孕期营养及环境因素对胎儿IGF2 DNA甲基化模式的影响
|
摘要
目的：
探讨“孕期营养及环境因素-IGF2 DNA甲基化模式-新生儿出生特征”三者之间的关系,为肿瘤的预防及早期营养干预提供重要线索。
方法：
1.研究对象的选择：选择2008年4月至2008年9月在郑州市某乡中心卫生院住院的健康产妇作为调查对象,排除具有乙肝、糖尿病及其它消化道慢性疾病史的妇女,告知研究目的和意义后,共计99名产妇参加研究。
2.血清中一碳营养物和血清锌的测定：化学发光免疫荧光法测定血清中叶酸、维生素B12；火焰原子吸收分光光度法测定血清锌。
3.IGF2 DNA甲基化水平的测定：实时荧光定量(Real Time) PCR分析IGF2基因甲基化水平。
4.新生儿出生特征的测量：电子秤称量新生儿体重；头围尺、卧式身长计分别测量新生儿头围和身高。
5.数据整理分析与统计学处理：采用SPSS12.0软件。主要方法有：配对样本的t检验、多重线性回归分析等,以α=0.05为检验水准。
结果：
1.新生儿出生特征与母体血清营养物含量及母亲孕期环境因素的关系：
(1)产妇及新生儿血清叶酸平均水平分别为2.29ng/ml和7.29ng/ml,维生素B12平均水平为175.34pg/ml和240.19pg/ml,锌平均水平为0.67μg/ml和0.93μg/ml。新生儿血清叶酸水平高于产妇叶酸水平(t=-12.183,P=0.001),且两者具有相关性(r=0.367,P=0.001)；新生儿血清维生素B12高于产妇(t=-4.432,P=0.001),两者具有相关性(r=0.325,P=0.001)；新生儿血清锌高于产妇(t=--5.551,P=0.001),但两者间无相关性。
(2)新生儿平均身高为49.48cm,平均体重为3.19kg,平均头围为33.83cm；新生儿出生体重、身长及头围分别与产妇孕前BMI相关(β=0.237,P=0.020；β=0.373,P=0.001；β=0.251,P=0.015)。
(3)新生儿出生体重、出生头围分别与新生儿性别相关(β=-0.292,P=0.004；β=-0.217,P=0.036)。
(4)新生儿身长与产妇剖宫产(β=0.210,P=0.034)相关。
2.产妇及新生儿血清营养物含量及母亲孕期环境因素与IGF2 DNA甲基化模式的关系：
(1)母血IGF2 P2甲基化率均值为2.84%,脐血为3.94%；母血IGF2 P3甲基化率均值为5.83%,脐血为4.11%。新生儿IGF2 P2的DNA甲基化水平高于产妇(t=-2.724,P=0.008),但两者之间无相关性；产妇IGF2 P3的DNA甲基化水平高于新生儿(t=4.376,P=0.001),且两者间具有高度相关性(β=0.403,P=0.001)。
(2)新生儿IGF2 P2的DNA甲基化状态与产妇剖宫产具有相关性(β=0.287,P=0.006)；新生儿IGF2 P3的DNA甲基化状态与产妇血清维生素B12(β=-0.279,P=0.004)、母亲受教育程度(β=0.213,P=0.030)分别相关。
(3)产妇IGF2 P2的甲基化状态与产妇血清维生素B12(β=-0.231,P=0.020)、孕期体重增加(β=0.229,P=0.023)和被动吸烟(β=0.231,P=0.020)分别相关。产妇IGF2 P3的甲基化状态与产妇血清锌(β=-0.234,P=0.022)和产妇受教育程度高(β=-0.290,P=0.005)分别相关。
3.产妇及新生儿IGF2 DNA甲基化状态与新生儿出生特征无相关性；
结论：
1.产妇孕前BMI及剖宫产可影响新生儿的出生体重、身长和头围。
2.母血及脐血IGF2甲基化的水平可能受母血维生素B12水平及孕期被动吸烟影响,且这种影响具有启动子区特异性。
3.未发现新生儿的出生体重、身长和头围与产妇及新生儿IGF2甲基化状态有关。
Objective:
The aim of this study was to explore the relationship among "maternal nutritional intake and environmental factors-IGF2 DNA methylation patterns in offsprings-birth characteristics", and to provide important clues for cancer prevention and nutritional intervention.
Methods:
1. Selection of subjects
Pregnant women, without medical conditions such as diabetes, hepatitis infection or other coeliac diseases, and came to the hospital for delivery between April and September 2008, were considered eligible for the study. The total of 99 mothers participated in this study after being informed the purpose and significance of this study.
2. Determination of one-carbon nutrients in serum
Serum folate and vitamin B12 were determined using paramagnetic particle chemiluminescent immunoassay method. Serum zinc was determined using Atomic absorption spectrophotometry.
3. The determination of IGF2 DNA methylation status
Methylation patterns of IGF2 were analyzed by Real time-PCR.
4. Measurement of birth characteristics
The body weight of offspring was weighed by electronic scale. The head circumference and the birth length of offspring were measured using horizontal length meter.
5. Data management and statistical analysis
All analyses were performed using the SPSS 12.0. Major methods included paired sample T-test, multiple linear regression analysis and so on. A P-value of less than 0.05 was considered statistically significant.
Results:
1. The association between birth characteristics with nutrient content of maternal serum and maternal environmental exposures during pregnancy.
(1) The mean level of serum folate was 2.29ng/ml for maternal and 7.29ng/ml for offsprings respectively. The mean level of serum vitamin B12 was 175.34pg/ml for maternal and 240.19pg/ml for offsprings respectively. The mean level of serum zinc was 0.67μg/ml for maternal and 0.93μg/ml for offsprings respectively. Serum folate levels (t=-12.183,P=0.001), vitamin B,2 levels (t=-4.432,P=0.001)and zinc levels (t=-5.551,P=0.001) in cord blood were significantly higher than in mother's blood respectively. Serum folate levels (r=0.367, P=0.001) and vitamin B12 levels (r=0.325, P=0.001) in cord blood were correlated with mother's blood respectively. Similar correlation, however, was not observed for zinc.
