c-fos基因去甲基化在氟致L-02细胞凋亡中的作用
|
摘要
地方性氟中毒是一种严重危害人体健康的全身性疾病,除损害机体骨相组织以外,还可损害机体的非骨相组织。肝脏是人体主要的解毒器官,氟化物对其毒性尤其受到人们的广泛关注。动物实验结果显示,过量氟对肝脏具有毒性作用,可致其产生脂质过氧化损伤;氟中毒可致大鼠肝细胞变形、索排列紊乱、胞浆结构疏松、细胞核膜皱折、固缩、核仁边集等改变,这些结果都说明氟对肝细胞有直接损害作用。随着研究的深入,细胞凋亡在氟致肝脏毒性机制中的作用引起了人们的关注。体外实验发现,氟化物可降低机体抗氧化能力,引起肝细胞凋亡,而以往的研究结果显示氧化应激在一定程度上可以诱导细胞凋亡。
原癌基因c-fos是受促分裂素原活化蛋白激酶(mitogen-activated protein kinases, MAPK)旁路调控而控制细胞增殖的即时早刻基因(immediately early genes, IEGs),具有促凋亡作用,在细胞生长调节和胞内信号传递中具有极为重要的作用。许多致癌因子均可通过对MAPK旁路中不同调控环节作用而诱导细胞c-fos基因异常表达,影响细胞的增殖和凋亡。业已证明,过量氟可导致成纤维细胞和成骨细胞凋亡,并伴有c-fos基因的表达。进一步研究发现,c-fos基因的异常甲基化可能是导致其表达失调的主要原因。在对肿瘤的大量研究中发现,c-fos基因的甲基化能够导致其表达下调,也因此抑制了肿瘤细胞的凋亡。在缺血再灌注损伤及对大鼠肝组织诱导损伤的研究中也得出相似结论。
DNA甲基化是哺乳动物中常见的一种结构修饰,也是外遗传体系中的一种重要机制。DNA甲基化是以S-腺苷甲硫氨酸(S-adenosylmethionine, SAM)为甲基供体,在DNA甲基转移酶(DNA methytransferse, Dnmts)催化下,将甲基加到CpG二核苷酸胞嘧啶的第五位碳原子上,使之变成5-甲基胞嘧啶(5mC)的化学修饰过程。在DNA甲基化过程中,Dnmts发挥了重要的作用。研究发现,Dnmts是外源化合物的作用靶点,外源化合物通过改变Dnmts的表达水平和活力,影响DNA甲基化和表观遗传的调节功能。目前认为,在哺乳动物中具有功能的DNA甲基转移酶可分2类:(1)Dnmt1:持续性DNA甲基转移酶,它能建立新的甲基化模式,即使DNA中未甲基化的碱基对CG的胞嘧啶甲基化,作用于仅有一条链甲基化的DNA双链,使其完全甲基化;(2)Dnmt3a、Dnmt3b:从头甲基转移酶,它们可甲基化CpG岛,使其半甲基化,继而全甲基化。一般认为,甲基化水平与基因表达呈负相关,即DNA甲基化程度越低,基因表达水平越高;反之,甲基化程度越高,基因表达水平越低。
鉴于过量氟是否会引起c-fos基因去甲基化及过量氟的肝毒性作用是否与c-fos基因去甲基化有关目前尚未见报道,因此本研究拟通过培养人胚胎肝细胞(L-02)接触不同剂量氟化钠(sodium fluoride, NaF)后,观察氟对c-fos、Dnmt1、Dnmt3a、Dnmt3b mRNA表达水平的影响以及氟诱导的细胞凋亡与c-fos基因去甲基化的关系,从而探讨c-fos基因去甲基化在氟致L-02细胞凋亡中的作用。
本研究主要由以下三部分组成
第一部分氟对L-02细胞凋亡、c-fos mRNA及蛋白表达的影响
目的探讨NaF对L-02细胞凋亡、c-fos mRNA及蛋白表达的影响。方法体外培养的L-02细胞暴露于不同浓度NaF(0、20、40、80μg/ml),24 h后检测细胞存活率、凋亡率、c-fos mRNA及蛋白表达水平。结果与对照组比较,40、80μg/ml染毒组细胞存活率明显降低,差异有统计学意义(P<0.05);细胞凋亡率随染毒剂量的升高呈上升趋势,且40、80μg/ml染毒组细胞凋亡率均明显高于对照组,差异有统计学意义(P<0.05);20、40、80μg/ml染毒组c-fos mRNA表达水平均明显高于对照组,差异有统计学意义(P<0.05);40、80μg/ml染毒组c-Fos蛋白表达水平均明显高于对照组,差异有统计学意义(P<0.05)。结论NaF可诱导L-02细胞凋亡,引起c-fos mRNA及蛋白表达水平的升高。
第二部分氟对L-02细胞Dnmtl、Dnmt3a和Dnmt3b mRNA表达的影响
目的探讨NaF对L-02细胞Dnmtl、Dnmt3a、Dnmt3b mRNA表达的影响。方法体外培养的L-02细胞暴露于不同浓度NaF(0、20、40、80μg/ml),24 h后检测Dnmtl、Dnmt3a、Dnmt3b mRNA表达水平的情况。结果随着NaF染毒剂量的增加,Dnmtl、Dnmt3a、Dnmt3b mRNA表达水平均呈下降趋势,20、40、80μg/ml染毒组Dnmtl mRNA表达水平均明显低于对照组,差异有统计学意义(P<0.05);80μg/ml染毒组Dnmt3a mRNA表达水平明显低于对照组,差异有统计学意义(P<0.05);40、80μg/ml染毒组Dnmt3b mRNA表达水平均明显低于对照组,差异有统计学意义(P<0.05)。结论NaF可使L-02细胞Dnmtl、Dnmt3a、Dnmt3b的mRNA表达水平降低。
第三部分亚硫酸氢钠修饰测序法检测NaF对L-02细胞c-fos基因甲基化的影响
目的用亚硫酸氢钠修饰后测序法检测氟染毒L-02细胞c-fos基因启动子区CpG岛甲基化状态。方法亚硫酸氢钠修饰不同浓度NaF(0、20、40、80μg/ml)染毒24 h的L-02细胞,针对c-fos基因启动子区DNA序列设计特异性引物,用普通PCR扩增,PCR产物纯化回收后测序比对。结果NaF染毒对照组L-02细胞c-fos基因启动子区扩增产物共检测出144个碱基,有10个CG未转变,其余C均转变为T;低、中、高剂量组各有1个CG未转变,其余C均转变为T。结论L-02细胞经NaF染毒后,c-fos基因甲基化水平下降,c-fos基因去甲基化活化可能是氟致L-02细胞凋亡过程中c-fos基因表达上调的一条途径。
Endemic fluorosis is prevalent in many parts of the world. Fluorosis can cause damage not only to skeletal tissue and teeth, but also to soft tissues. The liver is the primary organ for detoxification in human body, so the fluoride-induced liver toxicity has aroused wide public concern. Previous animal experiments have demonstrated that fluoride has toxic effects on the liver and cause lipid peroxidation. In addition, fluoride can lead to cell deformation, cords disorders, cytoplasmic, nuclear pyknosis, and nucleolar margination in hepatic cells. Apoptosis has been demonstrated to play an important role in toxicity of excessive fluoride in liver. Furthermore, some in vitro experimental studies shown that the toxicity of fluoride can lead to hepatocyte apoptosis and reduce antioxidation, and oxidative stress can induce apoptosis to some extent.
The proto-oncogene c-fos encodes a transcription factor that plays a pivotal role in cell proliferation, differentiation, and apoptosis. A lot of research showed that fluoride could induce fibroblast, osteoblast apoptosis and c-fos mRNA expression. Further study suggests the main reason of c-fos expression disorder is abnormal DNA methylation. Tumor research reported that the methylation of c-fos is the pivotal reason which inhibits tumor cells apoptosis. Ischemical reperfusion injury and induced injury in rat liver also came to similar conclusions.
DNA methylation is the major modification of eukaryotic genomes and is known to have a profound effect on gene expression. It is one of the regulatory processes that are referred to as epigenetic. It is a process that DNA methyltransferase (Dnmts) catalyst to S-adenosylmethionine (SAM) as a methyl donor to methyl added to cytosine dinucleotide CpG carbon atoms of the fifth to make it into a 5-methyl cytosine. Currently, three DNA methyltransferase members have been identified in humans. The most well-characterized DNA methyltransferase is Dnmt1. This enzyme is required for proper embryonic development in mammals, and is involved in copying the methylation pattern from an existing DNA strand to the newly synthesized DNA strand following DNA replication. For this reason, Dnmt1 is called the maintenance DNA methyltransferase. In contrast, Dnmt3a and Dnmt3b are believed to be de novo methyltransferases that can add a methyl group to a cytosine at a new location in the DNA strand, instead of just copying one that already exists.
So far, whether excessive floride can induce c-fos methylation and the relationship between hepatotoxicity and the c-fos methylation are not clear. In order to study the effect of c-fos demethylation on fluoride-induced apoptosis and provide some useful clues for further study of fluoride-induced hepatotoxicity. The expression levels of c-fos, Dnmt1, Dnmt3a and Dnmt3b, and the level of c-fos demethylation in human embryo hepatocyte L-02 cells were measured after in vitro cultured L-02 was exposed to sodium fluoride (NaF) at different doses.
This paper consists of three parts:
Part I Effects of fluoride on apoptosis, mRNA and protein expression levels of c-fos in L-02 cells in Vitro
Objective To investigate the effects of NaF on apoptosis, c-fos mRNA and protein expression levels in L-02 cells in Vitro. Methods L-02 cells were exposed to different concentrations of NaF (0, 20, 40, 80μg/ml) for 24 h, and then the cell survival rates, percentage of apoptosis, mRNA and protein expression levels of c-fos were measured. Results Compared with the control group, the cell survival rates in 20, 40 and 80μg/ml NaF-treated groups were significantly lower (P<0.05). The percentage of apoptosis in 40 and 80μg/ml NaF-treated groups were significantly higher than that of the control group (P<0.05), and increased as the dose of NaF increased concentrations; The mRNA and protein expression levels of c-fos in 40 and 80μg/ml NaF-treated groups were significantly higher than those of the control group (P<0.05). Conclusion NaF exposure can increase the mRNA and protein expression levels of c-fos and cause apoptosis in L-02 cells in vitro.
