新生儿出生特征及H19 DNA甲基化与孕期环境暴露关系
|
摘要
DNA甲基化是肿瘤的主要危险因素之一,且许多研究结果显示DNA甲基化模式在胎儿出生时已经形成,印记基因H19(imprinted maternally expressed transcript (non-protein coding))与多种肿瘤的发生相关,在胚胎期表达活跃,且主要受基因甲基化的控制,所以探索生命早期影响胎儿表观遗传(DNA甲基化)的因素,阐明H19甲基化与孕期环境及营养暴露之间的关系,可为肿瘤的预防及早期营养干预提供新的思路。
目的：
探索孕期血液一碳单位营养物(叶酸、维生素B12)、锌以及环境暴露与H19基因甲基化模式及新生儿出生特征之间的关系,为在胎儿期通过营养手段预防肿瘤提供线索。
材料与方法：
1.调查对象的选择：以2008年4月到2008年9月期间在郑州市侯寨中心卫生院分娩的、未患乙肝、糖尿病及其它慢性消化道疾病的(以临床诊断为准)健康母亲作为调查对象,提前告知本课题目的意义并签署知情同意书后,共99名母亲纳入调查范围。
2.资料的收集：根据此次研究的内容详细设计调查问卷(见附件),严格培训调查员并实施预调查后正式开始问卷调查,调查对象的个人信息均严格保密；收集2007年5月到2008年9月当地环保局公布的每周空气污染指数及分指数。
3.新生儿出生特征的测量：用头围尺经颅骨两眼眉弓及枕骨结节测量新生儿头围,用卧式身长计测量新生儿出生身长；用电子秤称量新生儿出生体重。
4.血清中一碳单位营养物及锌的测定：采用Access磁微粒化学发光免疫分析系统测定血清中叶酸、维生素B12；原子吸收法测定血清锌水平。
5.甲基化水平的测定：甲基化特异性荧光定量PCR (quantitativemethylation-specific polymerase chain reaction, QMS-PC R)测定H19基因启动子及差异甲基化区(different methylation region, DMR)甲基化率。6.数据整理和分析：数据录入采用Epidata3.1软件并采用SPSS12.0进行分析。主要分析检验方法有：配对t检验、多元线性回归分析等,检验水准α=0.05。
结果：
1.新生儿出生特征、母体血清营养物含量及产妇孕期环境因素的关系：
(1)新生儿共99例,男孩52例,女孩47例,出生身长为49.48±1.89cm,出生体重为49.48±1.89kg,出生头围为33.83±1.19cm；多元回归分析表明：新生儿出生体重与新生儿性别相关(β=0.198,P=0.046)；出生身长与产妇剖宫产相关(β=0.283,P=0.008)。出生体重、出生身长及出生头围分别与产妇孕前体质指数(body mass Index,BMI)相关(β=-0.198,P=0.046；β=0.336,P=0.003；β=0.314, P=0.012):
(2)产妇静脉血血清及新生儿脐带血血清叶酸水平分别为2.29±2.13ng/ml和7.29±4.80ng/ml,锌水平分别为0.67±0.31μg/ml和0.93±0.37μg/ml,维生素B12水平分别为175.34±154.78pg/ml和240.19±228.56pg/ml,其中,新生儿脐带血血清锌水平高于产妇(t=-5.551,P=0.001),但未发现二者具有相关关系：新生儿脐带血血清叶酸水平明显高于产妇血清叶酸水平(t=-12.183,P=0.001),且二者相关(r=0..367,P=0.001)；新生儿脐带血血清维生素B12水平高于产妇(t=-4.432,P=0.001),且二者具有相关性(r=0.325,P=0.001)。服用保健品组与未服用保健品组三种营养素水平差异均无统计学意义(P＜0.05)。
2.产妇静脉血血清和新生儿脐带血血清—碳单位营养物水平、母亲孕期环境因素与H19甲基化模式的关系：
(1)母血H19启动子甲基化率均值为68.53%,脐血为68.00%；两者差异无统计学意义(t=-0.256,P=0.798),且两者之间呈正相关关系(β=0.322,P=0.002)；母血H19DMR甲基化率均值为83.01%,脐血为83.25%；两者差异无统计学意义(t=-0.105,P=0.917),且两者之间呈正相关关系(β=0.472,P=0.001)。
(2)新生儿血清H19DNA启动子甲基化水平与孕期平均每周PM10污染分指数负相关(β=-1.559,P=0.049)；新生儿H19的DNA启动子甲基化状态与新生儿血清锌具有相关性(β=0.275,P=0.009)；脐带血H19DMR甲基化水平分别与脐血中叶酸水平,母亲被动吸烟和剖宫产相关(β=0.310,p=0.036；β=0.334, P=0.005；β=-0.284,P=0.018)；产妇H19DMR甲基化状态与产妇血清锌相关(β=0.420,P=0.008)。
(3)未发现新生儿H19启动子的甲基化状态与产妇血清叶酸、维生素B12、孕期体重增加、被动吸烟、孕妇年龄等因素相关；也未发现产妇H19启动子的甲基化状态与血清叶酸,维生素B12、被动吸烟、孕期体重增加、空气质量等因素相关。
结论：
1.产妇孕前BMI可影响新生儿的出生体重、出生身长和出生头围。
2.新生儿脐血中H19启动子、DMR甲基化率主要取决于母亲血液中H19基因的甲基化率。
3.产妇静脉血及新生儿脐血H19甲基化率受血液中营养物质及环境因素的共同影响。
DNA methylation is a kind of important factor in the progress of cancer. Many researchers have demonstrated that gene methylation model is established in fetus; Imprinted gene H19is transcripted highly in fetus, mainly controlled by gene methylation. It has been verified that it is related with many tumors. Thus, to explore the factors affecting the express of epigenetic gene, such as DNA methylation, and clarify the role of environment and nutrition in the establishment of methylation will provide an important clue for the prevention of cancer.
Objective:
The aim of this study was to explore the relationship among "maternal nutritional intake, environmental factors and H19DNA methylation patterns in offsprings and birth characteristics", and to provide basic data for cancer prevention and nutritional intervention.
Materials and methods:
1. Selection of subjects
Pregnant women who came to houzhai hospital for delivery between April and September2008were recruited into this study. Any one with diabetes, hepatitis B infection or other coeliac diseases was not included. Total99pregnant women were recruited as subjects and willing to participate in the study after being informed the prupose of the study.
2. Questionnaire was designed according to the purpose of this study. All investigator were trained strictly and conducted pre-investigation to make sure the success of the investigation. All the information was kept secret. Air pollution data of local region was collected through Environmental Protection Bureau.