(2) The average birth length of offspring was 49.48cm, the average weight was 3.19kg and the average head circumference was 33.83cm. Birth weight, length and head circumference of offsprings was related with pre-pregnancy body mass index of maternal respectively (β=0.237, P=0.020;β=0.373,P=0.001;β=0.251, P=0.015).
(3) Birth weight and head circumference of offsprings were related with sex of newborn respectively (β=-0.292, P=0.004;β=-0.217, P=0.036).
(4) Birth length of offsprings was related with maternal cesarean (β=0.210, P=0.034).
2. The association between serum nutrient content of maternal and offspring and maternal environmental exposures during pregnancy with IGF2 DNA methylation pattern.
(1) The mean percentages of methylation in P2 promoter were 2.84% for mother's blood and 3.94% for cord blood respectively. The percentages of methylation in P3 were 5.83% for mother's blood and 4.11% for cord blood respectively. The percentage of methylation in P2 in cord blood was significantly higher than in mother's blood (t=-2.724, P=0.008), but uncorrelated with each other. The percentage of methylation in P3 in mother's blood was significantly higher than that in cord blood (t=4.376, P=0.001), and significantly correlated with each other (β=0.403, P=0.001).
(2) IGF2 P2 DNA methylation status of offsprings was related with maternal cesarean (β=0.287, P=0.006). IGF2 P3 DNA methylation status of offsprings was related with maternal serum vitamin B12 (β=-0.279, P=0.004) and education level of mothers (β=0.213,P=0.030).
(3) IGF2 P2 DNA methylation status of maternal was related with maternal serum vitamin B12 (β=-0.231, P=0.020), weight gain during pregnancy (β=0.229,P=0.023) and passive smoking (β=0.231, P=0.020). IGF2 P3 DNA methylation status of maternal was related with maternal serum zinc (β=-0.234,P=0.022) and education level of mothers (β=-0.290,P=0.005).
3. The significant correlation between IGF2 DNA methylation pattern of maternal and offsprings was not found.
Conclusions:
1. Maternal pre-pregnancy body mass index and cesarean may be associated with birth characteristics of offsprings.
2. Exposure to passive smoking during pregnancy and maternal serum vitamin B12 may be associated with IGF2 methylation status of maternal and offsprings.
3. IGF2 methylation status of maternal and offsprings may not be associated with birth characteristics of offsprings.
探讨“孕期营养及环境因素-IGF2 DNA甲基化模式-新生儿出生特征”三者之间的关系,为肿瘤的预防及早期营养干预提供重要线索。
方法：
1.研究对象的选择：选择2008年4月至2008年9月在郑州市某乡中心卫生院住院的健康产妇作为调查对象,排除具有乙肝、糖尿病及其它消化道慢性疾病史的妇女,告知研究目的和意义后,共计99名产妇参加研究。
2.血清中一碳营养物和血清锌的测定：化学发光免疫荧光法测定血清中叶酸、维生素B12；火焰原子吸收分光光度法测定血清锌。
3.IGF2 DNA甲基化水平的测定：实时荧光定量(Real Time) PCR分析IGF2基因甲基化水平。
4.新生儿出生特征的测量：电子秤称量新生儿体重；头围尺、卧式身长计分别测量新生儿头围和身高。
5.数据整理分析与统计学处理：采用SPSS12.0软件。主要方法有：配对样本的t检验、多重线性回归分析等,以α=0.05为检验水准。
结果：
1.新生儿出生特征与母体血清营养物含量及母亲孕期环境因素的关系：
(1)产妇及新生儿血清叶酸平均水平分别为2.29ng/ml和7.29ng/ml,维生素B12平均水平为175.34pg/ml和240.19pg/ml,锌平均水平为0.67μg/ml和0.93μg/ml。新生儿血清叶酸水平高于产妇叶酸水平(t=-12.183,P=0.001),且两者具有相关性(r=0.367,P=0.001)；新生儿血清维生素B12高于产妇(t=-4.432,P=0.001),两者具有相关性(r=0.325,P=0.001)；新生儿血清锌高于产妇(t=--5.551,P=0.001),但两者间无相关性。
(2)新生儿平均身高为49.48cm,平均体重为3.19kg,平均头围为33.83cm；新生儿出生体重、身长及头围分别与产妇孕前BMI相关(β=0.237,P=0.020；β=0.373,P=0.001；β=0.251,P=0.015)。
(3)新生儿出生体重、出生头围分别与新生儿性别相关(β=-0.292,P=0.004；β=-0.217,P=0.036)。
(4)新生儿身长与产妇剖宫产(β=0.210,P=0.034)相关。
2.产妇及新生儿血清营养物含量及母亲孕期环境因素与IGF2 DNA甲基化模式的关系：
(1)母血IGF2 P2甲基化率均值为2.84%,脐血为3.94%；母血IGF2 P3甲基化率均值为5.83%,脐血为4.11%。新生儿IGF2 P2的DNA甲基化水平高于产妇(t=-2.724,P=0.008),但两者之间无相关性；产妇IGF2 P3的DNA甲基化水平高于新生儿(t=4.376,P=0.001),且两者间具有高度相关性(β=0.403,P=0.001)。
(2)新生儿IGF2 P2的DNA甲基化状态与产妇剖宫产具有相关性(β=0.287,P=0.006)；新生儿IGF2 P3的DNA甲基化状态与产妇血清维生素B12(β=-0.279,P=0.004)、母亲受教育程度(β=0.213,P=0.030)分别相关。
(3)产妇IGF2 P2的甲基化状态与产妇血清维生素B12(β=-0.231,P=0.020)、孕期体重增加(β=0.229,P=0.023)和被动吸烟(β=0.231,P=0.020)分别相关。产妇IGF2 P3的甲基化状态与产妇血清锌(β=-0.234,P=0.022)和产妇受教育程度高(β=-0.290,P=0.005)分别相关。
3.产妇及新生儿IGF2 DNA甲基化状态与新生儿出生特征无相关性；
结论：
1.产妇孕前BMI及剖宫产可影响新生儿的出生体重、身长和头围。
2.母血及脐血IGF2甲基化的水平可能受母血维生素B12水平及孕期被动吸烟影响,且这种影响具有启动子区特异性。
3.未发现新生儿的出生体重、身长和头围与产妇及新生儿IGF2甲基化状态有关。
Objective:
The aim of this study was to explore the relationship among "maternal nutritional intake and environmental factors-IGF2 DNA methylation patterns in offsprings-birth characteristics", and to provide important clues for cancer prevention and nutritional intervention.