Part II Effects of fluoride on mRNA expression levels of Dnmt1, Dnmt3a, and Dnmt3b in L-02 cells in Vitro
Objective To investigate the effects of NaF on Dnmt1, Dnmt3a, Dnmt3b mRNA expression levels in L-02 cells in Vitro. Methods L-02 cells were exposed to different concentrations of NaF (0, 20, 40, 80μg/ml) for 24 h, and then the mRNA expression levels of Dnmt1, Dnmt3a, and Dnmt3b were measured respectively. Results The mRNA expression levels of Dnmt1 in 20, 40 and 80μg/ml NaF-treated groups were significantly lower than those of the control group (P<0.05); The mRNA expression levels of Dnmt3a in 80μg/ml NaF-treated groups was significantly lower than that of the control group (P<0.05); The mRNA expression levels of Dnmt3b in 40 and 80μg/ml NaF-treated groups were significantly lower than those of the control group (P<0.05). Conclusion NaF exposure can decrease the mRNA expression levels of Dnmtl, Dnmt3a, Dnmt3b in L-02 cells in vitro.
Part III Effects of floride on c-fos demethylation measured by bisulfite sequencing
Objective To analysis the methylation status of CpG islands in c-fos promoter in L-02 cells by using bisulfite sequencing. Methods The genomic DNA were extracted from L-02 cells which were exposed to different concentrations of NaF (0, 20, 40, 80μg/ml) for 24 h, and then the cells were treated by bisulfite sodium, the methylation status of c-fos amplified by polymerse chain reaction, then the amplified DNA were sequencing. Results c-fos sequencing showed that there were 144 bases to be sequenced, in which 10 CG have not changed in control group, 1 CG has not changed in 20, 40, 80μg/ml NaF-treated groups respectively. Conclusion The methylation levels of c-fos is decrease during NaF exposure. Demethylation of c-fos possible involved in the process of c-fos activation which induced by NaF in L-02 cells.
原癌基因c-fos是受促分裂素原活化蛋白激酶(mitogen-activated protein kinases, MAPK)旁路调控而控制细胞增殖的即时早刻基因(immediately early genes, IEGs),具有促凋亡作用,在细胞生长调节和胞内信号传递中具有极为重要的作用。许多致癌因子均可通过对MAPK旁路中不同调控环节作用而诱导细胞c-fos基因异常表达,影响细胞的增殖和凋亡。业已证明,过量氟可导致成纤维细胞和成骨细胞凋亡,并伴有c-fos基因的表达。进一步研究发现,c-fos基因的异常甲基化可能是导致其表达失调的主要原因。在对肿瘤的大量研究中发现,c-fos基因的甲基化能够导致其表达下调,也因此抑制了肿瘤细胞的凋亡。在缺血再灌注损伤及对大鼠肝组织诱导损伤的研究中也得出相似结论。
DNA甲基化是哺乳动物中常见的一种结构修饰,也是外遗传体系中的一种重要机制。DNA甲基化是以S-腺苷甲硫氨酸(S-adenosylmethionine, SAM)为甲基供体,在DNA甲基转移酶(DNA methytransferse, Dnmts)催化下,将甲基加到CpG二核苷酸胞嘧啶的第五位碳原子上,使之变成5-甲基胞嘧啶(5mC)的化学修饰过程。在DNA甲基化过程中,Dnmts发挥了重要的作用。研究发现,Dnmts是外源化合物的作用靶点,外源化合物通过改变Dnmts的表达水平和活力,影响DNA甲基化和表观遗传的调节功能。目前认为,在哺乳动物中具有功能的DNA甲基转移酶可分2类:(1)Dnmt1:持续性DNA甲基转移酶,它能建立新的甲基化模式,即使DNA中未甲基化的碱基对CG的胞嘧啶甲基化,作用于仅有一条链甲基化的DNA双链,使其完全甲基化;(2)Dnmt3a、Dnmt3b:从头甲基转移酶,它们可甲基化CpG岛,使其半甲基化,继而全甲基化。一般认为,甲基化水平与基因表达呈负相关,即DNA甲基化程度越低,基因表达水平越高;反之,甲基化程度越高,基因表达水平越低。
鉴于过量氟是否会引起c-fos基因去甲基化及过量氟的肝毒性作用是否与c-fos基因去甲基化有关目前尚未见报道,因此本研究拟通过培养人胚胎肝细胞(L-02)接触不同剂量氟化钠(sodium fluoride, NaF)后,观察氟对c-fos、Dnmt1、Dnmt3a、Dnmt3b mRNA表达水平的影响以及氟诱导的细胞凋亡与c-fos基因去甲基化的关系,从而探讨c-fos基因去甲基化在氟致L-02细胞凋亡中的作用。
本研究主要由以下三部分组成
第一部分氟对L-02细胞凋亡、c-fos mRNA及蛋白表达的影响
目的探讨NaF对L-02细胞凋亡、c-fos mRNA及蛋白表达的影响。方法体外培养的L-02细胞暴露于不同浓度NaF(0、20、40、80μg/ml),24 h后检测细胞存活率、凋亡率、c-fos mRNA及蛋白表达水平。结果与对照组比较,40、80μg/ml染毒组细胞存活率明显降低,差异有统计学意义(P<0.05);细胞凋亡率随染毒剂量的升高呈上升趋势,且40、80μg/ml染毒组细胞凋亡率均明显高于对照组,差异有统计学意义(P<0.05);20、40、80μg/ml染毒组c-fos mRNA表达水平均明显高于对照组,差异有统计学意义(P<0.05);40、80μg/ml染毒组c-Fos蛋白表达水平均明显高于对照组,差异有统计学意义(P<0.05)。结论NaF可诱导L-02细胞凋亡,引起c-fos mRNA及蛋白表达水平的升高。
第二部分氟对L-02细胞Dnmtl、Dnmt3a和Dnmt3b mRNA表达的影响
目的探讨NaF对L-02细胞Dnmtl、Dnmt3a、Dnmt3b mRNA表达的影响。方法体外培养的L-02细胞暴露于不同浓度NaF(0、20、40、80μg/ml),24 h后检测Dnmtl、Dnmt3a、Dnmt3b mRNA表达水平的情况。结果随着NaF染毒剂量的增加,Dnmtl、Dnmt3a、Dnmt3b mRNA表达水平均呈下降趋势,20、40、80μg/ml染毒组Dnmtl mRNA表达水平均明显低于对照组,差异有统计学意义(P<0.05);80μg/ml染毒组Dnmt3a mRNA表达水平明显低于对照组,差异有统计学意义(P<0.05);40、80μg/ml染毒组Dnmt3b mRNA表达水平均明显低于对照组,差异有统计学意义(P<0.05)。结论NaF可使L-02细胞Dnmtl、Dnmt3a、Dnmt3b的mRNA表达水平降低。
第三部分亚硫酸氢钠修饰测序法检测NaF对L-02细胞c-fos基因甲基化的影响
目的用亚硫酸氢钠修饰后测序法检测氟染毒L-02细胞c-fos基因启动子区CpG岛甲基化状态。方法亚硫酸氢钠修饰不同浓度NaF(0、20、40、80μg/ml)染毒24 h的L-02细胞,针对c-fos基因启动子区DNA序列设计特异性引物,用普通PCR扩增,PCR产物纯化回收后测序比对。结果NaF染毒对照组L-02细胞c-fos基因启动子区扩增产物共检测出144个碱基,有10个CG未转变,其余C均转变为T;低、中、高剂量组各有1个CG未转变,其余C均转变为T。结论L-02细胞经NaF染毒后,c-fos基因甲基化水平下降,c-fos基因去甲基化活化可能是氟致L-02细胞凋亡过程中c-fos基因表达上调的一条途径。
Endemic fluorosis is prevalent in many parts of the world. Fluorosis can cause damage not only to skeletal tissue and teeth, but also to soft tissues. The liver is the primary organ for detoxification in human body, so the fluoride-induced liver toxicity has aroused wide public concern. Previous animal experiments have demonstrated that fluoride has toxic effects on the liver and cause lipid peroxidation. In addition, fluoride can lead to cell deformation, cords disorders, cytoplasmic, nuclear pyknosis, and nucleolar margination in hepatic cells. Apoptosis has been demonstrated to play an important role in toxicity of excessive fluoride in liver. Furthermore, some in vitro experimental studies shown that the toxicity of fluoride can lead to hepatocyte apoptosis and reduce antioxidation, and oxidative stress can induce apoptosis to some extent.
The proto-oncogene c-fos encodes a transcription factor that plays a pivotal role in cell proliferation, differentiation, and apoptosis. A lot of research showed that fluoride could induce fibroblast, osteoblast apoptosis and c-fos mRNA expression. Further study suggests the main reason of c-fos expression disorder is abnormal DNA methylation. Tumor research reported that the methylation of c-fos is the pivotal reason which inhibits tumor cells apoptosis. Ischemical reperfusion injury and induced injury in rat liver also came to similar conclusions.
DNA methylation is the major modification of eukaryotic genomes and is known to have a profound effect on gene expression. It is one of the regulatory processes that are referred to as epigenetic. It is a process that DNA methyltransferase (Dnmts) catalyst to S-adenosylmethionine (SAM) as a methyl donor to methyl added to cytosine dinucleotide CpG carbon atoms of the fifth to make it into a 5-methyl cytosine. Currently, three DNA methyltransferase members have been identified in humans. The most well-characterized DNA methyltransferase is Dnmt1. This enzyme is required for proper embryonic development in mammals, and is involved in copying the methylation pattern from an existing DNA strand to the newly synthesized DNA strand following DNA replication. For this reason, Dnmt1 is called the maintenance DNA methyltransferase. In contrast, Dnmt3a and Dnmt3b are believed to be de novo methyltransferases that can add a methyl group to a cytosine at a new location in the DNA strand, instead of just copying one that already exists.
So far, whether excessive floride can induce c-fos methylation and the relationship between hepatotoxicity and the c-fos methylation are not clear. In order to study the effect of c-fos demethylation on fluoride-induced apoptosis and provide some useful clues for further study of fluoride-induced hepatotoxicity. The expression levels of c-fos, Dnmt1, Dnmt3a and Dnmt3b, and the level of c-fos demethylation in human embryo hepatocyte L-02 cells were measured after in vitro cultured L-02 was exposed to sodium fluoride (NaF) at different doses.