3. Determination of birth characteristics
The birth weight of infants was weighed using electronic scale; The head circumference and the birth length of offsprings were measured using horizontal length meter.
4. Determination of one-carbon nutrients in serum
Serum folate and vitamin B12was determined by paramagnetic particle chemiluminescent immunoassay method. Serum zinc was determined by Atomic absorption spectrophotometry.
5. The determination of H19DNA methylation status Methylation patterns of H19promotor and H19DMR (Different methylation region) were tested by QMS-PCR (quantitative methylation-specific polymerase chain reaction)
6. Data management and statistical analysis
All the data was entering using software of Epidata3.1and furtherly analysed by the SPSS software, version12.0. Following methods were used in the study:paired sample T-test, multiple linear regression analysis and so on. A P-value of less than0.05was considered statistically significant.
Results:
1. The relationship among birth characteristics, nutrient content of maternal serum and maternal environmental exposures during pregnancy.
(1)The average birth lengh of infants was49.48cm, the average birth weight of infants was3.19kg, the average birth head circumference of infants was33.83cm; multiliner regressive modle showed that birth lengh, birth weight and birth head circumference were related with BMI (body mass index) of mother (β=-0.198, P=0.046;β=0.336,P=0.003;β=0.34, P=0.012); Birth weight was related with infant genders (β=-0.198, P=0.046); Birth lengh was related with maternal cesarean (β=0.283, P=0.008)。
(2)The average serum folate of mother and infants was29ng/ml and7.29ng/ml respectively; The average serum vitamin B12of mother and infants was175.34pg/ml and240.19pg/ml respectively; The average serum zinc of mother and infants was0.67μg/ml and0.93μg/ml respectively。 Serum folate level, vitamin B12and Zinc in cord blood was significantly higher than that in mother's blood respectively (t=-12.183, P=0.001;t=-4.432, P=0.001; t=-5.551, P=0.001); Serum folate level and vitamin B12in cord blood was correlated with that of mother's blood repectively (r=0.367,P=0.001; r=0.325, P=0.001); Serum Zinc level in cord blood was not correlated with that of mother's blood(P>0.05).
2.The relationship of serum nutrient content,maternal environmental exposures alld H19DNA methylation pattern.
(1)The average percentages of methylation in H19promoter were68.53%for mother's blood and68.00%for cord blood respectively.There was no significant difference of methylation in H19promoter between cord b1ood and mother's b1ood (t=0.256,P=0.798),but correlated with each other(β=0.275,P=0.009).There was no significant difference of methylation in H19DMR between cord blood and mother's blood(t=-0.105,P=0.917),but correlated with each other(β=0.472,p=0.001)
(2)H19DNA promoter methylation status ofmaternal was correlated with cord blood serum zinc (β=0.275,P=0.009)；H19DMR methylation status of infants was correlated with vitamin B12of infants,maternal cesarean and passive smoking respectively(β=0.310,P=0.036；β=-0.334,P=0.005；β=-0.284,P=0.018)；H19DMR methylation status of maternal was correlated with maternal serum zinc (β=-0.420,P=0.008)
(3)No correlation was observed between methylation in H19promoter of cord blood and maternal serum folate,vitalnin B12,weight gain during pregnanc,mother's age,air pollution；Neither was methylation in H19promoter of maternal blood.
Conclusion:1.Maternal pre-pregnancy body mass index is related with birth characteristics.
2.Methylation of cord blood mainly depelldents on maternal Serum Hl9methylation.
3.H19methylation is affected by nutrient of blood and environmental exposures
目的：
探索孕期血液一碳单位营养物(叶酸、维生素B12)、锌以及环境暴露与H19基因甲基化模式及新生儿出生特征之间的关系,为在胎儿期通过营养手段预防肿瘤提供线索。
材料与方法：
1.调查对象的选择：以2008年4月到2008年9月期间在郑州市侯寨中心卫生院分娩的、未患乙肝、糖尿病及其它慢性消化道疾病的(以临床诊断为准)健康母亲作为调查对象,提前告知本课题目的意义并签署知情同意书后,共99名母亲纳入调查范围。
2.资料的收集：根据此次研究的内容详细设计调查问卷(见附件),严格培训调查员并实施预调查后正式开始问卷调查,调查对象的个人信息均严格保密；收集2007年5月到2008年9月当地环保局公布的每周空气污染指数及分指数。
3.新生儿出生特征的测量：用头围尺经颅骨两眼眉弓及枕骨结节测量新生儿头围,用卧式身长计测量新生儿出生身长；用电子秤称量新生儿出生体重。
4.血清中一碳单位营养物及锌的测定：采用Access磁微粒化学发光免疫分析系统测定血清中叶酸、维生素B12；原子吸收法测定血清锌水平。
5.甲基化水平的测定：甲基化特异性荧光定量PCR (quantitativemethylation-specific polymerase chain reaction, QMS-PC R)测定H19基因启动子及差异甲基化区(different methylation region, DMR)甲基化率。6.数据整理和分析：数据录入采用Epidata3.1软件并采用SPSS12.0进行分析。主要分析检验方法有：配对t检验、多元线性回归分析等,检验水准α=0.05。
结果：
1.新生儿出生特征、母体血清营养物含量及产妇孕期环境因素的关系：
(1)新生儿共99例,男孩52例,女孩47例,出生身长为49.48±1.89cm,出生体重为49.48±1.89kg,出生头围为33.83±1.19cm；多元回归分析表明：新生儿出生体重与新生儿性别相关(β=0.198,P=0.046)；出生身长与产妇剖宫产相关(β=0.283,P=0.008)。出生体重、出生身长及出生头围分别与产妇孕前体质指数(body mass Index,BMI)相关(β=-0.198,P=0.046；β=0.336,P=0.003；β=0.314, P=0.012):
(2)产妇静脉血血清及新生儿脐带血血清叶酸水平分别为2.29±2.13ng/ml和7.29±4.80ng/ml,锌水平分别为0.67±0.31μg/ml和0.93±0.37μg/ml,维生素B12水平分别为175.34±154.78pg/ml和240.19±228.56pg/ml,其中,新生儿脐带血血清锌水平高于产妇(t=-5.551,P=0.001),但未发现二者具有相关关系：新生儿脐带血血清叶酸水平明显高于产妇血清叶酸水平(t=-12.183,P=0.001),且二者相关(r=0..367,P=0.001)；新生儿脐带血血清维生素B12水平高于产妇(t=-4.432,P=0.001),且二者具有相关性(r=0.325,P=0.001)。服用保健品组与未服用保健品组三种营养素水平差异均无统计学意义(P＜0.05)。
2.产妇静脉血血清和新生儿脐带血血清—碳单位营养物水平、母亲孕期环境因素与H19甲基化模式的关系：
(1)母血H19启动子甲基化率均值为68.53%,脐血为68.00%；两者差异无统计学意义(t=-0.256,P=0.798),且两者之间呈正相关关系(β=0.322,P=0.002)；母血H19DMR甲基化率均值为83.01%,脐血为83.25%；两者差异无统计学意义(t=-0.105,P=0.917),且两者之间呈正相关关系(β=0.472,P=0.001)。
(2)新生儿血清H19DNA启动子甲基化水平与孕期平均每周PM10污染分指数负相关(β=-1.559,P=0.049)；新生儿H19的DNA启动子甲基化状态与新生儿血清锌具有相关性(β=0.275,P=0.009)；脐带血H19DMR甲基化水平分别与脐血中叶酸水平,母亲被动吸烟和剖宫产相关(β=0.310,p=0.036；β=0.334, P=0.005；β=-0.284,P=0.018)；产妇H19DMR甲基化状态与产妇血清锌相关(β=0.420,P=0.008)。