Methods:
1. Selection of subjects
Pregnant women, without medical conditions such as diabetes, hepatitis infection or other coeliac diseases, and came to the hospital for delivery between April and September 2008, were considered eligible for the study. The total of 99 mothers participated in this study after being informed the purpose and significance of this study.
2. Determination of one-carbon nutrients in serum
Serum folate and vitamin B12 were determined using paramagnetic particle chemiluminescent immunoassay method. Serum zinc was determined using Atomic absorption spectrophotometry.
3. The determination of IGF2 DNA methylation status
Methylation patterns of IGF2 were analyzed by Real time-PCR.
4. Measurement of birth characteristics
The body weight of offspring was weighed by electronic scale. The head circumference and the birth length of offspring were measured using horizontal length meter.
5. Data management and statistical analysis
All analyses were performed using the SPSS 12.0. Major methods included paired sample T-test, multiple linear regression analysis and so on. A P-value of less than 0.05 was considered statistically significant.
Results:
1. The association between birth characteristics with nutrient content of maternal serum and maternal environmental exposures during pregnancy.
(1) The mean level of serum folate was 2.29ng/ml for maternal and 7.29ng/ml for offsprings respectively. The mean level of serum vitamin B12 was 175.34pg/ml for maternal and 240.19pg/ml for offsprings respectively. The mean level of serum zinc was 0.67μg/ml for maternal and 0.93μg/ml for offsprings respectively. Serum folate levels (t=-12.183,P=0.001), vitamin B,2 levels (t=-4.432,P=0.001)and zinc levels (t=-5.551,P=0.001) in cord blood were significantly higher than in mother's blood respectively. Serum folate levels (r=0.367, P=0.001) and vitamin B12 levels (r=0.325, P=0.001) in cord blood were correlated with mother's blood respectively. Similar correlation, however, was not observed for zinc.
(2) The average birth length of offspring was 49.48cm, the average weight was 3.19kg and the average head circumference was 33.83cm. Birth weight, length and head circumference of offsprings was related with pre-pregnancy body mass index of maternal respectively (β=0.237, P=0.020;β=0.373,P=0.001;β=0.251, P=0.015).
(3) Birth weight and head circumference of offsprings were related with sex of newborn respectively (β=-0.292, P=0.004;β=-0.217, P=0.036).
(4) Birth length of offsprings was related with maternal cesarean (β=0.210, P=0.034).
2. The association between serum nutrient content of maternal and offspring and maternal environmental exposures during pregnancy with IGF2 DNA methylation pattern.
(1) The mean percentages of methylation in P2 promoter were 2.84% for mother's blood and 3.94% for cord blood respectively. The percentages of methylation in P3 were 5.83% for mother's blood and 4.11% for cord blood respectively. The percentage of methylation in P2 in cord blood was significantly higher than in mother's blood (t=-2.724, P=0.008), but uncorrelated with each other. The percentage of methylation in P3 in mother's blood was significantly higher than that in cord blood (t=4.376, P=0.001), and significantly correlated with each other (β=0.403, P=0.001).
(2) IGF2 P2 DNA methylation status of offsprings was related with maternal cesarean (β=0.287, P=0.006). IGF2 P3 DNA methylation status of offsprings was related with maternal serum vitamin B12 (β=-0.279, P=0.004) and education level of mothers (β=0.213,P=0.030).
(3) IGF2 P2 DNA methylation status of maternal was related with maternal serum vitamin B12 (β=-0.231, P=0.020), weight gain during pregnancy (β=0.229,P=0.023) and passive smoking (β=0.231, P=0.020). IGF2 P3 DNA methylation status of maternal was related with maternal serum zinc (β=-0.234,P=0.022) and education level of mothers (β=-0.290,P=0.005).
3. The significant correlation between IGF2 DNA methylation pattern of maternal and offsprings was not found.
Conclusions:
1. Maternal pre-pregnancy body mass index and cesarean may be associated with birth characteristics of offsprings.
2. Exposure to passive smoking during pregnancy and maternal serum vitamin B12 may be associated with IGF2 methylation status of maternal and offsprings.
