cortex as the selected regions for the early warning on MMC toxicity. (4) The accumulation quantity of mercury in the rat brain exposed by Hg-polluted rice for 20days and 30days was significantly increased compared to that in control group and the data from the group exposed for 30days was significantly increased than those for 20days. The Hg content in the rat brain in simulated group was also increased significantly compared to that in control group. The accumulation is relative to the Hg species and the accumulation course in the groups exposed by Hg-polluted rice is slower than those by MMC. The uptake of MeHg by brain is easier than that of HgCl2, which is, probably, due to the higher affinity of MeHg; Selenium(Se) shows an effect on the accumulation and ionic Se can reduce the Hg uptake. The expression of C-JUN /C-FOS protein in different regions of rat brain, hippocampus and cortex as well as ependyma, were induced by the mercury polluted rice. The expression of c-jun /c-fos mRNA and the expression of C-JUN /C-FOS protein in hippocampus and cortex as well as ependyma of rats exposed by using the mercury polluted rice for 20days and 30days was more significantly increased than which
exposed by unpolluted rice. And the expression could keep a long time. This phenomena suggests that it should be cautious for human being to eat any kind of food Hg-polluted. In a world the expression changes of IEG c-fos、c-jun in brain of rats is possible to apply as the early warnning for the neuotoxicity of mercury. (5) The expression of c-jun /c-fos mRNA and of C-JUN /C-FOS protein in hippocampus,cortex and ependyma of rats in the group exposed with normal rice and MMC was higher than that exposed with normal rice and HgCl2. This proves again that the expression of mRNA and of the protein is relative to Hg species. Like above, the expression of c-jun /c-fos mRNA and of C-JUN /C-FOS protein in hippocampus and cortex of rats exposed with the normal rice and Se-Hg was significantly decreased than that exposed with normal rice and MMC. This demonstrated the antagonisis between selenium and mercury on the expression of c-jun /c-fos mRNA and of C-JUN /C-FOS protein in hippocampus and cortex of rats. (6) Combined with animal model, gene chip could be used to analyze gene expression patterns in the neuotoxicity of MMC, as well to screen the sensitive expressed genes, between normal group and exposed group in large and high-speed and high sensitivity and reliability . So genechip technology can play an important role in exploring the neuotoxicity of MMC mechanism at genetic level.
引文
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