(3)未发现新生儿H19启动子的甲基化状态与产妇血清叶酸、维生素B12、孕期体重增加、被动吸烟、孕妇年龄等因素相关；也未发现产妇H19启动子的甲基化状态与血清叶酸,维生素B12、被动吸烟、孕期体重增加、空气质量等因素相关。
结论：
1.产妇孕前BMI可影响新生儿的出生体重、出生身长和出生头围。
2.新生儿脐血中H19启动子、DMR甲基化率主要取决于母亲血液中H19基因的甲基化率。
3.产妇静脉血及新生儿脐血H19甲基化率受血液中营养物质及环境因素的共同影响。
DNA methylation is a kind of important factor in the progress of cancer. Many researchers have demonstrated that gene methylation model is established in fetus; Imprinted gene H19is transcripted highly in fetus, mainly controlled by gene methylation. It has been verified that it is related with many tumors. Thus, to explore the factors affecting the express of epigenetic gene, such as DNA methylation, and clarify the role of environment and nutrition in the establishment of methylation will provide an important clue for the prevention of cancer.
Objective:
The aim of this study was to explore the relationship among "maternal nutritional intake, environmental factors and H19DNA methylation patterns in offsprings and birth characteristics", and to provide basic data for cancer prevention and nutritional intervention.
Materials and methods:
1. Selection of subjects
Pregnant women who came to houzhai hospital for delivery between April and September2008were recruited into this study. Any one with diabetes, hepatitis B infection or other coeliac diseases was not included. Total99pregnant women were recruited as subjects and willing to participate in the study after being informed the prupose of the study.
2. Questionnaire was designed according to the purpose of this study. All investigator were trained strictly and conducted pre-investigation to make sure the success of the investigation. All the information was kept secret. Air pollution data of local region was collected through Environmental Protection Bureau.
3. Determination of birth characteristics
The birth weight of infants was weighed using electronic scale; The head circumference and the birth length of offsprings were measured using horizontal length meter.
4. Determination of one-carbon nutrients in serum
Serum folate and vitamin B12was determined by paramagnetic particle chemiluminescent immunoassay method. Serum zinc was determined by Atomic absorption spectrophotometry.
5. The determination of H19DNA methylation status Methylation patterns of H19promotor and H19DMR (Different methylation region) were tested by QMS-PCR (quantitative methylation-specific polymerase chain reaction)
6. Data management and statistical analysis
All the data was entering using software of Epidata3.1and furtherly analysed by the SPSS software, version12.0. Following methods were used in the study:paired sample T-test, multiple linear regression analysis and so on. A P-value of less than0.05was considered statistically significant.
Results:
1. The relationship among birth characteristics, nutrient content of maternal serum and maternal environmental exposures during pregnancy.
(1)The average birth lengh of infants was49.48cm, the average birth weight of infants was3.19kg, the average birth head circumference of infants was33.83cm; multiliner regressive modle showed that birth lengh, birth weight and birth head circumference were related with BMI (body mass index) of mother (β=-0.198, P=0.046;β=0.336,P=0.003;β=0.34, P=0.012); Birth weight was related with infant genders (β=-0.198, P=0.046); Birth lengh was related with maternal cesarean (β=0.283, P=0.008)。
(2)The average serum folate of mother and infants was29ng/ml and7.29ng/ml respectively; The average serum vitamin B12of mother and infants was175.34pg/ml and240.19pg/ml respectively; The average serum zinc of mother and infants was0.67μg/ml and0.93μg/ml respectively。 Serum folate level, vitamin B12and Zinc in cord blood was significantly higher than that in mother's blood respectively (t=-12.183, P=0.001;t=-4.432, P=0.001; t=-5.551, P=0.001); Serum folate level and vitamin B12in cord blood was correlated with that of mother's blood repectively (r=0.367,P=0.001; r=0.325, P=0.001); Serum Zinc level in cord blood was not correlated with that of mother's blood(P>0.05).
2.The relationship of serum nutrient content,maternal environmental exposures alld H19DNA methylation pattern.
(1)The average percentages of methylation in H19promoter were68.53%for mother's blood and68.00%for cord blood respectively.There was no significant difference of methylation in H19promoter between cord b1ood and mother's b1ood (t=0.256,P=0.798),but correlated with each other(β=0.275,P=0.009).There was no significant difference of methylation in H19DMR between cord blood and mother's blood(t=-0.105,P=0.917),but correlated with each other(β=0.472,p=0.001)
(2)H19DNA promoter methylation status ofmaternal was correlated with cord blood serum zinc (β=0.275,P=0.009)；H19DMR methylation status of infants was correlated with vitamin B12of infants,maternal cesarean and passive smoking respectively(β=0.310,P=0.036；β=-0.334,P=0.005；β=-0.284,P=0.018)；H19DMR methylation status of maternal was correlated with maternal serum zinc (β=-0.420,P=0.008)
(3)No correlation was observed between methylation in H19promoter of cord blood and maternal serum folate,vitalnin B12,weight gain during pregnanc,mother's age,air pollution；Neither was methylation in H19promoter of maternal blood.
Conclusion:1.Maternal pre-pregnancy body mass index is related with birth characteristics.
2.Methylation of cord blood mainly depelldents on maternal Serum Hl9methylation.