3. IGF2 methylation status of maternal and offsprings may not be associated with birth characteristics of offsprings.
引文
[1]Barker DJ. The fetal and infant origins of adult disease [J], BMJ,1990,301(6761):1111
[2]孙红,王留娣.孕妇血清叶酸水平与早产、婴儿出生体重的关系[J].重庆医学,2002,31(7)：595-596
[3]Jensen CB, Storgaas H, Dela F, et al. Early differential defects of insulin secretion and action in 19-year-old caucasian men who had lowbirth weight [J]. Diabetes,2002,51(4):1271-1280
[4]McCormack VA, Dos Santos Silva I, De Stavola BL, 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
[5]Dos Santos Silva I, De Stavola BL, Hardy RJ, Kuh DJ, et al. Is the association of birth weight with premenopausal breast cancer risk mediated through childhood growth? [J]. Br J Cancer,2004,91(3):519-524
[6]Kaijser M, Akre O, Cnattingius S, et al. Preterm birth, birth weight, and subsequent risk of female breast cancer [J].Br J Cancer,2003,89(9):1664-1666
[7]McCormack VA, Dos Santos Silva I, Koupill, et al. Birth characteristics and adult cancer incidence:Swedish cohort of over 11,000 men and women [J]. Int J Cancer,2005,115 (4): 611-617
[8]Mellemkjaer L, Olsen ML, Sorensen HT, et al. Birth weight and risk of early-onset breast cancer (Denmark) [J]. Cancer Causes Control,2003,14(1):61-64
[9]Vatten LJ, Nilsen TI, Tretli S, et al. Size at birth and risk of breast cancer:prospective population-based study [J]. Int J Cancer,2005,114(3):461-464
[10]金立.出生因素与妇女发生乳腺癌的危险性有关[J].国外医学情报,2001,22(11)：40
[11]胡佳乐,陈云RASSF1A基因甲基化作为肿瘤生物学标志的临床应用[J].中国肿瘤生物治疗杂志,2008,15(3)：296-300
[12]Martens JW, Margossian AL, SchmittM, et al. DNA methylation as a biomarker in breast cancer[J]. Future Oncol,2009,5(8):1245-1256
[13]Wu G, Bazer FW, Cudd TA, et al. Maternal nutrition and fetal development [J]. J Nutr, 2004,134(9):2169-2172
[14]薛京伦.表观遗传学-原理、技术与实践.第1版[M].上海：上海科学技术出版社,2006.64
[15]Sachin Bhusari, Bing Yang, Jessica Kueck, et al. Insulin-like Growth Factor-2(IGF2) Loss of Imprinting Marks a Field Defect Within Human Prostates Containing Cancer [J]. Prostate,2011, doi:10.1002/pros.21379. [Epub ahead of print]
[16]Lee DH, Singh P, Tsark WM, et al. Complete biallelic insulation at the H19/Igf2 imprinting control region position results in fetal growth retardation and perinatal lethality [J]. PLoS One.2010,5(9):el2630
[17]Ravenel JD, Broman KW, Perlman EJ, et al. Loss of imprinting of insulin-like growth factor-II (IGF2) gene in distinguishing specific biologic subtypes of Wilms tumor [J]. J Natl Cancer Inst 2001,93(22):1698-1703
[18]Van den Veyver IB. Genetic effects of methylation diets [J]. Annu Rev Nutr,2002,22 (1): 255-282
[19]马艳春.山西省非综合征性唇鳄裂影响因素病例对照研究[M].[硕士学位论文].太原：山西医科大学,2008
[20]郭新节,吕式瑗,灵爱真,等.孕妇被动吸烟对胎儿的危害[J].中华护理杂志,1993,28(7)：387-389
[21]Gallou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome:new perspective against the epidemic [J]. Diabetes,2005,54(70):1899-1906
[22]孙长颢.营养与食品卫生学.第6版[M].北京：人民卫生出版社,2007.97-98
[23]钱宁,侯新琳,杨艳玲,等.母亲维生素B12缺乏导致婴儿继发性甲基丙二酸尿症的诊断与治疗分析[J].中华围产医学杂志,2005,8(3)：179-182
[24]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
[25]Beeghly AC, Katsaros D, Wiley AL, et al. IGF-II promoter methylation and ovarian cancer prognosis [J]. J Cancer Res Clin Oncol,2007,133(10):713-723
[26]Sussenbach J, Steenbergh PH, Holthuizen P, et al. Structure and expression of the human insulin-like growth factor genes [J]. rowth Regul,1992,2(1):1-9
[27]张农.人肝癌中IGF2表达与基因印迹异常调控的关系[J].上海医科大学学报,1999,26(2)：79-82
[28]Lingeng Lu, Dionyssios Katsaros, Irene A. Rigault de la Longrais, 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 Res 2007,67(21):10117-10122
[29]Beard J, StoltzfusR. Iron-deficiency anaemia:reexamining the nature and magnitude of the public health problem. Proceedings of a conference. May 21-24,2000. Belmont, Maryland, USA [J]. J Nutr,2001,131 (2S-2):563S-703S
[30]杨慧明,毛萌.早期营养对生命质量的远期影响[J].实用儿科临床杂志,2009,24(11)：803-805
[31]党少农,颜虹,邢远,等.育龄妇女血清叶酸及血红蛋白水平调查[J].中国公共卫生2009,25(2)：134-136
[32]尹国武,杨梦庚,王金声,等.产妇血清脐血及乳汁中叶酸和维生素Bi2水平测定及意义[J].中国实用妇科与产科杂志,1997,13(5)：278-280
[33]黄达勇.孕妇和脐带血的铁蛋白、叶酸、维生素B12的相关性研究[D].[硕十学位论文].天津：天津医科大学,2003
[34]Ek J. Plasma and red cell folate value newborn infant and their mother in relation to gestational age [J]. J Pediatr,1980,97(2):288-292
[35]夏怡.叶酸-应受重视的维生素[J].精细与专用化学品,2000,8(6)：19
[36]张家颖,左文静,武广恒,等MTHFR基因C677T多态性与习惯性流产的关联性分析[J].吉林大学学报：医学版,2009,35(4)：698-701
[37]赵培忠,徐令璧.正常妊娠各期红细胞、血清Zn、Cu、Fe及SFe、CP、A含量的研究[J].徐州医学院学报,1992,12(4)：305-306
[38]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,1988,2：4-5
[39]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,1996,25(2)：171-172
[40]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,1992,21(4)：193-196
[41]孙长颢,营养与食品卫生学.第六版[M].北京：人民卫生出版社.2007.63-64
[42]周超,王佳,陈萍萍,等.脐血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(4)：856-858
[43]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,2005,20(22)：2933
[44]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,2001,17(2)：108-109
[45]仇小强,曾小云,黄栋,等.锌干预对妊娠结局和新生儿生长发育的影响[J].中国临床康复,2004(36)：8298-8299