This paper consists of three parts:
Part I Effects of fluoride on apoptosis, mRNA and protein expression levels of c-fos in L-02 cells in Vitro
Objective To investigate the effects of NaF on apoptosis, c-fos mRNA and protein expression levels in L-02 cells in Vitro. Methods L-02 cells were exposed to different concentrations of NaF (0, 20, 40, 80μg/ml) for 24 h, and then the cell survival rates, percentage of apoptosis, mRNA and protein expression levels of c-fos were measured. Results Compared with the control group, the cell survival rates in 20, 40 and 80μg/ml NaF-treated groups were significantly lower (P<0.05). The percentage of apoptosis in 40 and 80μg/ml NaF-treated groups were significantly higher than that of the control group (P<0.05), and increased as the dose of NaF increased concentrations; The mRNA and protein expression levels of c-fos in 40 and 80μg/ml NaF-treated groups were significantly higher than those of the control group (P<0.05). Conclusion NaF exposure can increase the mRNA and protein expression levels of c-fos and cause apoptosis in L-02 cells in vitro.
Part II Effects of fluoride on mRNA expression levels of Dnmt1, Dnmt3a, and Dnmt3b in L-02 cells in Vitro
Objective To investigate the effects of NaF on Dnmt1, Dnmt3a, Dnmt3b mRNA expression levels in L-02 cells in Vitro. Methods L-02 cells were exposed to different concentrations of NaF (0, 20, 40, 80μg/ml) for 24 h, and then the mRNA expression levels of Dnmt1, Dnmt3a, and Dnmt3b were measured respectively. Results The mRNA expression levels of Dnmt1 in 20, 40 and 80μg/ml NaF-treated groups were significantly lower than those of the control group (P<0.05); The mRNA expression levels of Dnmt3a in 80μg/ml NaF-treated groups was significantly lower than that of the control group (P<0.05); The mRNA expression levels of Dnmt3b in 40 and 80μg/ml NaF-treated groups were significantly lower than those of the control group (P<0.05). Conclusion NaF exposure can decrease the mRNA expression levels of Dnmtl, Dnmt3a, Dnmt3b in L-02 cells in vitro.
Part III Effects of floride on c-fos demethylation measured by bisulfite sequencing
Objective To analysis the methylation status of CpG islands in c-fos promoter in L-02 cells by using bisulfite sequencing. Methods The genomic DNA were extracted from L-02 cells which were exposed to different concentrations of NaF (0, 20, 40, 80μg/ml) for 24 h, and then the cells were treated by bisulfite sodium, the methylation status of c-fos amplified by polymerse chain reaction, then the amplified DNA were sequencing. Results c-fos sequencing showed that there were 144 bases to be sequenced, in which 10 CG have not changed in control group, 1 CG has not changed in 20, 40, 80μg/ml NaF-treated groups respectively. Conclusion The methylation levels of c-fos is decrease during NaF exposure. Demethylation of c-fos possible involved in the process of c-fos activation which induced by NaF in L-02 cells.
引文
1. Guo XY, Sun GF, Sun YC. Oxidative stress from fluoride induced hepatotoxicity in rats [J]. Fluoride, 2003, 36(1):25-29.
2.边晓燕,吴振铎,李红,等.氟对大鼠肝细胞影响及SOD阻断因子的透射电镜研究[J].中国地方病学杂志, 1993, 12(3):136-137.
3.李键学,全笑江,吴云鹏.氟对大鼠肝、肾、脑细胞活性氧代谢的影响.中国氟研究文选[C]:73-75.
4.卜丽莎,张文岚,薄立华,尹文京,李广生.过量氟对大鼠肝细胞内钙水平和肝细胞凋亡的影响[J].中国地方病防治杂志, 2003, 18(5):257-259.
5. Zhan XA, Wang M, Xu ZR, Li WF, Li JX. Evaluation of caspase-dependent apoptosis during fluoride-induced liver lesion in pigs [J]. Archives of Toxicology, 2006, 80(2):74-80.
6.井玲,邵宗俊,任立群,李广生.氟中毒大鼠肝细胞凋亡研究[J].中国地方病学杂志,1999,18(2):84-86.
7.王爱国,夏涛,褚启龙,刘方,张明,杨克敌.氟对人胚肝细胞DNA损伤及凋亡的影响[J].中国公共卫生, 2004, 20(2):159-160.
8. Hiraku Y, Kawanishi S. Oxidative DNA Damage and Apoptosis Induced by Benzene Metabolites [J].Cancer Research, 1996, 56(22):5172-5178.
9. Amendola R, Bellini A, Cervelli M, Degan P, Marcocci L, Martini F, Mariottini P. Direct oxidative DNA damage, apoptosis and radio sensitivity by spermine oxidase activitie in mouse neuroblastoma cells [J]. Biochim Biophys Acta, 2005, 1755(1): 15-24.
10. Müller I, Jenner A, Bruchelt G, Niethammer D, Halliwell B. Effect of concentration on the cytotoxic mechanism of doxorubicin apoptosis and oxidative DNA damage [J]. Biochem Biophys Res Commun, 1997, 230(2): 254-257.
11. Chen X, Yang CS. Esophageal adenocarcinoma: a review and perspectives on the mechanism of carcinogenesis and chemoprevention [J]. Carcinogenesis, 2001, 22(8):1119-1129.
12. Hoffman GE, Smith MS, Verbalis JG. c-fos and related immediate early gene products as markers of activity in neuroendocrine systems[J]. Front Neuroendocrinol, 1993, 14(3):173-213.
13. Takeuehi K, Nakamura N, Cook NS, et al. AngiotensinⅡcan regulate gene expression by the AP-1 binding sequence via a protein kinase c-dependent pathway [J].Biochem Biophys Res Commun, 1990, 172(3): 1189-1194.
14.余日安,马良,陈学敏.硒对大鼠肝细胞凋亡和原癌基因c-myc、c-fos和c-jun表达的影响.卫生毒理学杂志[J]. 2004, 18(2):68-70.
15.王兰,王红梅,张建龙,孙湛.大鼠肝缺血再灌注损伤时c-fos、Bcl-2在肝组织的表达及与肝细胞凋亡的关系[J].新疆医科大学学报, 2005, 28(4): 344-346.
16.张文岚,崔亚南,高申,张秀云,李广生.过量摄入氟后激活的成骨细胞系中原癌基因的表达.[J].中华预防医学杂志, 2003, 37(4): 246-250.
17.陈璐璐,童安莉,余达林,陈荣安. NaF对乳鼠成骨细胞c-fos、c-jun基因表达及细胞增殖的影响[J].中华预防医学杂志, 2000, 34(6):327-329.
18. Gilman MZ, Wilson RN, Weinberg RA. Multiple protein-binding sites in the
5'-flanking region regulate c-fos expression [J]. Mol Cell Biol. 1986, 6(12): 4305-4316.
19. Uehara Y, Ono T, Kurishita A, Kokuryu H, Okada S. Age-dependent and tissue-specific changes of DNA methylation within and around the c-fos gene in mice [J]. Oncogene, 1989, 4(8):1023-8.
20. Greenberg ME, Siegfried Z, Ziff EB. Mutation of the c-fos gene dyad symmetry element inhibits serum inducibility of transcription in vitro and the nuclear regulatory factor binding in vitro [J]. Mol Cell Biol, 1987, 7(3): 1217-1225.
21. Bernd Kaina, Simone Haas, Holger Kappes. A General Role for c-fos in Cellular Protection against DNA-damaging Carcinogens and Cytostatic Drugs [J]. Cancer Research, 1997, 57(13): 2721-2731.
22. Shimizu K, Onishi M, Sugata E, Sokuza Y, Mori C, Nishikawa T, Honoki K, Tsujiuchi T. Disturbance of DNA methylation patterns in the early phase of hepatocarcinogenesis induced by a choline-deficient L-amino acid-defined diet in rats [J]. Cancer Sci, 2007,
98(9):1318-1322.
23. Choi EK, Uyeno S, Nishida N, et a1. On alterations of c-fos gene methylation in the processes of aging and tumorigenesis in human liver [J]. Mutation Research, 1996,354(1):123-128.
24. Counts JL, Sarmiento JI, Harbison ML, et a1. Cell proliferation and global methylation status changes in mouse liver after phenobarbital and/or choline-devoid,methionine deficient diet administration[J]. Carcinogenesis, 1996, 17(6):1251-1257.
25. Tao L, Yang S, Xie M, et a1. Effect of trichloroethylene and its metabolites, dichloroacetic acid and trichloroacetic acid, on the methylation and expression of c-jun and c-myc protooncogenes in mouse liver: prevention by methionine [J]. Toxieol Sci, 2000, 54(2):399-407.
26. Tao L, Wang W, Li L, et a1. DNA hypomethylation induced by drinking water disinfection by-products in mouse and rat kidney [J].Toxicol Sci, 2005, 87(2):344-352.
27.刘莉莉,陈家垄,安社娟,等.结晶型硫化镍及反式-BPDE恶性转化16HB细hMSH2基因甲基化的研究[J].癌变·畸变·突变, 2005, 17(3):129-132.
28. Thrane EV, Refsnes M, Thoresen GH, et al. Fluoride-induced apoptosis in epithelial lung cells involves activation of MAP kinases p38 and possibly JNK [J]. Toxicol, 2001, 61(1):83-91.
29. Wang AG, Chu QL, He WH, et a1. Effects on protein and mRNA expression levels of p53 induced by fluoride in human embryonic hepatocytes [J]. Toxicol Lett. 2005, 158(2):158-163.
30. Robertson KD, Wolffe AP. DNA methylation in health and disease [J], Nature Reviews Genetics, 2000, 1(1):11-9.
31. Razin A, Riggs AD. DNA methylation and gene function [J]. Science, 1980, 210(4470): 604-610.
32. Doerfler W. DNA Methylation and Cene Activity [J]. Annual Review of Biochemistry, 1983, 52:93-124.
33. Bird A. The essentials of DNA methylation [J].Cell, 1992, 70(l):5-8.
34. Martin JL, McMillan FM. SAM(dependent)IAM: the S-adenosylmethionine-dependent methyltransferase fold[J]. Curr Opin Struct Biol, 2002, 12(6):783-93.
35. Fatemi M, Pao MM, Jeong S, et a1. Footprinting of mammalian promoters: use of aCpG DNA methyltransferase revealing nucleosome positions at a single molecule level[J]. Nucleic Acids Res, 2005, 33 (20): 176.