3.H19methylation is affected by nutrient of blood and environmental exposures
引文
[1]Chmurzynska A. Fetal programming:link between early nutrition, DNA methylation, and complex diseases[J]. Nutrition reviews,2010,68(2):87-98
[2]Xu Y., Williams S., O'Brien D., et al. Hypoxia or nutrient restriction during pregnancy in rats leads to progressive cardiac remodeling and impairs postischemic recovery in adult male offspring[J]. The FASEB Journal,2006,20(8):1251
[3]Rich-Edwards J., Colditz G, Stampfer M, et al. Birthweight and the risk for type 2 diabetes mellitus in adult women[J]. Annals of Internal Medicine,1999,130(4 Part 1):278
[4]Wu G, Bazer F., Cudd T., et al. Maternal nutrition and fetal development[J]. Journal of Nutrition, 2004,134(9):2169
[5]Van den Veyver I. Genetic effects of methylation diets[J]. Annual review of nutrition,2002, 22(1):255-282
[6]Friso S., Choi S., Girelli D., et al. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status[J]. Proceedings of the National Academy of Sciences of the United States of America,2002,99(8): 5606
[7]DeBaun M., Niemitz E., Feinberg A. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of L1T1 and H19[J]. The American Journal of Human Genetics,2003,72(1):156-160
[8]Wolff G, Kodell R., Moore S., et al. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice[J]. The FASEB Journal,1998,12(11):949
[9]Trichopoulos D. Hypothesis:does breast cancer originate in utero?[J]. The Lancet,1990, 335(8695):939-940
[10]Bourque D.K., Avila L., Penaherrera M., et al. Decreased placental methylation at the H19/IGF2 imprinting control region is associated with normotensive intrauterine growth restriction but not preeclampsia[J]. Placenta,2010,31(3):197-202
[11]Charalambous M., Menheniott T., Bennett W., et al. An enhancer element at the Igf2/H 19 locus drives gene expression in both imprinted and non-imprinted tissues[J]. Developmental biology, 2004,271(2):488-497
[12]Angiolini E., Fowden A., Coan P., et al. Regulation of placental efficiency for nutrient transport by imprinted genes[J]. Placenta,2006,27:98-102
[13]Reik W., Walter J. Genomic imprinting:parental influence on the genome[J]. Nature Reviews Genetics,2001,2(1):21-32
[14]McCormack V.A., dos Santos Silva I., De Stavola B.L., et al. Fetal growth and subsequent risk of breast cancer:results from long term follow up of Swedish cohort[J]. BMJ,2003,326(7383): 248
[15]Bartholdi D., Krajewska-Walasek M., Ounap K., et al. Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS):Results from a large cohort of patients with SRS and SRS-like phenotypes[J]. Journal of medical genetics,2009,46(3):192-197
[16]Scott R.H., Douglas J., Baskcomb L., et al. Constitutional 11 p 15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumorfJ]. Nature genetics, 2008,40(11):1329-1334
[17]Chang A., Moley K., Wangler M., et al. Association between Beckwith-Wiedemann syndrome and assisted reproductive technology:a case series of 19 patients[J]. Fertility and sterility,2005, 83(2):349-354
[18]叶静,韦伟,张芳婷等.H19基因在乳腺癌中的印迹状态和表达[J].现代肿瘤医学,2008,No.89(11)：1914-1916
[19]Berteaux N., Aptel N., Cathala G., et al. A novel H19 antisense RNA overexpressed in breast cancer contributes to paternal IGF2 expression[J]. Mol Cell Biol,2008,28(22):6731-45
[20]Dammann R.H., Kirsch S., Schagdarsurengin U., et al. Frequent aberrant methylation of the imprinted IGF2/H19 locus and LINE1 hypomethylation in ovarian carcinoma[J]. Int J Oncol, 2010,36(1):171-9
[21]董治龙,钟甘平.H19基因与膀胱移行细胞癌关系的研究进展[J].国际泌尿系统杂志2006(01)：43-45
[22]孟静,印迹基因H19、LIT1和MEST在肺癌发生中的作用机制研究.2008,大连医科大学.
[23]邱剑萍.宫颈癌中H19基因的特异表达模式及印记缺失分析[J].中国现代医药杂志,2008(11)：3 1-33
[24]王文玲,高英敏,高俊丽等.印迹基因H19在宫颈癌中的表达及意义[J].肿瘤,2008,No.179(01)：89-90
[25]王月玲,杨新园,李旭.印记基因H19和胰岛素样生长因子Ⅱ在人子宫颈癌组织中印记缺失及意义[J].西安交通大学学报(医学版),2006(04)：372-376
[26]武静,覃扬,李波等.人原发性肝癌胰岛素样生长因子2和H19基因印迹研究[J].四川大学学报(医学版),2007(01)：49-52
[27]中国居民血清7种元素正常参考值范围[J].世界元素医学,2005(4)：57
[28]Lu L., Katsaros D., Rigault de la Longrais I.A., et al. Hypermethylation of let-7a-3 in epithelial ovarian cancer is associated with low insulin-like growth factor-II expression and favorable prognosis[J]. Cancer research,2007,67(21):10117
[29]郝玲,唐仪.孕妇血液叶酸水平及其影响因素[J].中华预防医学杂志,1996(06)：57-59
[30]孙红,王留娣.124例孕妇妊娠期血清叶酸水平动态观察[J].上海预防医学杂志,2002(02)：60-61
[31]尹国武,杨梦庚.产妇血清脐血及乳汁中叶酸和维生素B12水平测定及意义[J].中国实用妇科与产科杂志,1997,13(005)：279-280
[32]夏怡.叶酸——应受重视的维生素[J].精细与专用化学品,2000,8(8)：19-20
[33]赵培忠,徐令璧.正常妊娠各期红细胞、血清Zn、CU、Fe及SFe、CU、A含量的研究[J].徐州医学院学报,1992(04)：305-306+288
[34]阎素文,艾旭,黄华芬等.沈阳地区正常妊娠妇女血清锌、铜测定分析[J].医学情报通讯,1988(02)：4-5
[35]关婷,尹菊,王彦.正常孕妇血清、脐带血血清及胎盘组织的锌、铜含量及转运[J].中国医科大学学报,1996(02)
[36]Henkin R., Marshall J., Meret S. Maternal metabolism of Cu and Zn at term[J]. Am J Obstet Gynecol,1971,110:131-134
[37]杨月欣,潘丽梅,刘建宇等.正常妊娠妇女血清锌及发锌含量的研究[J].卫生研究,1992(04)：193-196+224
[38]孙长颢.营养与食品卫生学.第六版ed[M].北京：人民卫生出版社,2007.63-64
[39]周超,下佳,陈萍萍等.脐血清与临产妇血清钙、铁、锌含量与新生儿身长的关系[J].郑州大学学报(医学版),2009,44(04)：856-858
[40]罗怀清,庄宝玲,王兆玲.妊娠期母体血清铁蛋白,叶酸,VitB12水平与贫血的关系及保健[J].中国妇幼保健,2006,20(22)：2933-2935
[41]高树生,李黎,潘兴华等.妊娠晚期孕妇血浆叶酸和同型半胱氨酸含量的临床意义[J].中国优生与遗传杂志,2002(03)：62-97
[42]黄建辉.补锌与妊娠结局及新生儿发育指标的关系[J].职业与健康,2001(02)：108-109