[46]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),2004,31(5)：496-501
[47]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(1)：34-35
[48]覃耀明.广西农村120 145例新生儿出生体重分析[J].中国儿童保健杂志,2008,16(2)：168-169
[49]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,2008,37(3)：222-224
[50]Yajn IK, Deshpande SS, Jackson AA, et al. Vitamin B12 and folate concentrations during p regnancy and insulin resistance in the offspring:the pune maternal nutrition study [J]. D iabetologia,2008,51 (1):29-38
[51]蒋文跃,韩巍,李志新.成人疾病胎源学说的证据及机制[J].北京大学学报,2007,39(1)：96-100
[52]Reik W, Constancia M, Fowden A, et al. Regulation of supply and demand for maternal nutrients in mammals by imprinted genes [J]. Physiol,2003,5(47):35-44
[53]Langley-Evans SC, McMullen S. Developmental origins of adult disease [J]. Med Princ Pract,2010,19(2):87-98
[54]McCormack VA, Dos Santo Silva I, Koupil I, et al. Birth characteristics and adult cancer incidence:Swedish cohort of over 11,000 men and women [J]. Int J Cancer,2005,115 (4): 611-617
[55]Wolff GL, Kodell RL, Moore, SR, et al. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice[J]. FASEB J,1998,12(11):949-957
[56]Waterland RA, Jirtle RL. Transposable elements:targets for early nutritional effects on epigenetic gene regulation [J]. Mol Cell Biol,2003,23(15):5293-5300
[57]Lillycrop KA, Phillips ES, Jackson A A, et al. Dietary protein restriction of pregnant rats induces and folate supplementation prevents epigenetic modification of hepatic gene expression in the offspring [J]. J Nutr,2005,135(6):1382-1386
[1]Barker DJ. The fetal and infant origins of adult disease [J]. BMJ,1990,301(6761):1111
[2]Laird PW. Cancer epigenetics [J]. Hum mol Genet,2005,14(1):65-76
[3]董玉玮,侯进慧,朱必才,等.表观遗传学的相关概念和研究进展[J].生物学杂志,2005,22(1)：1-3
[4]Ulrey CL, Liu L, Andrews LG, et al. The impact of metabolism on DNA methylation [J]. Human Molecular Genetics,2005,14(1):139-147
[5]Huang TH, Perry MR, Laux DE, Methylation profiling of CpG island in human breast cancer cells [J]. Hum MolGenet,1999,8(3):459-470
[6]Robertson KD. DNA methylation and chromatin-unraveling the tangled web [J]. Oncogene, 2002,21(35):5361-5379
[7]Okano M, Bell DW, Haber DA, et al. DNA methyltransferases DNMT3a and DNMT3b are essential for de novo methylation and mammalian development [J]. Cell,1999,99(3): 247-257
[8]陆娟,房静远.叶酸、DNA甲基化与消化性肿瘤[J].胃肠病学,2002,7(2)：111-112
[9]马景丽.叶酸缺乏对DNA修复、合成及甲基化过程的影响及其对宫颈癌发生、发展的作用[D].[硕士学位论文].太原：山西医科大学,2008
[10]薛京伦.表观遗传学-原理、技术与实践.第1版[M].上海：上海科学技术出版社,2006.293-294
[11]Fowler BM, Giuliano AR, Piyathilake C, et al. Hypomethylation in cervical tissue:is there a correlation with folate status [J]. Cancer Epidemiol Biomarker Prev,1998,7(10):901-906
[12]Fenech M. The role of folate and Vitamin B12 in genomic stability of human cells [J]. Mutat Res,2001,475(1-2):57-67
[13]Jacob RA, Gretz DM, Tayior PC, et al. Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women [J]. J Nutr,1998,128(7):1204-1212
[14]Ghoshal K. Li X. Datta J, et al. A folate-and methyl-deficient diet alters the expression of DNA methyltransferases and methyl CpG binding proteins involved in epigenetic gene silencing in livers of f344 rats [J]. J Nutr,2006,136(6):1522-1527
[15]Kim YI, Pogribny IP, Basnakian AG, et al. Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene[J]. Am J Clin Natr, 1997,65(1):46-52
[16]Shiff SJ, Qiao L, Tsai U, et al. Sulindac sulfide, an aspirin-like compound, inhibits proliferation, cause cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells [J]. J Clin Invest,1995,96(1):491-503
[17]Kim YI, Pogribny IP, Salomon RN, et al. Exon-specific DNA hpyomethylation of the p53 gene of rat colon induced by dimethylhydrazine. Modulation by dietary folate [J]. Am J Pathol,1996,149(4):1129-1137
[18]孙红,王留娣.孕妇血清叶酸水平与早产、婴儿出生体重的关系[J].重庆医学,2002,31(7)：595-596
[19]Jensen CB, Storgaas H, Dela F, et al. Early differential defects of insulin secretion and action in 19-year-old Caucasian men who had lowbirth weight[J]. Diabetes,2002,51(4): 1271-1280
[20]Rich-Edwards JW, Colditz GA, Stanpfer MJ, et al. Birthweight and the risk for type 2 diabetes mellitus in adult women [J]. Ann Intern Med,1999,130(4 pt 1):278-284
[21]LawCM, Shiell AW, Newsome CA, et al. Fetal, infant, and child-hood growth and adult blood pressure:a longitudinal study from birth to22 years ofage[J].Circulation,2002, 105(9):1088-1092
[22]Trichopoulos D. Hypothesis:does breast cancer originate in utero?[J]. Lancet,1990, 335(8695):939-940
[23]McCormack VA, Dos Santos Silva I, De Stavola BL, 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
[24]Dos Santos Silva I, De Stavola BL, Hardy RJ, et al. Is the association of birth weight with premenopausal breast cancer risk mediated through childhood growth? [J]. Br J Cancer,2004,91(3):519-524
[25]Kaijser M, Akre O, Cnattingius S, et al. Preterm birth, birth weight, and subsequent risk of female breast cancer [J]. BrJ Cancer,2003,89(9):1664-1666