36. Li E, Bestor, T H, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality [J]. Cell, 1992, 69(6):915–926.
37. Yoder JA, Soman NS, VerdineGL, Bestor TH. DNA (cytosine-5)-methyltransferases in mouse cells and tissues [J]. Mol Biol, 1997, 270:385-395.
38. Yoder JA. A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast [J]. Hum Mol Genet, 1998, 7(2):279-284.
39. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for denovo methylation and mammalian development [J]. Cell, 1999, 99(3):247-257.
40. Walsh CP, Chaillet JR, Bestor TH. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation [J]. Nat Genet, 1998, 20(2):116-117.
41. Bird AP. Gene number, noise reduction and biological complexity [J]. Trends Genet, 1995, 11(3):94-100.
42.尹斌,沈岩. DNA的甲基化修饰与DNA甲基转移酶[J].国外医学遗传学分册, 2001, 24(1):5-8.
43. Clark SJ, Melki J. DNA methylation and gene silencing in cancer: which is the guilty party?[J]. Oncogene, 2002, 21(35):5380-5387.
44. Bestor TH. Gene silencing, methylation meets acetylation [J]. Nature, 1998, 393(6683): 311-312.
45.司徒镇强,吴军正主编,细胞培养.世界图书出版公司, 1996:186-187.
46. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics [J]. Cancer, 1972, 26(4): 239–257.
47. Najimi M. Hepatocyte apoptosis [J]. Methods Mol Biol.2009, 481:59-74.
48. Tung JW, Heydari K, Tirouvanziam R, et a1. Modern flow cytometry: a practical approach [J]. Clin Lab Med. 2007, 27(3): 453-468.
49. Goto S, Matsumoto I, Kamada N, et a1. The induction of immediate early genes in postischemic and transplanted liver in rats, Its relation to organ survival [J]. Transplantation, 1994, 58(7):840 -845.
50. Estus S, Zaks WJ, Freeman RS, Gruda M, Bravo R, Johnson EM Jr. Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis [J]. Cell Biol, 1994, 127(6): 1717-1727.
51. Teruaki Sakurai, Toshikazu Kaise, Chiyo Matsubara. Inorganic and Methylated Arsenic Compounds Induce Cell Death in Murine Macrophages via Different Mechanisms [J].Chem. Res. Toxicol, 1998, 11 (4):273–283.
52. Ferret B, Hubsch A, Dreyfus H, Massarelli R. Exogenous gangliosides may affect methylation mechanisms in neuronal cell cultures [J].Neurochemical Research.1991, 16(2):137-144.
53. Beator TH, Cloning of a mammalian DNA methyltransferase [J]. Gene, 1988, 74(1):9-12.
54. Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases[J]. Nat Genet, 1998, 19(3):210- 220.
55. Desaulniers D, Xiao GH, Leingartner K, Chu I, Musicki B, Tsang BK. Comparisons of brain, uterus, and liver mRNA expression for cytochrome P450s, DNA methyltransferase-1, and Catechol-O-Methyltransferase in prepubertal female Sprague-Dawley rats exposed to a mixture of Aryl Hydrocarbon Receptor Agonists[J]. Toxicological Sciences, 2005, 86(1):175-184.
56. Sato K, Fukata H, Kogo Y, et al. Neonatal exposure to diethylstilbestrol alters the expression of DNA methyltransferases and methylation of genomic DNA in the epididymis of mice [J]. Endocr, 2006, 53(3):331-337.
57. Jenkins S, Rowell C, Wang J, Lamartiniere CA. Prenatal TCDD exposure predisposes for mammary cancer in rats [J]. Reprod Toxicol, 2007, 23(3):391-396.
58. Yen RW, Vertino PM, Nelkin BD, et al. Isolation and characterization of the cDNA encoding human DNA methyltransferase[J].Nucleic Acids Res, 1992,20 (9):2287-2291.
59. Tucker KL, Talbot D, Lee MA, Leonhardt H, Jaenisch R. Complementation of methylation deficiency in embryonic stem cells by a DNA methyltransferase minigene [J]. Proc Natl Acad Sci USA, 1996; 93(25):12920-12925.
60. Babinger P, Volkl R, Cakstina I, et al. Maintenance DNA methyltransferase(Metl) and silencing of CpG-methylated foreign DNA in Volvox carteri[J].Plant Mol Biol, 2007,63:325-336.
61. Hansen RS, Wijmenga C, Luo P, et al. The Dnmt3b DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome [J]. Proc Nat Acad Sci, 1999, 96(25):14412.
62. Rountree MR, Bachman KE, Baylin SB. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci [J]. Nat Genet, 2000, 25(3):269-277.
63. Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP. DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters [J]. Nat Genet, 2000, 25(3):338-342.
64. Nielsen SJ, Schneider R, Bauer UM, Bannister AJ, Morrison A, O’Carroll D, Firesteink R, Clearyk M, Jenuwein T, Herrera RE, Kouzarides T. Rb targets histone H3 methylation and HP1 to promoters[J]. Nature, 2001, 412(6846):561-565.
65. Zhang HS, Dean DC. Rb-mediated chromatin structure regulation and transcriptional repression [J]. Oncogene, 2001, 20(24):3134-3138.
66. Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T. Retinoblastoma protein recruits histone deacetylase to repress transcription[J]. Nature, 1998, 391(6667):597-601.
67. Rountree MR, Bachman KE, Herman JG, et al. DNA methylation, chromatin inheritance, and caner[J].Oncogene, 2001, 20(24):3156.
68.许军,樊红,赵主江,张建琼,谢维. RNAi及DNA芯片分析肝癌细胞系中受Dnmt3b调控的下游基因[J].遗传学报,2005年,32(11):1115-1127.
69. Sato K, Fukata H, Kogo Y, et al. Neonatal exposure to diethylstilbestrol alters the expression of DNA methyltransferases and methylation of genomic DNA in the epididymis of mice [J]. Endocr, 2006, 53(3):331-337.
70. Wu Q, Ohsako S, Ishimura R, et al. Exposure of mouse preimplantation embryos to 2,
3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) alters the methylation status of imprinted genes H19 and Igf2[J]. Biology of Reproduction, 2004, 70(6):1790-1797.
71. Ho S, TangW, Belmonte de Frausto J, Prins G. Developmental exposure to estradiol and bisphenol a increases susceptibility to prostate carcinogenesis and epigenetically1regulates phosphodiesterase type 4 variant 4[J]. Cancer Res, 2006, 66(11): 5624–5632.
72. Sciandrelo G, Caradonna F, Mauro M, et a1.Amenic-induced DNA hypomethylation afects chromosomal instability inmammulian cells [J]. Carcinogenesis, 2004, 25(3):413-417.
73. Chen Hua, Li Shuangfang, Liu Jie, et a1.Chronic inorganic arsenic expose induces hepatic global and individual gene hypomethylation: implications for arsenic hepatocarcinogenesis [J]. Carcinogenesis, 2004, 25(9):1779-1786.
74.雷毅雄, Joseph P,吴中亮,等.镉转化细胞DNA异常甲基化对肿瘤相关基因表达的影响[J].中华劳动卫生职业病杂志, 2003, 21(2):114-116.
75. Tao L, Yang S, Xie M. Effect of Irichl0r0ethylene and its metatocites, dichloroacetic acid and expression of c-jun and c-myc protooncogenesis in mouse liver prevention by methionine.[J].Toxicol Sci,2000,54(2):399-407.
76. Weihrauch M, Benicke M, Lehnert G, et a1. Frequent k-ras-2 mutations and p16 (1NK4A) methylation in hepatocellular carcinomas in workers exposed to vinyl chloride.[J]. Cancer, 2001, 84(7):982-989.
77. Yoder JA, Bestor TH. A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast [J]. Hum Mol Genet, 1998; 7(2):279-284.
78. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development [J]. Cell, 1999, 99(3):247-257.
79. Walsh CP, Chaillet JR, Bestor TH.Transcription of IAP endogenous retroviruses is constrained by cytosine methylation [J]. Nat Genet, 1998, 20(2):116-117.
80. Frommer M, McDonald LE, Millar DS, et al. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands [J]. Proc Natl Acad, 1992, 89(5):1827-1831.
81. Clark SJ, Harrison J, Paul CL, Frommer M. High sensitivity mapping of methylated cytosines [J]. Nucleic Acids Res, 1994, 22(15):2990-2997.
82.沈佳尧,侯鹏,祭美菊,等. DNA甲基化方法研究现状[J].生命的化学, 2003, 23(2):149-151.
1. Lorincz MC, Dickerson DR, Schmitt M, Groudine M. Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells [J]. Nat Struct Mol Biol, 2004, 11(11):1068-1075.
2. Paulsen M, Ferguson-Smith AC. DNA methylation in genomic imprinting, development, and disease [J]. J Pathol, 2001, 195(1):97-110
3. Kass SU, Wolffe AP. DNA methylation, nucleosomes and the inheritance of chromatin structure and function [J]. Novartis Found Symp, 1998, 214:22-35.
4. Bird A. The essentials of DNA methylation [J].Cell, 1992, 70(1):461-467.
5. Ahmad I, Rao DN. Chemistry and biology of DNA methyltransferases [J]. Crit Rev Biochem Mol Biol, 1996, 31(5-6):361-380.
6. Vertino PM, Yen RW, Gao J, et al. De novo methylation of CpG islands sequences in human fibroblasts overexpressing DNA (cytosine-5)-methyltransferase [J]. Mol Cell Biol, 1996, 16 (8):45-55.
7. Takai D, Jones PA. Comprehensive analysis of CpG islands in human chromosomes 21and 22 [J].Proc Nail Acad Sci USA, 2002, 99(6):3740-3745.
8. Saxonov S, Berg P, Douglas L. Brutlag A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters [J]. Proc Natl Acad Sci, 2006, 103(5):1412-1417.
9. Mehrnaz Fatemi, Martha M. Pao, Shinwu Jeong, Einav Nili Gal-Yam, Gerda Egger, Daniel J. Weisenberger, Peter A Jones. Footprinting of mammalian promoters: use of a CpG DNA methyltransferase revealing nucleosome positions at a single molecule level[J] Nucleic Acids Res, 2005, 33(20):e176.
10. Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics [J]. Science, 2001, 293(5532):1068-1070.
11. Yoder JA, Walsh CP, Bestor TH. Cytosine methylation and the ecology of intragenomic parasites [J]. Trends Genet, 1997, 13(8):335-340.
12. Walsh CP. Chaillet JR, Bestor TH. Tran scription of IAP endoge nous retroviruses is consained by cytosine methylation [J].NatGenet, 1998, 20(2):116-117.
13. Bird AP. Gene number noise reduction and biological complexity [J].Trends Genet,1995,11(3):94-100.
14. Jones PA.The DNA methylation paradox [J].Trends Genet, 1999, 15(1):34-37.
15. Kaneda A, Kaminishi M, Yanagihara K, Sugimura T, Ushijima T. Identification of silencing of nine genes in human gastric cancer[J].Cancer Res,2002,62(22):6645-6650.
16.沈珝琲.染色质与基因活化[J].中国医学科学学院学报, 2000, 22:403-406.
17. N H, Zhang Y, Hendrich B, et a1. MBD2 is a transcriptional repressor belonging to the MeCP 1 histone deacetylase complex [J].Nat Genet,J 1999,23 (1):58-61.
18. Ding F, Chaillet JR. In vitro stabilization of the Dnmt1 (cytosine-5)-methyltransferase protein [J]. PNAS, 2002, 99(23):14861-14866.
19. Robert MF, Morin S, Beaulieu N, Gauthier F, Chute IC, Barsalou A, MacLeod AR. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells [J]. Nature Genetics, 2003, 33(1):61-65.
20. Farrellw E, Claytonr N. Molecular pathogenesis of pituitary tumors [J].Front Neuroendocrinol, 2000, 21 (3):174-198.
21. Chedin F, Lieber MR, Hsieh CL.The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a[J]. Proc Natl Acad Sci USA, 2002, 99(26):16916-16921.
22. Chih-Lin, Hsieh. In vitro activity of murine denovo methyltransferases, Dnmt3a and Dnmt3b [J]. Mol Cell Biol, 1999, 19(12):8211-8218.
23. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for denovo methylation and mammalian development [J].Cell,1999, 99(3):247-57.
24. Lehnertz B, Ueda Y, Derijck A A, et a1.Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin [J].Curr Bio1.2003.13(14):1192-1200.
25. Wolffe AP, Jones PL, Wade PA. DNA demethylation.[J].Proc Natl Acod Sci,1999, 96(11):5894-5896.
26. Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E, Sasaki H. Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting [J]. Nature, 2004, 429(6994):900-903.
27. Matthew D. Anway, Stephen S. Rekow, Michael K. Skinner.Transgenerational epigenetic programming of the embryonic testis transcriptome [J]. Genomics, 2008, 91(1):30-40.
28. Liebestor TH, Jaenisch R. Targeted mutation of the DNA methyltra feras gene results in embryonic lethality [J].Cell, 1992, 69:915-926.
29. Okano M, Bell DW, Haber DA, et a1. DNA methyltransferases Dnmt 3a and Dnmt3b are essential for denovo methylation and mammalian development [J]. Cell, l999, 99: 217-257.
30. Balestar E, Esteler M. The impact of chromatin in human cancer: linking DNA methylation to gene silencing [J].Carcinogenesis, 2002, 23(7):1103-1109.
31. Hendrich B, Methylation moves into medicine [J]. Curr Biol, 2000, 10(2):R60-3.
32. Robertson KD, Wolffe AP, DNA methylation in health and disease [J]. Nat Rev Genet, 2000, 1(1):11-19.
33. Chen JX, Zheng Y, West M, Tang MS. Carcinogen spreferentially bind at methylated CpG in The p53 mutational hot spots. [J].CancerRes, 1998, 58(10):2070-2075.
34. Cooper DN, Youssoufian H, The CpG dinucleotide and human genetic disease [J]. Hum Genet, 1988, 78(2):151-155.
35. Wong E, Yang K, Kuraguchi M, Werling U, Avdievich E, Fan K, Fazzari M, Jin B, Brown AM, Lipkin M, Edelmann W, Mbd4 inactivation increases Cright-arrowT transition mutations and promotes gastrointestinal tumor formation [J]. Proc Natl Acad Sci, 2002, 99(23):14937-14942.
36. Esteller M, González S, Risques RA, Marcuello E, Mangues R, GermàJR, Herman JG, CapellàG, Peinado MA. K-ras and p16 aberrations confer poor prognosis in human colorectal cancer [J] Clin Oncol 2001, 19(2):299-304.
37. Esteller M, Risques RA, Toyota M, Capella G, Moreno V, Peinado MA, Baylin SB, Herman JG. Promoter hypermethylation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase is associated with the presence of G:C to A:T transition mutations in p53 in human colorectal tumorigenesis[J]. Cancer Res, 2001, 61(12):4689-4692.
38. Xu GL, Bestor TH, Bourc’his D, et a1. Chromosome instability and immunodeficiencysyndrome caused by mutations in a DNA methyltransferase gene[J]. Nature, 1999, 402(6758):187-191.
39. Bachman KE, Rountree MR, Baylin SB. Dnmt3a and Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin. [J] Biol Chem, 2001, 276(34):32282-32287.
40. Tate PH, Bird AP. Effects of DNA methylation on DNA-binding proteins and gene expression [J]. Curr Opin Genet Dev, 1993; 3(2):226-231.
41. Fan G, Hutnick L. Methyl-CpG binding proteins in the nervous system [J]. Cell Res, 2005, 15(4):255-261.
42. Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators Trends [J]. Biochem Sci. 2006, 31(2):89-97.
43. Nan X, Ng HH, Johnson CA, et a1. A transcriptional repression by the Methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex [J].Nanture, 1998, 393(6683):386-389.
44. Jones PL, Veenstra GJ, Wade PA, et a1. Methylated DNA and MeCP2 recruit histone deaeetylase to repress transprition [J].Nat Genet, 1998, 19(2):187-191.
45.杨建平,朱志良,袁建辉,庄志雄. DNA甲基化在毒理学中的应用前景[J].环境与职业医学,2007,24(5):546-549.
46. Hua Naranmandura, Noriyuki Suzuki, Kazuo T, Suzuki. Trivalent arsenicals are bound to proteins during reductive methylation [J]. Chemical research in toxicology, 2006, 19 (8):1010–1018.
47. Wilson VL, Jones PA. Inhibition of DNA methylation by chemical carcinogens in vitro [J]. Cell, 1983, 32(1):239-246.
48. Ho S, TangW, Belmonte de Frausto J, Prins G. Developmental exposure to estradiol and bisphenol a increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4[J]. Cancer Res, 2006; 66(11):5624-5632.
49. Sciandrelo G, Caradonna F, Mauro M, et a1. Amenic-induced DNA hypomethylation afects chromosomal instability inmammulian cells [J]. Carcinogenesis, 2004, 25(3):413-417.
50. Chen H, Li S, Liu J, Diwan BA, Barrett JC, Waalkes MP. Chronic inorganic arsenicexpose induces hepatic global and individual gene hypomethylation: implications for arsenic hepatocarcinogenesis [J]. Carcinogenesis, 2004, 25(9):1779-1786.
51. Watson R E, Curtin G M, Doolitfle DJ, et al. Progressive alterations in obal and GC rich DNA methylation during tumorigenesis [J]. Toxicological Sciences, 2003, 75(2):289-299.
52. Davis CD, Uthus EO, Finley JW. Dietary selenium and arsenic affect DNA methylation in vitro in Caco-2 ceilsan d in vitro in rat liver and colon [J].Nutri, 2000, 130(12):2903-2909.
53. Desaulniers GH, Xiao K, Leingartner Chu, Musicki, B K Tsang. Comparisons of brain, uterus, and liver mRNA expression for cytochrome P450s, DNA methyltransferase-1, and Catechol-O-Methyltransferase in prepubertal female Sprague-Dawley rats exposed to a mixture of Aryl Hydrocarbon Receptor Agonists. Toxicological [J] Sciences, 2005, 86(1):175-184.
54. Sato K, Fukata H, Kogo Y, et a1. Neonatal exposure to diethylstilbestrol alters the expression of DNA methyltransferases and methylation of genomic DNA in the epididymis of mice [J]. Endocr, 2006, 53(3):331-337.
55. Jenkins S, Rowell C, Wang J, Lamartiniere CA. Prenatal TCDD exposure predisposes for mammary cancer in rats [J]. Reprod Toxicol, 2007, 23(3):391-396.
56. Wu Q, Ohsako S, Ishimura R, Suzuki JS, Tohyama C..Exposure of mouse preimplantation embryos to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) alters the methylation status of imprinted genes H19 and Igf2[J]. Biol Reprod, 2004, 70(6):1790-1797.
57. Fang M, Chen D, Yang CS. Dietary polyphenols may affect DNA methylation [J]. Nutrition, 2007, 137(1 Suppl):223S-228S
58. Poirier LA, Vlasova TI. The prospective role of abnormal methyl metabolism in cadmium toxicity [J]. Environ Health Perspect, 2002, 110(Suppl 5):793-795.
59. Sadikovic B, Andrews J, Rodenhiser DI. DNA methylation analysis using CpG microarrays is impaired in benzopyrene exposed cells [J]. Toxicol Appl Pharmacol, 2007, 225(3):300-309.
60. Leah A, Damiani1, Christin M, et a1. Carcinogen-induced gene promoterhypermethylation is mediated by Dnmt1 and causal for transformation of immortalized bronchial epithelial cells [J]. Cancer Res, 2008; 68(21):9005-9014.
61. Ruchirawat M, Becker FF, Lapeyre JN. Mechanism of rat liver DNA methyltransferase interraction with anti-benzo[a]pyrenediol epoxide modified DNA templates [J]. Biochemistry, 1984, 23(23):5426-5432.
62. Panayiotidis MI, Rancourt RC, Allen CB, et a1. Hyperoxia-induced DNA damage causes decreased DNA methylation in human lung epithelial-like A549 cells [J]. Antioxid Redox Signal, 2004, 6(1):129-136.
63. Pfohl-Leszkowicz A, Fuchs RP, Keith G, Dirheimer G.. Enzymatic methylation of chicken erythrocyte DNA modified by two carcinogens,2-(N-acetoxyacetylamino) fluorene and methylnitrosourea[J]. Recent Results Cancer Res, 1983, 84:193-201.