[43]袁伟,耿国柱,陈爱民等.妊娠期农妇补锌对幼儿生长发育的影响[J].复旦学报(医学版),2004(05)：496-501
[44]郭新节,吕式瑷.孕妇被动吸烟对胎儿的危害[J].中华护理杂志,1993,28(007)：387-389
[45]巢健茜，鲁磊.影响剖宫产有关因素的探讨[J].中国初级卫生保健,2002,16(001)：34-35
[46]覃耀明.广西农村120145例新生儿出生体重分析[J].中国儿童保健杂志,2008,16(2)：168-169
[47]梁黎,何梦藻.从宫内发育研究代谢综合征的发病机制[J].浙江大学学报：医学版,2008,37(3)： 221-225
[48]Yajnik C., Deshpande S., Jackson A., et al. Vitamin B 12 and folate concentrations during pregnancy and insulin resistance in the offspring:the Pune Maternal Nutrition Study[J]. Diabetologia,2008,51(1):29-38
[49]Reik W., Constancia M., Fowden A., et al. Regulation of supply and demand for maternal nutrients in mammals by imprinted genes[J]. The Journal of physiology,2003,547(1):35-44
[50]Takai D., Gonzales F.A., Tsai Y.C., et al. Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer[J]. Hum Mol Genet,2001,10(23):2619-26
[1]Corry G.N., Tanasijevic B., Barry E.R., et al. Epigenetic regulatory mechanisms during preimplantation development[J]. Birth Defects Research Part C:Embryo Today:Reviews,2009, 87(4):297-313
[2]Trichopoulos D. Hypothesis:does breast cancer originate in utero?[J]. The Lancet,1990, 335(8695):939-940
[3]张玉英,杨玮丽,朱琍燕等.孕产期母鼠体内给予尼古丁对其子代肾脏RAS发育的影响[J].苏州大学学报(医学版),2010,4
[4]李光辉,黄醒华.孕产妇营养对子代的近远期影响[J].中国实用妇科与产科杂志,2007,23(4)： 256-259
[5]Taby R., Issa J.P.J. Cancer epigenetics[J]. CA:a cancer journal for clinicians,2010,60(6): 376-392
[6]张扬.肿瘤发生的表观遗传机制和表观治疗方法[J].中山大学研究生学刊：自然科学与医学版,2008,29(004)：13-20
[7]宫安静.胶质瘤DNA甲基化与叶酸代谢[J].国际神经病学神经外科学杂志IST1C,2010, 37(6)
[8]阚静,李莉,许激扬.叶酸的生物合成及其代谢工程研究进展[J].中国生化药物杂志,2009,30(004)：284-286
[9]余立萍,谭德福.维生素B12缺乏症的研究进展[J].现代中西医结合杂志,2007,16(11)：1584-1585
[10]周艳红,王新.叶酸代谢与出生缺陷的关系研究[J].医学临床研究,2006(09)：1454-1456
[11]李云飞,管英俊,于丽.Wnt信号通路与神经管缺陷关系的研究进展[J].神经解剖学杂志2009,25(002)：236-238
[12]Xu Y., Williams S., O'Brien D., et al. Hypoxia or nutrient restriction during pregnancy in rats leads to progressive cardiac remodeling and impairs postischemic recovery in adult male offspring[J]. The FASEB Journal,2006,20(8):1251
[13]Rich-Edwards J., Colditz G., Stampfer M., et al. Birthweight and the risk for type 2 diabetes mellitus in adult women[J]. Annals of Internal Medicine,1999,130(4 Part 1):278
[14]Kawakami T., Zhang C., Okada Y., et al. Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin[J]. Oncogene,2006,25(23):3225-36
[15]Hajkova P., Erhardt S., Lane N., et al. Epigenetic reprogramming in mouse primordial germ cells[J]. Mechanisms of Development,2002,117(1-2):15-23
[16]Park C.H., Kim H.S., Lee S.G., et al. Methylation status of differentially methylated regions at Igf2/H19 locus in porcine gametes and preimplantation embryos[J]. Genomics,2009,93(2): 179-86
[17]Ouko L.A., Shantikumar K., Knezovich J., et al. Effect of alcohol consumption on CpG methylation in the differentially methylated regions of H19 and IG-DMR in male gametes: implications for fetal alcohol spectrum disorders[J]. Alcohol Clin Exp Res,2009,33(9):1615-27
[18]Horike S., Ferreira J.C., Meguro-Horike M., et al. Screening of DNA methylation at the H19 promoter or the distal region of its ICR1 ensures efficient detection of chromosome 11p15 epimutations in Russell-Silver syndrome[J]. Am J Med Genet A,2009,149A(11):2415-23
[19]Yamamoto E., Suzuki H., Takamaru H., et al. Role of DNA methylation in the development of diffuse-type gastric cancer[J]. Digestion,2011,83(4):241-249
[20]CHAN A.W.H., CHAN M.W.Y., LEE T.L., et al. Promoter hypermethylation of Death-associated protein-kinase gene associated with advance stage gastric canccr[J]. Oncology reports,2005, 13(5):937-941
[21]Liu W., Li X., Chu E.S.H., et al. Paired box gene 5 is a novel tumor suppressor in hepatocellular carcinoma through interaction with p53 signaling pathway[J]. Hepatology,2011,53(3):843-853
[22]Uhm K.O., Lee E.S., Lee Y.M., et al. Aberrant promoter CpG islands methylation of tumor suppressor genes in cholangiocarcinoma[J]. Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics,2008,17(4):151-157
[23]Belinsky S.A., Nikula K.J., Palmisano W.A., et al. Aberrant methylation of p16INK4a is an early event in lung cancer and a potential biomarker for early diagnosis[J]. Proceedings of the National Academy of Sciences,1998,95(20):11891
[24]Roa J., Anabalon L., Roa I., et al. Promoter methylation profile in gastric canccr][J]. Revista medica de Chile,2005,133(8):874
[25]叶静,韦伟,张芳婷等.H19基因在乳腺癌中的印迹状态和表达[J].现代肿瘤医学,2008,No.89(11)：1914-1916
[26]Berteaux N., Aptel N., Cathala G., et al. A novel H19 antisense RNA overexpressed in breast cancer contributes to paternal IGF2 expression[J]. Mol Cell Biol,2008,28(22):6731-45
[27]Adriaenssens E., Dumont L., Lottin S., et al. H19 Overexpression in Breast Adenocarcinoma Stromal Cells Is Associated with Tumor Values and Steroid Receptor Status but Independent of p53 and Ki-67 Expression[J]. The American journal of pathology,1998,153(5):1597-1607
[28]Dammann R.H., Kirsch S., Schagdarsurengin U., et al. Frequent aberrant methylation of the imprinted IGF2/H19 locus and LINE1 hypomethylation in ovarian carcinoma[J]. Int J Oncol, 2010,36(1):171-9
[29]董治龙,钟甘平.H19基因与膀胱移行细胞癌关系的研究进展[J].国际泌尿系统杂志,2006(01)：43-45
[30]孟静,印迹基因H19、LIT1和MEST在肺癌发生中的作用机制研究.2008,大连医科大学.