[26]McCormack VA, Dos Santos Silva I, Koupil I, et al. Birth characteristics and adult cancer incidence:Swedish cohort of over 11,000 men and women [J]. Int J Cancer,2005,115 (4): 611-617
[27]Mellemkjaer L, Olsen ML, Sorensen HT, et al. Birth weight and risk of early-onset breast cancer (Denmark)[J]. Cancer Causes Control,2003,14(1):61-64
[28]HoltRI, Byrne CD. Intrauterine growth, the vascular system, and the metabolic syndrome [J]. Semin Vase Med,2002,2(1):33-43
[29]姚建凤,杨晓煜,郑鸣.表观遗传影响胚胎发育研究进展[J].解剖学杂志,2009,32(1)：124-126
[30]Park SY, Kwon HJ, Lee HE, et al. Promoter CpG island hypermethylation during breast cancer progression [J]. Virchows Arch,2011,458(1):73-84
[31]程焕臣,马军.表观遗传修饰与肿瘤[J].内科理论与实践,2009,4(1)：72-75
[32]Paz MF, Fraga MF, Avila S, et al. A systematic profile of DNA methylation in human cancer cell line [J]. Cancer Res,2003,63(5):1114-1121
[33]薛京伦.表观遗传学-原理、技术与实践.第1版[M].上海：上海科学技术出版社,2006.64
[34]Schofield PN, Joyce JA, Lam WK, et al. Genomic imprinting and cancer; new paradigms in the genetics of neoplasia [J]. Toxicol Lett,2001,120(1-3):151-160
[35]Tycko B. Epigenetic gene silencing in cancer [J]. J Clin Invest,2000,105(4):401-407
[36]Ravenel JD, Broman KW, Perlman EJ, et al. Loss of imprinting of insulinlike growth factor-II (IGF2) gene in distinguishing specific biologic subtypes of Wilms tumor [J]. J Natl Cancer Inst,2001,93(22):1698-1703
[37]Bates P, Fisher R, Ward A, et al. Mammary cancer in transgenic mice expressing insulin-like growth factor II (IGF-II)[J]. Br J Cancer,1995,72(5):1189-1193
[38]Van Roozendaal CE, Gillis AJ, Klijn JG, et al. Loss of imprinting of IGF2 and not H19 in breast cancer, adjacent normal tissue and derived fibroblast cultures [J]. FEBS Lett,1998, 437(1-2):107-111
[39]McCann AH, Miller N, O'Meara A, et al. Biallelic expression of the IGF2 gene in human breast disease [J]. Hum Mol Genet,1996,5(8):1123-1127
[40]Charalambous M, Menheniott TR, Bennett WR, et al. An enhancer element at the Igf2/H19 locus drives gene expression in both imprinted and non-imprinted tissues [J]. Dev Biol, 2004,271(2):488-497
[41]Angiolini E, Fowden A, Coan P, et al. Regulation of placental efficiency for nutrient transport by imprinted genes [J]. Placenta,2006,27 (1):.98-102
[42]Reik W.Walter J. Genomic imprinting:parental influence on the genome [J]. Nat Rev Genet,2001,2(1):21-32
[43]Chang AS, Moley KH, Wangler M, et al. Association between Beckwith-Wiedemann syndrome and assisted reproductive technology:a case series of 19 patients [J]. Fertil Steril, 2005,83(2):349-354
[44]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]. Biol Reprod,2004,70(6):1790-1797
[2]孙红,王留娣.孕妇血清叶酸水平与早产、婴儿出生体重的关系[J].重庆医学,2002,31(7)：595-596
[3]Jensen CB, Storgaas H, Dela F, et al. Early differential defects of insulin secretion and action in 19-year-old caucasian men who had lowbirth weight [J]. Diabetes,2002,51(4):1271-1280
[4]McCormack VA, Dos Santos Silva I, De Stavola BL, 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
[5]Dos Santos Silva I, De Stavola BL, Hardy RJ, Kuh DJ, et al. Is the association of birth weight with premenopausal breast cancer risk mediated through childhood growth? [J]. Br J Cancer,2004,91(3):519-524
[6]Kaijser M, Akre O, Cnattingius S, et al. Preterm birth, birth weight, and subsequent risk of female breast cancer [J].Br J Cancer,2003,89(9):1664-1666
[7]McCormack VA, Dos Santos Silva I, Koupill, et al. Birth characteristics and adult cancer incidence:Swedish cohort of over 11,000 men and women [J]. Int J Cancer,2005,115 (4): 611-617
[8]Mellemkjaer L, Olsen ML, Sorensen HT, et al. Birth weight and risk of early-onset breast cancer (Denmark) [J]. Cancer Causes Control,2003,14(1):61-64
[9]Vatten LJ, Nilsen TI, Tretli S, et al. Size at birth and risk of breast cancer:prospective population-based study [J]. Int J Cancer,2005,114(3):461-464
[10]金立.出生因素与妇女发生乳腺癌的危险性有关[J].国外医学情报,2001,22(11)：40
[11]胡佳乐,陈云RASSF1A基因甲基化作为肿瘤生物学标志的临床应用[J].中国肿瘤生物治疗杂志,2008,15(3)：296-300
[12]Martens JW, Margossian AL, SchmittM, et al. DNA methylation as a biomarker in breast cancer[J]. Future Oncol,2009,5(8):1245-1256
[13]Wu G, Bazer FW, Cudd TA, et al. Maternal nutrition and fetal development [J]. J Nutr, 2004,134(9):2169-2172
[14]薛京伦.表观遗传学-原理、技术与实践.第1版[M].上海：上海科学技术出版社,2006.64
[15]Sachin Bhusari, Bing Yang, Jessica Kueck, et al. Insulin-like Growth Factor-2(IGF2) Loss of Imprinting Marks a Field Defect Within Human Prostates Containing Cancer [J]. Prostate,2011, doi:10.1002/pros.21379. [Epub ahead of print]
[16]Lee DH, Singh P, Tsark WM, et al. Complete biallelic insulation at the H19/Igf2 imprinting control region position results in fetal growth retardation and perinatal lethality [J]. PLoS One.2010,5(9):el2630
[17]Ravenel JD, Broman KW, Perlman EJ, et al. Loss of imprinting of insulin-like growth factor-II (IGF2) gene in distinguishing specific biologic subtypes of Wilms tumor [J]. J Natl Cancer Inst 2001,93(22):1698-1703
[18]Van den Veyver IB. Genetic effects of methylation diets [J]. Annu Rev Nutr,2002,22 (1): 255-282