64. Hassa PO, Hottiger MO.An epigenetic code for DNA damage repair pathways? [J].Biochem Cell Biol, 2005, 83(3):270-85.
65. Goodman JI, Watson RE. Altered DNA methylation: a secondary mechanism involved in carcinogenesis [J]. Annu Rev Pharmacol Toxicol, 2002; 42:501-525.
66.雷毅雄, Joseph P,吴中亮,等.镉转化细胞DNA异常甲基化对肿瘤相关基因表达的影响.中华劳动卫生职业病杂志, 2003,21(2):114-116.
67. Hua Chen, Kaoru Yoshida, Hideki Wanibuchi, et a1. Methylation and demethylation of dimethylarsinic acid in rats following chronic oral exposure [J]. Applied organometallic chemistry, 1996, 10(9):741-745.
68. Corinne R, Lehr, Elena Polishchuk, Una Radoja, William R. Demethylation of methylarsenic species by Mycobacterium neoaurum Environment[J]. Biology and Toxicology, 2003, 17(11):831-834.
69. Tao L, Yang S, Xie M, Kramer PM, Pereira MA. Effect of trichloroethylene and its metatocites, dichloroacetic acid and expression of c-jun and c-myc protooncogenesis in mouse liver prevention by methionine [J].Toxicol Sci, 2000,54(2):399-407.
70. Weihrauch M, Benicke M, Lehnert G, et a1. Frequent k-ras-2 mutations and p16(1NK4A) methylation in hepatocellular carcinomas in workers exposed to vinyl chloride [J]. Cancer, 2001, 84(7):982-989.
2.边晓燕,吴振铎,李红,等.氟对大鼠肝细胞影响及SOD阻断因子的透射电镜研究[J].中国地方病学杂志, 1993, 12(3):136-137.
3.李键学,全笑江,吴云鹏.氟对大鼠肝、肾、脑细胞活性氧代谢的影响.中国氟研究文选[C]:73-75.
4.卜丽莎,张文岚,薄立华,尹文京,李广生.过量氟对大鼠肝细胞内钙水平和肝细胞凋亡的影响[J].中国地方病防治杂志, 2003, 18(5):257-259.
5. Zhan XA, Wang M, Xu ZR, Li WF, Li JX. Evaluation of caspase-dependent apoptosis during fluoride-induced liver lesion in pigs [J]. Archives of Toxicology, 2006, 80(2):74-80.
6.井玲,邵宗俊,任立群,李广生.氟中毒大鼠肝细胞凋亡研究[J].中国地方病学杂志,1999,18(2):84-86.
7.王爱国,夏涛,褚启龙,刘方,张明,杨克敌.氟对人胚肝细胞DNA损伤及凋亡的影响[J].中国公共卫生, 2004, 20(2):159-160.
8. Hiraku Y, Kawanishi S. Oxidative DNA Damage and Apoptosis Induced by Benzene Metabolites [J].Cancer Research, 1996, 56(22):5172-5178.
9. Amendola R, Bellini A, Cervelli M, Degan P, Marcocci L, Martini F, Mariottini P. Direct oxidative DNA damage, apoptosis and radio sensitivity by spermine oxidase activitie in mouse neuroblastoma cells [J]. Biochim Biophys Acta, 2005, 1755(1): 15-24.
10. Müller I, Jenner A, Bruchelt G, Niethammer D, Halliwell B. Effect of concentration on the cytotoxic mechanism of doxorubicin apoptosis and oxidative DNA damage [J]. Biochem Biophys Res Commun, 1997, 230(2): 254-257.
11. Chen X, Yang CS. Esophageal adenocarcinoma: a review and perspectives on the mechanism of carcinogenesis and chemoprevention [J]. Carcinogenesis, 2001, 22(8):1119-1129.
12. Hoffman GE, Smith MS, Verbalis JG. c-fos and related immediate early gene products as markers of activity in neuroendocrine systems[J]. Front Neuroendocrinol, 1993, 14(3):173-213.
13. Takeuehi K, Nakamura N, Cook NS, et al. AngiotensinⅡcan regulate gene expression by the AP-1 binding sequence via a protein kinase c-dependent pathway [J].Biochem Biophys Res Commun, 1990, 172(3): 1189-1194.
14.余日安,马良,陈学敏.硒对大鼠肝细胞凋亡和原癌基因c-myc、c-fos和c-jun表达的影响.卫生毒理学杂志[J]. 2004, 18(2):68-70.
15.王兰,王红梅,张建龙,孙湛.大鼠肝缺血再灌注损伤时c-fos、Bcl-2在肝组织的表达及与肝细胞凋亡的关系[J].新疆医科大学学报, 2005, 28(4): 344-346.
16.张文岚,崔亚南,高申,张秀云,李广生.过量摄入氟后激活的成骨细胞系中原癌基因的表达.[J].中华预防医学杂志, 2003, 37(4): 246-250.
17.陈璐璐,童安莉,余达林,陈荣安. NaF对乳鼠成骨细胞c-fos、c-jun基因表达及细胞增殖的影响[J].中华预防医学杂志, 2000, 34(6):327-329.
18. Gilman MZ, Wilson RN, Weinberg RA. Multiple protein-binding sites in the
5'-flanking region regulate c-fos expression [J]. Mol Cell Biol. 1986, 6(12): 4305-4316.
19. Uehara Y, Ono T, Kurishita A, Kokuryu H, Okada S. Age-dependent and tissue-specific changes of DNA methylation within and around the c-fos gene in mice [J]. Oncogene, 1989, 4(8):1023-8.
20. Greenberg ME, Siegfried Z, Ziff EB. Mutation of the c-fos gene dyad symmetry element inhibits serum inducibility of transcription in vitro and the nuclear regulatory factor binding in vitro [J]. Mol Cell Biol, 1987, 7(3): 1217-1225.
21. Bernd Kaina, Simone Haas, Holger Kappes. A General Role for c-fos in Cellular Protection against DNA-damaging Carcinogens and Cytostatic Drugs [J]. Cancer Research, 1997, 57(13): 2721-2731.
22. Shimizu K, Onishi M, Sugata E, Sokuza Y, Mori C, Nishikawa T, Honoki K, Tsujiuchi T. Disturbance of DNA methylation patterns in the early phase of hepatocarcinogenesis induced by a choline-deficient L-amino acid-defined diet in rats [J]. Cancer Sci, 2007,
98(9):1318-1322.
23. Choi EK, Uyeno S, Nishida N, et a1. On alterations of c-fos gene methylation in the processes of aging and tumorigenesis in human liver [J]. Mutation Research, 1996,354(1):123-128.
24. Counts JL, Sarmiento JI, Harbison ML, et a1. Cell proliferation and global methylation status changes in mouse liver after phenobarbital and/or choline-devoid,methionine deficient diet administration[J]. Carcinogenesis, 1996, 17(6):1251-1257.
25. Tao L, Yang S, Xie M, et a1. Effect of trichloroethylene and its metabolites, dichloroacetic acid and trichloroacetic acid, on the methylation and expression of c-jun and c-myc protooncogenes in mouse liver: prevention by methionine [J]. Toxieol Sci, 2000, 54(2):399-407.
26. Tao L, Wang W, Li L, et a1. DNA hypomethylation induced by drinking water disinfection by-products in mouse and rat kidney [J].Toxicol Sci, 2005, 87(2):344-352.
27.刘莉莉,陈家垄,安社娟,等.结晶型硫化镍及反式-BPDE恶性转化16HB细hMSH2基因甲基化的研究[J].癌变·畸变·突变, 2005, 17(3):129-132.
28. Thrane EV, Refsnes M, Thoresen GH, et al. Fluoride-induced apoptosis in epithelial lung cells involves activation of MAP kinases p38 and possibly JNK [J]. Toxicol, 2001, 61(1):83-91.
29. Wang AG, Chu QL, He WH, et a1. Effects on protein and mRNA expression levels of p53 induced by fluoride in human embryonic hepatocytes [J]. Toxicol Lett. 2005, 158(2):158-163.
30. Robertson KD, Wolffe AP. DNA methylation in health and disease [J], Nature Reviews Genetics, 2000, 1(1):11-9.
31. Razin A, Riggs AD. DNA methylation and gene function [J]. Science, 1980, 210(4470): 604-610.
32. Doerfler W. DNA Methylation and Cene Activity [J]. Annual Review of Biochemistry, 1983, 52:93-124.
33. Bird A. The essentials of DNA methylation [J].Cell, 1992, 70(l):5-8.
34. Martin JL, McMillan FM. SAM(dependent)IAM: the S-adenosylmethionine-dependent methyltransferase fold[J]. Curr Opin Struct Biol, 2002, 12(6):783-93.
35. Fatemi M, Pao MM, Jeong S, et a1. Footprinting of mammalian promoters: use of aCpG DNA methyltransferase revealing nucleosome positions at a single molecule level[J]. Nucleic Acids Res, 2005, 33 (20): 176.
36. Li E, Bestor, T H, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality [J]. Cell, 1992, 69(6):915–926.
37. Yoder JA, Soman NS, VerdineGL, Bestor TH. DNA (cytosine-5)-methyltransferases in mouse cells and tissues [J]. Mol Biol, 1997, 270:385-395.
38. Yoder JA. A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast [J]. Hum Mol Genet, 1998, 7(2):279-284.
39. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for denovo methylation and mammalian development [J]. Cell, 1999, 99(3):247-257.
40. Walsh CP, Chaillet JR, Bestor TH. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation [J]. Nat Genet, 1998, 20(2):116-117.
41. Bird AP. Gene number, noise reduction and biological complexity [J]. Trends Genet, 1995, 11(3):94-100.
42.尹斌,沈岩. DNA的甲基化修饰与DNA甲基转移酶[J].国外医学遗传学分册, 2001, 24(1):5-8.
43. Clark SJ, Melki J. DNA methylation and gene silencing in cancer: which is the guilty party?[J]. Oncogene, 2002, 21(35):5380-5387.
44. Bestor TH. Gene silencing, methylation meets acetylation [J]. Nature, 1998, 393(6683): 311-312.
45.司徒镇强,吴军正主编,细胞培养.世界图书出版公司, 1996:186-187.
46. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics [J]. Cancer, 1972, 26(4): 239–257.