[31]邱剑萍.宫颈癌中H19基因的特异表达模式及印记缺失分析[J].中国现代医药杂志,2008(11)：31-33
[32]王文玲,高英敏,高俊丽等.印迹基因H19在宫颈癌中的表达及意义[J].肿瘤,2008,No.179(01)：89-90
[33]王月玲,杨新园,李旭.印记基因H19和胰岛素样生长因子Ⅱ在人子宫颈癌组织中印记缺失及意义[J].西安交通大学学报(医学版),2006(04)：372-376
[34]武静,覃扬,李波等.人原发性肝癌胰岛素样生长因子2和H19基因印迹研究[J].四川大学学报(医学版),2007(01)：49-52
[35]Chang A., Moley K., Wangler M., et al. Association between Beckwith-Wiedemann syndrome and assisted reproductive technology:a case series of 19 patients[J]. Fertility and sterility,2005, 83(2):349-354
[36]Cui H., Niemitz E.L., Ravenel J.D., et al. Loss of imprinting of insulin-like growth factor-Ⅱ in Wilms'tumor commonly involves altered methylation but not mutations of CTCF or its binding site[J]. Cancer research,2001,61(13):4947
[37]Nakagawa H., Chadwick R.B., Peltomaki P., et al. Loss of imprinting of the insulin-like growth factor Ⅱ gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer[J]. Proceedings of the National Academy of Sciences,2001,98(2):591
[38]Takai D., Gonzales F.A., Tsai Y.C., et al. Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer[J]. Hum Mol Genet,2001,10(23):2619-26
[39]Feinberg A.P., Cui H., Ohlsson R. DNA methylation and genomic imprinting:insights from cancer into epigenetic mechanisms.2002:Elsevier.
[40]Han L., Lee D.H., Szabo P.E. CTCF is the master organizer of domain-wide allele-specific chromatin at the H19/Igf2 imprinted region[J]. Molecular and cellular biology,2008,28(3): 1124-1135
[41]Cadieux B., Ching T.T., VandenBerg S.R., et al. Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation[J]. Cancer research,2006,66(17):8469-8476
[42]de Caceres I.I., Battagli C., Esteller M., et al. Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients[J]. Cancer research,2004,64(18):6476
[43]马琳,张军航,刘芙蓉等.卵巢上皮性恶性肿瘤组织RASSF1A基因启动子区甲基化的研究[J].中华肿瘤杂志,2006,27(11)：657-659
[2]Xu Y., Williams S., O'Brien D., et al. Hypoxia or nutrient restriction during pregnancy in rats leads to progressive cardiac remodeling and impairs postischemic recovery in adult male offspring[J]. The FASEB Journal,2006,20(8):1251
[3]Rich-Edwards J., Colditz G, Stampfer M, et al. Birthweight and the risk for type 2 diabetes mellitus in adult women[J]. Annals of Internal Medicine,1999,130(4 Part 1):278
[4]Wu G, Bazer F., Cudd T., et al. Maternal nutrition and fetal development[J]. Journal of Nutrition, 2004,134(9):2169
[5]Van den Veyver I. Genetic effects of methylation diets[J]. Annual review of nutrition,2002, 22(1):255-282
[6]Friso S., Choi S., Girelli D., et al. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status[J]. Proceedings of the National Academy of Sciences of the United States of America,2002,99(8): 5606
[7]DeBaun M., Niemitz E., Feinberg A. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of L1T1 and H19[J]. The American Journal of Human Genetics,2003,72(1):156-160
[8]Wolff G, Kodell R., Moore S., et al. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice[J]. The FASEB Journal,1998,12(11):949
[9]Trichopoulos D. Hypothesis:does breast cancer originate in utero?[J]. The Lancet,1990, 335(8695):939-940
[10]Bourque D.K., Avila L., Penaherrera M., et al. Decreased placental methylation at the H19/IGF2 imprinting control region is associated with normotensive intrauterine growth restriction but not preeclampsia[J]. Placenta,2010,31(3):197-202
[11]Charalambous M., Menheniott T., Bennett W., et al. An enhancer element at the Igf2/H 19 locus drives gene expression in both imprinted and non-imprinted tissues[J]. Developmental biology, 2004,271(2):488-497
[12]Angiolini E., Fowden A., Coan P., et al. Regulation of placental efficiency for nutrient transport by imprinted genes[J]. Placenta,2006,27:98-102
[13]Reik W., Walter J. Genomic imprinting:parental influence on the genome[J]. Nature Reviews Genetics,2001,2(1):21-32
[14]McCormack V.A., dos Santos Silva I., De Stavola B.L., et al. Fetal growth and subsequent risk of breast cancer:results from long term follow up of Swedish cohort[J]. BMJ,2003,326(7383): 248
[15]Bartholdi D., Krajewska-Walasek M., Ounap K., et al. Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS):Results from a large cohort of patients with SRS and SRS-like phenotypes[J]. Journal of medical genetics,2009,46(3):192-197
[16]Scott R.H., Douglas J., Baskcomb L., et al. Constitutional 11 p 15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumorfJ]. Nature genetics, 2008,40(11):1329-1334
[17]Chang A., Moley K., Wangler M., et al. Association between Beckwith-Wiedemann syndrome and assisted reproductive technology:a case series of 19 patients[J]. Fertility and sterility,2005, 83(2):349-354
[18]叶静,韦伟,张芳婷等.H19基因在乳腺癌中的印迹状态和表达[J].现代肿瘤医学,2008,No.89(11)：1914-1916
[19]Berteaux N., Aptel N., Cathala G., et al. A novel H19 antisense RNA overexpressed in breast cancer contributes to paternal IGF2 expression[J]. Mol Cell Biol,2008,28(22):6731-45
[20]Dammann R.H., Kirsch S., Schagdarsurengin U., et al. Frequent aberrant methylation of the imprinted IGF2/H19 locus and LINE1 hypomethylation in ovarian carcinoma[J]. Int J Oncol, 2010,36(1):171-9
[21]董治龙,钟甘平.H19基因与膀胱移行细胞癌关系的研究进展[J].国际泌尿系统杂志2006(01)：43-45
[22]孟静,印迹基因H19、LIT1和MEST在肺癌发生中的作用机制研究.2008,大连医科大学.