[19]马艳春.山西省非综合征性唇鳄裂影响因素病例对照研究[M].[硕士学位论文].太原：山西医科大学,2008
[20]郭新节,吕式瑗,灵爱真,等.孕妇被动吸烟对胎儿的危害[J].中华护理杂志,1993,28(7)：387-389
[21]Gallou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome:new perspective against the epidemic [J]. Diabetes,2005,54(70):1899-1906
[22]孙长颢.营养与食品卫生学.第6版[M].北京：人民卫生出版社,2007.97-98
[23]钱宁,侯新琳,杨艳玲,等.母亲维生素B12缺乏导致婴儿继发性甲基丙二酸尿症的诊断与治疗分析[J].中华围产医学杂志,2005,8(3)：179-182
[24]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
[25]Beeghly AC, Katsaros D, Wiley AL, et al. IGF-II promoter methylation and ovarian cancer prognosis [J]. J Cancer Res Clin Oncol,2007,133(10):713-723
[26]Sussenbach J, Steenbergh PH, Holthuizen P, et al. Structure and expression of the human insulin-like growth factor genes [J]. rowth Regul,1992,2(1):1-9
[27]张农.人肝癌中IGF2表达与基因印迹异常调控的关系[J].上海医科大学学报,1999,26(2)：79-82
[28]Lingeng Lu, Dionyssios Katsaros, Irene A. Rigault de la Longrais, 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 Res 2007,67(21):10117-10122
[29]Beard J, StoltzfusR. Iron-deficiency anaemia:reexamining the nature and magnitude of the public health problem. Proceedings of a conference. May 21-24,2000. Belmont, Maryland, USA [J]. J Nutr,2001,131 (2S-2):563S-703S
[30]杨慧明,毛萌.早期营养对生命质量的远期影响[J].实用儿科临床杂志,2009,24(11)：803-805
[31]党少农,颜虹,邢远,等.育龄妇女血清叶酸及血红蛋白水平调查[J].中国公共卫生2009,25(2)：134-136
[32]尹国武,杨梦庚,王金声,等.产妇血清脐血及乳汁中叶酸和维生素Bi2水平测定及意义[J].中国实用妇科与产科杂志,1997,13(5)：278-280
[33]黄达勇.孕妇和脐带血的铁蛋白、叶酸、维生素B12的相关性研究[D].[硕十学位论文].天津：天津医科大学,2003
[34]Ek J. Plasma and red cell folate value newborn infant and their mother in relation to gestational age [J]. J Pediatr,1980,97(2):288-292
[35]夏怡.叶酸-应受重视的维生素[J].精细与专用化学品,2000,8(6)：19
[36]张家颖,左文静,武广恒,等MTHFR基因C677T多态性与习惯性流产的关联性分析[J].吉林大学学报：医学版,2009,35(4)：698-701
[37]赵培忠,徐令璧.正常妊娠各期红细胞、血清Zn、Cu、Fe及SFe、CP、A含量的研究[J].徐州医学院学报,1992,12(4)：305-306
[38]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,1988,2：4-5
[39]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,1996,25(2)：171-172
[40]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,1992,21(4)：193-196
[41]孙长颢,营养与食品卫生学.第六版[M].北京：人民卫生出版社.2007.63-64
[42]周超,王佳,陈萍萍,等.脐血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(4)：856-858
[43]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,2005,20(22)：2933
[44]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,2001,17(2)：108-109
[45]仇小强,曾小云,黄栋,等.锌干预对妊娠结局和新生儿生长发育的影响[J].中国临床康复,2004(36)：8298-8299
[46]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),2004,31(5)：496-501
[47]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(1)：34-35
[48]覃耀明.广西农村120 145例新生儿出生体重分析[J].中国儿童保健杂志,2008,16(2)：168-169
[49]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,2008,37(3)：222-224
[50]Yajn IK, Deshpande SS, Jackson AA, et al. Vitamin B12 and folate concentrations during p regnancy and insulin resistance in the offspring:the pune maternal nutrition study [J]. D iabetologia,2008,51 (1):29-38
[51]蒋文跃,韩巍,李志新.成人疾病胎源学说的证据及机制[J].北京大学学报,2007,39(1)：96-100
[52]Reik W, Constancia M, Fowden A, et al. Regulation of supply and demand for maternal nutrients in mammals by imprinted genes [J]. Physiol,2003,5(47):35-44
[53]Langley-Evans SC, McMullen S. Developmental origins of adult disease [J]. Med Princ Pract,2010,19(2):87-98
[54]McCormack VA, Dos Santo Silva I, Koupil I, et al. Birth characteristics and adult cancer incidence:Swedish cohort of over 11,000 men and women [J]. Int J Cancer,2005,115 (4): 611-617
[55]Wolff GL, Kodell RL, Moore, SR, et al. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice[J]. FASEB J,1998,12(11):949-957
[56]Waterland RA, Jirtle RL. Transposable elements:targets for early nutritional effects on epigenetic gene regulation [J]. Mol Cell Biol,2003,23(15):5293-5300
[57]Lillycrop KA, Phillips ES, Jackson A A, et al. Dietary protein restriction of pregnant rats induces and folate supplementation prevents epigenetic modification of hepatic gene expression in the offspring [J]. J Nutr,2005,135(6):1382-1386
[1]Barker DJ. The fetal and infant origins of adult disease [J]. BMJ,1990,301(6761):1111
[2]Laird PW. Cancer epigenetics [J]. Hum mol Genet,2005,14(1):65-76
[3]董玉玮,侯进慧,朱必才,等.表观遗传学的相关概念和研究进展[J].生物学杂志,2005,22(1)：1-3
[4]Ulrey CL, Liu L, Andrews LG, et al. The impact of metabolism on DNA methylation [J]. Human Molecular Genetics,2005,14(1):139-147
[5]Huang TH, Perry MR, Laux DE, Methylation profiling of CpG island in human breast cancer cells [J]. Hum MolGenet,1999,8(3):459-470
[6]Robertson KD. DNA methylation and chromatin-unraveling the tangled web [J]. Oncogene, 2002,21(35):5361-5379
[7]Okano M, Bell DW, Haber DA, et al. DNA methyltransferases DNMT3a and DNMT3b are essential for de novo methylation and mammalian development [J]. Cell,1999,99(3): 247-257
[8]陆娟,房静远.叶酸、DNA甲基化与消化性肿瘤[J].胃肠病学,2002,7(2)：111-112
[9]马景丽.叶酸缺乏对DNA修复、合成及甲基化过程的影响及其对宫颈癌发生、发展的作用[D].[硕士学位论文].太原：山西医科大学,2008
[10]薛京伦.表观遗传学-原理、技术与实践.第1版[M].上海：上海科学技术出版社,2006.293-294