47. Najimi M. Hepatocyte apoptosis [J]. Methods Mol Biol.2009, 481:59-74.
48. Tung JW, Heydari K, Tirouvanziam R, et a1. Modern flow cytometry: a practical approach [J]. Clin Lab Med. 2007, 27(3): 453-468.
49. Goto S, Matsumoto I, Kamada N, et a1. The induction of immediate early genes in postischemic and transplanted liver in rats, Its relation to organ survival [J]. Transplantation, 1994, 58(7):840 -845.
50. Estus S, Zaks WJ, Freeman RS, Gruda M, Bravo R, Johnson EM Jr. Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis [J]. Cell Biol, 1994, 127(6): 1717-1727.
51. Teruaki Sakurai, Toshikazu Kaise, Chiyo Matsubara. Inorganic and Methylated Arsenic Compounds Induce Cell Death in Murine Macrophages via Different Mechanisms [J].Chem. Res. Toxicol, 1998, 11 (4):273–283.
52. Ferret B, Hubsch A, Dreyfus H, Massarelli R. Exogenous gangliosides may affect methylation mechanisms in neuronal cell cultures [J].Neurochemical Research.1991, 16(2):137-144.
53. Beator TH, Cloning of a mammalian DNA methyltransferase [J]. Gene, 1988, 74(1):9-12.
54. Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases[J]. Nat Genet, 1998, 19(3):210- 220.
55. Desaulniers D, Xiao GH, Leingartner K, Chu I, Musicki B, Tsang BK. Comparisons of brain, uterus, and liver mRNA expression for cytochrome P450s, DNA methyltransferase-1, and Catechol-O-Methyltransferase in prepubertal female Sprague-Dawley rats exposed to a mixture of Aryl Hydrocarbon Receptor Agonists[J]. Toxicological Sciences, 2005, 86(1):175-184.
56. Sato K, Fukata H, Kogo Y, et al. Neonatal exposure to diethylstilbestrol alters the expression of DNA methyltransferases and methylation of genomic DNA in the epididymis of mice [J]. Endocr, 2006, 53(3):331-337.
57. Jenkins S, Rowell C, Wang J, Lamartiniere CA. Prenatal TCDD exposure predisposes for mammary cancer in rats [J]. Reprod Toxicol, 2007, 23(3):391-396.
58. Yen RW, Vertino PM, Nelkin BD, et al. Isolation and characterization of the cDNA encoding human DNA methyltransferase[J].Nucleic Acids Res, 1992,20 (9):2287-2291.
59. Tucker KL, Talbot D, Lee MA, Leonhardt H, Jaenisch R. Complementation of methylation deficiency in embryonic stem cells by a DNA methyltransferase minigene [J]. Proc Natl Acad Sci USA, 1996; 93(25):12920-12925.
60. Babinger P, Volkl R, Cakstina I, et al. Maintenance DNA methyltransferase(Metl) and silencing of CpG-methylated foreign DNA in Volvox carteri[J].Plant Mol Biol, 2007,63:325-336.
61. Hansen RS, Wijmenga C, Luo P, et al. The Dnmt3b DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome [J]. Proc Nat Acad Sci, 1999, 96(25):14412.
62. Rountree MR, Bachman KE, Baylin SB. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci [J]. Nat Genet, 2000, 25(3):269-277.
63. Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP. DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters [J]. Nat Genet, 2000, 25(3):338-342.
64. Nielsen SJ, Schneider R, Bauer UM, Bannister AJ, Morrison A, O’Carroll D, Firesteink R, Clearyk M, Jenuwein T, Herrera RE, Kouzarides T. Rb targets histone H3 methylation and HP1 to promoters[J]. Nature, 2001, 412(6846):561-565.
65. Zhang HS, Dean DC. Rb-mediated chromatin structure regulation and transcriptional repression [J]. Oncogene, 2001, 20(24):3134-3138.
66. Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T. Retinoblastoma protein recruits histone deacetylase to repress transcription[J]. Nature, 1998, 391(6667):597-601.
67. Rountree MR, Bachman KE, Herman JG, et al. DNA methylation, chromatin inheritance, and caner[J].Oncogene, 2001, 20(24):3156.
68.许军,樊红,赵主江,张建琼,谢维. RNAi及DNA芯片分析肝癌细胞系中受Dnmt3b调控的下游基因[J].遗传学报,2005年,32(11):1115-1127.
69. Sato K, Fukata H, Kogo Y, et al. Neonatal exposure to diethylstilbestrol alters the expression of DNA methyltransferases and methylation of genomic DNA in the epididymis of mice [J]. Endocr, 2006, 53(3):331-337.
70. Wu Q, Ohsako S, Ishimura R, et al. Exposure of mouse preimplantation embryos to 2,
3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) alters the methylation status of imprinted genes H19 and Igf2[J]. Biology of Reproduction, 2004, 70(6):1790-1797.
71. Ho S, TangW, Belmonte de Frausto J, Prins G. Developmental exposure to estradiol and bisphenol a increases susceptibility to prostate carcinogenesis and epigenetically1regulates phosphodiesterase type 4 variant 4[J]. Cancer Res, 2006, 66(11): 5624–5632.
72. Sciandrelo G, Caradonna F, Mauro M, et a1.Amenic-induced DNA hypomethylation afects chromosomal instability inmammulian cells [J]. Carcinogenesis, 2004, 25(3):413-417.
73. Chen Hua, Li Shuangfang, Liu Jie, et a1.Chronic inorganic arsenic expose induces hepatic global and individual gene hypomethylation: implications for arsenic hepatocarcinogenesis [J]. Carcinogenesis, 2004, 25(9):1779-1786.
74.雷毅雄, Joseph P,吴中亮,等.镉转化细胞DNA异常甲基化对肿瘤相关基因表达的影响[J].中华劳动卫生职业病杂志, 2003, 21(2):114-116.
75. Tao L, Yang S, Xie M. Effect of Irichl0r0ethylene and its metatocites, dichloroacetic acid and expression of c-jun and c-myc protooncogenesis in mouse liver prevention by methionine.[J].Toxicol Sci,2000,54(2):399-407.
76. Weihrauch M, Benicke M, Lehnert G, et a1. Frequent k-ras-2 mutations and p16 (1NK4A) methylation in hepatocellular carcinomas in workers exposed to vinyl chloride.[J]. Cancer, 2001, 84(7):982-989.
77. Yoder JA, Bestor TH. A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast [J]. Hum Mol Genet, 1998; 7(2):279-284.
78. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development [J]. Cell, 1999, 99(3):247-257.
79. Walsh CP, Chaillet JR, Bestor TH.Transcription of IAP endogenous retroviruses is constrained by cytosine methylation [J]. Nat Genet, 1998, 20(2):116-117.
80. Frommer M, McDonald LE, Millar DS, et al. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands [J]. Proc Natl Acad, 1992, 89(5):1827-1831.
81. Clark SJ, Harrison J, Paul CL, Frommer M. High sensitivity mapping of methylated cytosines [J]. Nucleic Acids Res, 1994, 22(15):2990-2997.
82.沈佳尧,侯鹏,祭美菊,等. DNA甲基化方法研究现状[J].生命的化学, 2003, 23(2):149-151.
1. Lorincz MC, Dickerson DR, Schmitt M, Groudine M. Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells [J]. Nat Struct Mol Biol, 2004, 11(11):1068-1075.
2. Paulsen M, Ferguson-Smith AC. DNA methylation in genomic imprinting, development, and disease [J]. J Pathol, 2001, 195(1):97-110
3. Kass SU, Wolffe AP. DNA methylation, nucleosomes and the inheritance of chromatin structure and function [J]. Novartis Found Symp, 1998, 214:22-35.
4. Bird A. The essentials of DNA methylation [J].Cell, 1992, 70(1):461-467.
5. Ahmad I, Rao DN. Chemistry and biology of DNA methyltransferases [J]. Crit Rev Biochem Mol Biol, 1996, 31(5-6):361-380.
6. Vertino PM, Yen RW, Gao J, et al. De novo methylation of CpG islands sequences in human fibroblasts overexpressing DNA (cytosine-5)-methyltransferase [J]. Mol Cell Biol, 1996, 16 (8):45-55.
7. Takai D, Jones PA. Comprehensive analysis of CpG islands in human chromosomes 21and 22 [J].Proc Nail Acad Sci USA, 2002, 99(6):3740-3745.
8. Saxonov S, Berg P, Douglas L. Brutlag A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters [J]. Proc Natl Acad Sci, 2006, 103(5):1412-1417.
9. Mehrnaz Fatemi, Martha M. Pao, Shinwu Jeong, Einav Nili Gal-Yam, Gerda Egger, Daniel J. Weisenberger, Peter A Jones. Footprinting of mammalian promoters: use of a CpG DNA methyltransferase revealing nucleosome positions at a single molecule level[J] Nucleic Acids Res, 2005, 33(20):e176.
10. Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics [J]. Science, 2001, 293(5532):1068-1070.
11. Yoder JA, Walsh CP, Bestor TH. Cytosine methylation and the ecology of intragenomic parasites [J]. Trends Genet, 1997, 13(8):335-340.
12. Walsh CP. Chaillet JR, Bestor TH. Tran scription of IAP endoge nous retroviruses is consained by cytosine methylation [J].NatGenet, 1998, 20(2):116-117.
13. Bird AP. Gene number noise reduction and biological complexity [J].Trends Genet,1995,11(3):94-100.
14. Jones PA.The DNA methylation paradox [J].Trends Genet, 1999, 15(1):34-37.
15. Kaneda A, Kaminishi M, Yanagihara K, Sugimura T, Ushijima T. Identification of silencing of nine genes in human gastric cancer[J].Cancer Res,2002,62(22):6645-6650.
16.沈珝琲.染色质与基因活化[J].中国医学科学学院学报, 2000, 22:403-406.
17. N H, Zhang Y, Hendrich B, et a1. MBD2 is a transcriptional repressor belonging to the MeCP 1 histone deacetylase complex [J].Nat Genet,J 1999,23 (1):58-61.
18. Ding F, Chaillet JR. In vitro stabilization of the Dnmt1 (cytosine-5)-methyltransferase protein [J]. PNAS, 2002, 99(23):14861-14866.
19. Robert MF, Morin S, Beaulieu N, Gauthier F, Chute IC, Barsalou A, MacLeod AR. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells [J]. Nature Genetics, 2003, 33(1):61-65.