[23]邱剑萍.宫颈癌中H19基因的特异表达模式及印记缺失分析[J].中国现代医药杂志,2008(11)：3 1-33
[24]王文玲,高英敏,高俊丽等.印迹基因H19在宫颈癌中的表达及意义[J].肿瘤,2008,No.179(01)：89-90
[25]王月玲,杨新园,李旭.印记基因H19和胰岛素样生长因子Ⅱ在人子宫颈癌组织中印记缺失及意义[J].西安交通大学学报(医学版),2006(04)：372-376
[26]武静,覃扬,李波等.人原发性肝癌胰岛素样生长因子2和H19基因印迹研究[J].四川大学学报(医学版),2007(01)：49-52
[27]中国居民血清7种元素正常参考值范围[J].世界元素医学,2005(4)：57
[28]Lu L., Katsaros D., Rigault de la Longrais I.A., et al. Hypermethylation of let-7a-3 in epithelial ovarian cancer is associated with low insulin-like growth factor-II expression and favorable prognosis[J]. Cancer research,2007,67(21):10117
[29]郝玲,唐仪.孕妇血液叶酸水平及其影响因素[J].中华预防医学杂志,1996(06)：57-59
[30]孙红,王留娣.124例孕妇妊娠期血清叶酸水平动态观察[J].上海预防医学杂志,2002(02)：60-61
[31]尹国武,杨梦庚.产妇血清脐血及乳汁中叶酸和维生素B12水平测定及意义[J].中国实用妇科与产科杂志,1997,13(005)：279-280
[32]夏怡.叶酸——应受重视的维生素[J].精细与专用化学品,2000,8(8)：19-20
[33]赵培忠,徐令璧.正常妊娠各期红细胞、血清Zn、CU、Fe及SFe、CU、A含量的研究[J].徐州医学院学报,1992(04)：305-306+288
[34]阎素文,艾旭,黄华芬等.沈阳地区正常妊娠妇女血清锌、铜测定分析[J].医学情报通讯,1988(02)：4-5
[35]关婷,尹菊,王彦.正常孕妇血清、脐带血血清及胎盘组织的锌、铜含量及转运[J].中国医科大学学报,1996(02)
[36]Henkin R., Marshall J., Meret S. Maternal metabolism of Cu and Zn at term[J]. Am J Obstet Gynecol,1971,110:131-134
[37]杨月欣,潘丽梅,刘建宇等.正常妊娠妇女血清锌及发锌含量的研究[J].卫生研究,1992(04)：193-196+224
[38]孙长颢.营养与食品卫生学.第六版ed[M].北京：人民卫生出版社,2007.63-64
[39]周超,下佳,陈萍萍等.脐血清与临产妇血清钙、铁、锌含量与新生儿身长的关系[J].郑州大学学报(医学版),2009,44(04)：856-858
[40]罗怀清,庄宝玲,王兆玲.妊娠期母体血清铁蛋白,叶酸,VitB12水平与贫血的关系及保健[J].中国妇幼保健,2006,20(22)：2933-2935
[41]高树生,李黎,潘兴华等.妊娠晚期孕妇血浆叶酸和同型半胱氨酸含量的临床意义[J].中国优生与遗传杂志,2002(03)：62-97
[42]黄建辉.补锌与妊娠结局及新生儿发育指标的关系[J].职业与健康,2001(02)：108-109
[43]袁伟,耿国柱,陈爱民等.妊娠期农妇补锌对幼儿生长发育的影响[J].复旦学报(医学版),2004(05)：496-501
[44]郭新节,吕式瑷.孕妇被动吸烟对胎儿的危害[J].中华护理杂志,1993,28(007)：387-389
[45]巢健茜，鲁磊.影响剖宫产有关因素的探讨[J].中国初级卫生保健,2002,16(001)：34-35
[46]覃耀明.广西农村120145例新生儿出生体重分析[J].中国儿童保健杂志,2008,16(2)：168-169
[47]梁黎,何梦藻.从宫内发育研究代谢综合征的发病机制[J].浙江大学学报：医学版,2008,37(3)： 221-225
[48]Yajnik C., Deshpande S., Jackson A., et al. Vitamin B 12 and folate concentrations during pregnancy and insulin resistance in the offspring:the Pune Maternal Nutrition Study[J]. Diabetologia,2008,51(1):29-38
[49]Reik W., Constancia M., Fowden A., et al. Regulation of supply and demand for maternal nutrients in mammals by imprinted genes[J]. The Journal of physiology,2003,547(1):35-44
[50]Takai D., Gonzales F.A., Tsai Y.C., et al. Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer[J]. Hum Mol Genet,2001,10(23):2619-26
[1]Corry G.N., Tanasijevic B., Barry E.R., et al. Epigenetic regulatory mechanisms during preimplantation development[J]. Birth Defects Research Part C:Embryo Today:Reviews,2009, 87(4):297-313
[2]Trichopoulos D. Hypothesis:does breast cancer originate in utero?[J]. The Lancet,1990, 335(8695):939-940
[3]张玉英,杨玮丽,朱琍燕等.孕产期母鼠体内给予尼古丁对其子代肾脏RAS发育的影响[J].苏州大学学报(医学版),2010,4
[4]李光辉,黄醒华.孕产妇营养对子代的近远期影响[J].中国实用妇科与产科杂志,2007,23(4)： 256-259
[5]Taby R., Issa J.P.J. Cancer epigenetics[J]. CA:a cancer journal for clinicians,2010,60(6): 376-392
[6]张扬.肿瘤发生的表观遗传机制和表观治疗方法[J].中山大学研究生学刊：自然科学与医学版,2008,29(004)：13-20
[7]宫安静.胶质瘤DNA甲基化与叶酸代谢[J].国际神经病学神经外科学杂志IST1C,2010, 37(6)
[8]阚静,李莉,许激扬.叶酸的生物合成及其代谢工程研究进展[J].中国生化药物杂志,2009,30(004)：284-286
[9]余立萍,谭德福.维生素B12缺乏症的研究进展[J].现代中西医结合杂志,2007,16(11)：1584-1585
[10]周艳红,王新.叶酸代谢与出生缺陷的关系研究[J].医学临床研究,2006(09)：1454-1456
[11]李云飞,管英俊,于丽.Wnt信号通路与神经管缺陷关系的研究进展[J].神经解剖学杂志2009,25(002)：236-238
[12]Xu Y., Williams S., O'Brien D., et al. Hypoxia or nutrient restriction during pregnancy in rats leads to progressive cardiac remodeling and impairs postischemic recovery in adult male offspring[J]. The FASEB Journal,2006,20(8):1251
[13]Rich-Edwards J., Colditz G., Stampfer M., et al. Birthweight and the risk for type 2 diabetes mellitus in adult women[J]. Annals of Internal Medicine,1999,130(4 Part 1):278
[14]Kawakami T., Zhang C., Okada Y., et al. Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin[J]. Oncogene,2006,25(23):3225-36
[15]Hajkova P., Erhardt S., Lane N., et al. Epigenetic reprogramming in mouse primordial germ cells[J]. Mechanisms of Development,2002,117(1-2):15-23
[16]Park C.H., Kim H.S., Lee S.G., et al. Methylation status of differentially methylated regions at Igf2/H19 locus in porcine gametes and preimplantation embryos[J]. Genomics,2009,93(2): 179-86