[11]Fowler BM, Giuliano AR, Piyathilake C, et al. Hypomethylation in cervical tissue:is there a correlation with folate status [J]. Cancer Epidemiol Biomarker Prev,1998,7(10):901-906
[12]Fenech M. The role of folate and Vitamin B12 in genomic stability of human cells [J]. Mutat Res,2001,475(1-2):57-67
[13]Jacob RA, Gretz DM, Tayior PC, et al. Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women [J]. J Nutr,1998,128(7):1204-1212
[14]Ghoshal K. Li X. Datta J, et al. A folate-and methyl-deficient diet alters the expression of DNA methyltransferases and methyl CpG binding proteins involved in epigenetic gene silencing in livers of f344 rats [J]. J Nutr,2006,136(6):1522-1527
[15]Kim YI, Pogribny IP, Basnakian AG, et al. Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene[J]. Am J Clin Natr, 1997,65(1):46-52
[16]Shiff SJ, Qiao L, Tsai U, et al. Sulindac sulfide, an aspirin-like compound, inhibits proliferation, cause cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells [J]. J Clin Invest,1995,96(1):491-503
[17]Kim YI, Pogribny IP, Salomon RN, et al. Exon-specific DNA hpyomethylation of the p53 gene of rat colon induced by dimethylhydrazine. Modulation by dietary folate [J]. Am J Pathol,1996,149(4):1129-1137
[18]孙红,王留娣.孕妇血清叶酸水平与早产、婴儿出生体重的关系[J].重庆医学,2002,31(7)：595-596
[19]Jensen CB, Storgaas H, Dela F, et al. Early differential defects of insulin secretion and action in 19-year-old Caucasian men who had lowbirth weight[J]. Diabetes,2002,51(4): 1271-1280
[20]Rich-Edwards JW, Colditz GA, Stanpfer MJ, et al. Birthweight and the risk for type 2 diabetes mellitus in adult women [J]. Ann Intern Med,1999,130(4 pt 1):278-284
[21]LawCM, Shiell AW, Newsome CA, et al. Fetal, infant, and child-hood growth and adult blood pressure:a longitudinal study from birth to22 years ofage[J].Circulation,2002, 105(9):1088-1092
[22]Trichopoulos D. Hypothesis:does breast cancer originate in utero?[J]. Lancet,1990, 335(8695):939-940
[23]McCormack VA, Dos Santos Silva I, De Stavola BL, 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
[24]Dos Santos Silva I, De Stavola BL, Hardy RJ, et al. Is the association of birth weight with premenopausal breast cancer risk mediated through childhood growth? [J]. Br J Cancer,2004,91(3):519-524
[25]Kaijser M, Akre O, Cnattingius S, et al. Preterm birth, birth weight, and subsequent risk of female breast cancer [J]. BrJ Cancer,2003,89(9):1664-1666
[26]McCormack VA, Dos Santos Silva I, Koupil I, et al. Birth characteristics and adult cancer incidence:Swedish cohort of over 11,000 men and women [J]. Int J Cancer,2005,115 (4): 611-617
[27]Mellemkjaer L, Olsen ML, Sorensen HT, et al. Birth weight and risk of early-onset breast cancer (Denmark)[J]. Cancer Causes Control,2003,14(1):61-64
[28]HoltRI, Byrne CD. Intrauterine growth, the vascular system, and the metabolic syndrome [J]. Semin Vase Med,2002,2(1):33-43
[29]姚建凤,杨晓煜,郑鸣.表观遗传影响胚胎发育研究进展[J].解剖学杂志,2009,32(1)：124-126
[30]Park SY, Kwon HJ, Lee HE, et al. Promoter CpG island hypermethylation during breast cancer progression [J]. Virchows Arch,2011,458(1):73-84
[31]程焕臣,马军.表观遗传修饰与肿瘤[J].内科理论与实践,2009,4(1)：72-75
[32]Paz MF, Fraga MF, Avila S, et al. A systematic profile of DNA methylation in human cancer cell line [J]. Cancer Res,2003,63(5):1114-1121
[33]薛京伦.表观遗传学-原理、技术与实践.第1版[M].上海：上海科学技术出版社,2006.64
[34]Schofield PN, Joyce JA, Lam WK, et al. Genomic imprinting and cancer; new paradigms in the genetics of neoplasia [J]. Toxicol Lett,2001,120(1-3):151-160
[35]Tycko B. Epigenetic gene silencing in cancer [J]. J Clin Invest,2000,105(4):401-407
[36]Ravenel JD, Broman KW, Perlman EJ, et al. Loss of imprinting of insulinlike growth factor-II (IGF2) gene in distinguishing specific biologic subtypes of Wilms tumor [J]. J Natl Cancer Inst,2001,93(22):1698-1703
[37]Bates P, Fisher R, Ward A, et al. Mammary cancer in transgenic mice expressing insulin-like growth factor II (IGF-II)[J]. Br J Cancer,1995,72(5):1189-1193
[38]Van Roozendaal CE, Gillis AJ, Klijn JG, et al. Loss of imprinting of IGF2 and not H19 in breast cancer, adjacent normal tissue and derived fibroblast cultures [J]. FEBS Lett,1998, 437(1-2):107-111
[39]McCann AH, Miller N, O'Meara A, et al. Biallelic expression of the IGF2 gene in human breast disease [J]. Hum Mol Genet,1996,5(8):1123-1127
[40]Charalambous M, Menheniott TR, Bennett WR, et al. An enhancer element at the Igf2/H19 locus drives gene expression in both imprinted and non-imprinted tissues [J]. Dev Biol, 2004,271(2):488-497
[41]Angiolini E, Fowden A, Coan P, et al. Regulation of placental efficiency for nutrient transport by imprinted genes [J]. Placenta,2006,27 (1):.98-102
[42]Reik W.Walter J. Genomic imprinting:parental influence on the genome [J]. Nat Rev Genet,2001,2(1):21-32
[43]Chang AS, Moley KH, Wangler M, et al. Association between Beckwith-Wiedemann syndrome and assisted reproductive technology:a case series of 19 patients [J]. Fertil Steril, 2005,83(2):349-354
[44]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]. Biol Reprod,2004,70(6):1790-1797