20. Farrellw E, Claytonr N. Molecular pathogenesis of pituitary tumors [J].Front Neuroendocrinol, 2000, 21 (3):174-198.
21. Chedin F, Lieber MR, Hsieh CL.The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a[J]. Proc Natl Acad Sci USA, 2002, 99(26):16916-16921.
22. Chih-Lin, Hsieh. In vitro activity of murine denovo methyltransferases, Dnmt3a and Dnmt3b [J]. Mol Cell Biol, 1999, 19(12):8211-8218.
23. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for denovo methylation and mammalian development [J].Cell,1999, 99(3):247-57.
24. Lehnertz B, Ueda Y, Derijck A A, et a1.Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin [J].Curr Bio1.2003.13(14):1192-1200.
25. Wolffe AP, Jones PL, Wade PA. DNA demethylation.[J].Proc Natl Acod Sci,1999, 96(11):5894-5896.
26. Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E, Sasaki H. Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting [J]. Nature, 2004, 429(6994):900-903.
27. Matthew D. Anway, Stephen S. Rekow, Michael K. Skinner.Transgenerational epigenetic programming of the embryonic testis transcriptome [J]. Genomics, 2008, 91(1):30-40.
28. Liebestor TH, Jaenisch R. Targeted mutation of the DNA methyltra feras gene results in embryonic lethality [J].Cell, 1992, 69:915-926.
29. Okano M, Bell DW, Haber DA, et a1. DNA methyltransferases Dnmt 3a and Dnmt3b are essential for denovo methylation and mammalian development [J]. Cell, l999, 99: 217-257.
30. Balestar E, Esteler M. The impact of chromatin in human cancer: linking DNA methylation to gene silencing [J].Carcinogenesis, 2002, 23(7):1103-1109.
31. Hendrich B, Methylation moves into medicine [J]. Curr Biol, 2000, 10(2):R60-3.
32. Robertson KD, Wolffe AP, DNA methylation in health and disease [J]. Nat Rev Genet, 2000, 1(1):11-19.
33. Chen JX, Zheng Y, West M, Tang MS. Carcinogen spreferentially bind at methylated CpG in The p53 mutational hot spots. [J].CancerRes, 1998, 58(10):2070-2075.
34. Cooper DN, Youssoufian H, The CpG dinucleotide and human genetic disease [J]. Hum Genet, 1988, 78(2):151-155.
35. Wong E, Yang K, Kuraguchi M, Werling U, Avdievich E, Fan K, Fazzari M, Jin B, Brown AM, Lipkin M, Edelmann W, Mbd4 inactivation increases Cright-arrowT transition mutations and promotes gastrointestinal tumor formation [J]. Proc Natl Acad Sci, 2002, 99(23):14937-14942.
36. Esteller M, González S, Risques RA, Marcuello E, Mangues R, GermàJR, Herman JG, CapellàG, Peinado MA. K-ras and p16 aberrations confer poor prognosis in human colorectal cancer [J] Clin Oncol 2001, 19(2):299-304.
37. Esteller M, Risques RA, Toyota M, Capella G, Moreno V, Peinado MA, Baylin SB, Herman JG. Promoter hypermethylation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase is associated with the presence of G:C to A:T transition mutations in p53 in human colorectal tumorigenesis[J]. Cancer Res, 2001, 61(12):4689-4692.
38. Xu GL, Bestor TH, Bourc’his D, et a1. Chromosome instability and immunodeficiencysyndrome caused by mutations in a DNA methyltransferase gene[J]. Nature, 1999, 402(6758):187-191.
39. Bachman KE, Rountree MR, Baylin SB. Dnmt3a and Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin. [J] Biol Chem, 2001, 276(34):32282-32287.
40. Tate PH, Bird AP. Effects of DNA methylation on DNA-binding proteins and gene expression [J]. Curr Opin Genet Dev, 1993; 3(2):226-231.
41. Fan G, Hutnick L. Methyl-CpG binding proteins in the nervous system [J]. Cell Res, 2005, 15(4):255-261.
42. Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators Trends [J]. Biochem Sci. 2006, 31(2):89-97.
43. Nan X, Ng HH, Johnson CA, et a1. A transcriptional repression by the Methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex [J].Nanture, 1998, 393(6683):386-389.
44. Jones PL, Veenstra GJ, Wade PA, et a1. Methylated DNA and MeCP2 recruit histone deaeetylase to repress transprition [J].Nat Genet, 1998, 19(2):187-191.
45.杨建平,朱志良,袁建辉,庄志雄. DNA甲基化在毒理学中的应用前景[J].环境与职业医学,2007,24(5):546-549.
46. Hua Naranmandura, Noriyuki Suzuki, Kazuo T, Suzuki. Trivalent arsenicals are bound to proteins during reductive methylation [J]. Chemical research in toxicology, 2006, 19 (8):1010–1018.
47. Wilson VL, Jones PA. Inhibition of DNA methylation by chemical carcinogens in vitro [J]. Cell, 1983, 32(1):239-246.
48. Ho S, TangW, Belmonte de Frausto J, Prins G. Developmental exposure to estradiol and bisphenol a increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4[J]. Cancer Res, 2006; 66(11):5624-5632.
49. Sciandrelo G, Caradonna F, Mauro M, et a1. Amenic-induced DNA hypomethylation afects chromosomal instability inmammulian cells [J]. Carcinogenesis, 2004, 25(3):413-417.
50. Chen H, Li S, Liu J, Diwan BA, Barrett JC, Waalkes MP. Chronic inorganic arsenicexpose induces hepatic global and individual gene hypomethylation: implications for arsenic hepatocarcinogenesis [J]. Carcinogenesis, 2004, 25(9):1779-1786.
51. Watson R E, Curtin G M, Doolitfle DJ, et al. Progressive alterations in obal and GC rich DNA methylation during tumorigenesis [J]. Toxicological Sciences, 2003, 75(2):289-299.
52. Davis CD, Uthus EO, Finley JW. Dietary selenium and arsenic affect DNA methylation in vitro in Caco-2 ceilsan d in vitro in rat liver and colon [J].Nutri, 2000, 130(12):2903-2909.
53. Desaulniers GH, Xiao K, Leingartner Chu, Musicki, B K Tsang. Comparisons of brain, uterus, and liver mRNA expression for cytochrome P450s, DNA methyltransferase-1, and Catechol-O-Methyltransferase in prepubertal female Sprague-Dawley rats exposed to a mixture of Aryl Hydrocarbon Receptor Agonists. Toxicological [J] Sciences, 2005, 86(1):175-184.
54. Sato K, Fukata H, Kogo Y, et a1. Neonatal exposure to diethylstilbestrol alters the expression of DNA methyltransferases and methylation of genomic DNA in the epididymis of mice [J]. Endocr, 2006, 53(3):331-337.
55. Jenkins S, Rowell C, Wang J, Lamartiniere CA. Prenatal TCDD exposure predisposes for mammary cancer in rats [J]. Reprod Toxicol, 2007, 23(3):391-396.
56. Wu Q, Ohsako S, Ishimura R, Suzuki JS, Tohyama C..Exposure of mouse preimplantation embryos to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) alters the methylation status of imprinted genes H19 and Igf2[J]. Biol Reprod, 2004, 70(6):1790-1797.
57. Fang M, Chen D, Yang CS. Dietary polyphenols may affect DNA methylation [J]. Nutrition, 2007, 137(1 Suppl):223S-228S
58. Poirier LA, Vlasova TI. The prospective role of abnormal methyl metabolism in cadmium toxicity [J]. Environ Health Perspect, 2002, 110(Suppl 5):793-795.
59. Sadikovic B, Andrews J, Rodenhiser DI. DNA methylation analysis using CpG microarrays is impaired in benzopyrene exposed cells [J]. Toxicol Appl Pharmacol, 2007, 225(3):300-309.
60. Leah A, Damiani1, Christin M, et a1. Carcinogen-induced gene promoterhypermethylation is mediated by Dnmt1 and causal for transformation of immortalized bronchial epithelial cells [J]. Cancer Res, 2008; 68(21):9005-9014.
61. Ruchirawat M, Becker FF, Lapeyre JN. Mechanism of rat liver DNA methyltransferase interraction with anti-benzo[a]pyrenediol epoxide modified DNA templates [J]. Biochemistry, 1984, 23(23):5426-5432.
62. Panayiotidis MI, Rancourt RC, Allen CB, et a1. Hyperoxia-induced DNA damage causes decreased DNA methylation in human lung epithelial-like A549 cells [J]. Antioxid Redox Signal, 2004, 6(1):129-136.
63. Pfohl-Leszkowicz A, Fuchs RP, Keith G, Dirheimer G.. Enzymatic methylation of chicken erythrocyte DNA modified by two carcinogens,2-(N-acetoxyacetylamino) fluorene and methylnitrosourea[J]. Recent Results Cancer Res, 1983, 84:193-201.
64. Hassa PO, Hottiger MO.An epigenetic code for DNA damage repair pathways? [J].Biochem Cell Biol, 2005, 83(3):270-85.
65. Goodman JI, Watson RE. Altered DNA methylation: a secondary mechanism involved in carcinogenesis [J]. Annu Rev Pharmacol Toxicol, 2002; 42:501-525.
66.雷毅雄, Joseph P,吴中亮,等.镉转化细胞DNA异常甲基化对肿瘤相关基因表达的影响.中华劳动卫生职业病杂志, 2003,21(2):114-116.
67. Hua Chen, Kaoru Yoshida, Hideki Wanibuchi, et a1. Methylation and demethylation of dimethylarsinic acid in rats following chronic oral exposure [J]. Applied organometallic chemistry, 1996, 10(9):741-745.
68. Corinne R, Lehr, Elena Polishchuk, Una Radoja, William R. Demethylation of methylarsenic species by Mycobacterium neoaurum Environment[J]. Biology and Toxicology, 2003, 17(11):831-834.
69. Tao L, Yang S, Xie M, Kramer PM, Pereira MA. Effect of trichloroethylene and its metatocites, dichloroacetic acid and expression of c-jun and c-myc protooncogenesis in mouse liver prevention by methionine [J].Toxicol Sci, 2000,54(2):399-407.
70. Weihrauch M, Benicke M, Lehnert G, et a1. Frequent k-ras-2 mutations and p16(1NK4A) methylation in hepatocellular carcinomas in workers exposed to vinyl chloride [J]. Cancer, 2001, 84(7):982-989.