[17]Ouko L.A., Shantikumar K., Knezovich J., et al. Effect of alcohol consumption on CpG methylation in the differentially methylated regions of H19 and IG-DMR in male gametes: implications for fetal alcohol spectrum disorders[J]. Alcohol Clin Exp Res,2009,33(9):1615-27
[18]Horike S., Ferreira J.C., Meguro-Horike M., et al. Screening of DNA methylation at the H19 promoter or the distal region of its ICR1 ensures efficient detection of chromosome 11p15 epimutations in Russell-Silver syndrome[J]. Am J Med Genet A,2009,149A(11):2415-23
[19]Yamamoto E., Suzuki H., Takamaru H., et al. Role of DNA methylation in the development of diffuse-type gastric cancer[J]. Digestion,2011,83(4):241-249
[20]CHAN A.W.H., CHAN M.W.Y., LEE T.L., et al. Promoter hypermethylation of Death-associated protein-kinase gene associated with advance stage gastric canccr[J]. Oncology reports,2005, 13(5):937-941
[21]Liu W., Li X., Chu E.S.H., et al. Paired box gene 5 is a novel tumor suppressor in hepatocellular carcinoma through interaction with p53 signaling pathway[J]. Hepatology,2011,53(3):843-853
[22]Uhm K.O., Lee E.S., Lee Y.M., et al. Aberrant promoter CpG islands methylation of tumor suppressor genes in cholangiocarcinoma[J]. Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics,2008,17(4):151-157
[23]Belinsky S.A., Nikula K.J., Palmisano W.A., et al. Aberrant methylation of p16INK4a is an early event in lung cancer and a potential biomarker for early diagnosis[J]. Proceedings of the National Academy of Sciences,1998,95(20):11891
[24]Roa J., Anabalon L., Roa I., et al. Promoter methylation profile in gastric canccr][J]. Revista medica de Chile,2005,133(8):874
[25]叶静,韦伟,张芳婷等.H19基因在乳腺癌中的印迹状态和表达[J].现代肿瘤医学,2008,No.89(11)：1914-1916
[26]Berteaux N., Aptel N., Cathala G., et al. A novel H19 antisense RNA overexpressed in breast cancer contributes to paternal IGF2 expression[J]. Mol Cell Biol,2008,28(22):6731-45
[27]Adriaenssens E., Dumont L., Lottin S., et al. H19 Overexpression in Breast Adenocarcinoma Stromal Cells Is Associated with Tumor Values and Steroid Receptor Status but Independent of p53 and Ki-67 Expression[J]. The American journal of pathology,1998,153(5):1597-1607
[28]Dammann R.H., Kirsch S., Schagdarsurengin U., et al. Frequent aberrant methylation of the imprinted IGF2/H19 locus and LINE1 hypomethylation in ovarian carcinoma[J]. Int J Oncol, 2010,36(1):171-9
[29]董治龙,钟甘平.H19基因与膀胱移行细胞癌关系的研究进展[J].国际泌尿系统杂志,2006(01)：43-45
[30]孟静,印迹基因H19、LIT1和MEST在肺癌发生中的作用机制研究.2008,大连医科大学.
[31]邱剑萍.宫颈癌中H19基因的特异表达模式及印记缺失分析[J].中国现代医药杂志,2008(11)：31-33
[32]王文玲,高英敏,高俊丽等.印迹基因H19在宫颈癌中的表达及意义[J].肿瘤,2008,No.179(01)：89-90
[33]王月玲,杨新园,李旭.印记基因H19和胰岛素样生长因子Ⅱ在人子宫颈癌组织中印记缺失及意义[J].西安交通大学学报(医学版),2006(04)：372-376
[34]武静,覃扬,李波等.人原发性肝癌胰岛素样生长因子2和H19基因印迹研究[J].四川大学学报(医学版),2007(01)：49-52
[35]Chang A., Moley K., Wangler M., et al. Association between Beckwith-Wiedemann syndrome and assisted reproductive technology:a case series of 19 patients[J]. Fertility and sterility,2005, 83(2):349-354
[36]Cui H., Niemitz E.L., Ravenel J.D., et al. Loss of imprinting of insulin-like growth factor-Ⅱ in Wilms'tumor commonly involves altered methylation but not mutations of CTCF or its binding site[J]. Cancer research,2001,61(13):4947
[37]Nakagawa H., Chadwick R.B., Peltomaki P., et al. Loss of imprinting of the insulin-like growth factor Ⅱ gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer[J]. Proceedings of the National Academy of Sciences,2001,98(2):591
[38]Takai D., Gonzales F.A., Tsai Y.C., et al. Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer[J]. Hum Mol Genet,2001,10(23):2619-26
[39]Feinberg A.P., Cui H., Ohlsson R. DNA methylation and genomic imprinting:insights from cancer into epigenetic mechanisms.2002:Elsevier.
[40]Han L., Lee D.H., Szabo P.E. CTCF is the master organizer of domain-wide allele-specific chromatin at the H19/Igf2 imprinted region[J]. Molecular and cellular biology,2008,28(3): 1124-1135
[41]Cadieux B., Ching T.T., VandenBerg S.R., et al. Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation[J]. Cancer research,2006,66(17):8469-8476
[42]de Caceres I.I., Battagli C., Esteller M., et al. Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients[J]. Cancer research,2004,64(18):6476
[43]马琳,张军航,刘芙蓉等.卵巢上皮性恶性肿瘤组织RASSF1A基因启动子区甲基化的研究[J].中华肿瘤杂志,2006,27(11)：657-659