基因组印迹与生殖疾病

表观遗传修饰中印迹基因对胎儿的发育具有重要的作用,对个体的生长与行为也有深远影响,特别是对胎盘发育极为重要。印迹基因的异常和失调不仅影响胚胎和胎盘发育,还可诱发出生后的发育异常而导致多种疾病发生。大量证据表明,许多肿瘤的发生都与其相应基因组印迹丢失有关。许多研究工作分析了辅助生殖技术和印迹失调之间的联系。对印迹基因和各种表观遗传疾病做文献综述,并对辅助生殖技术所致的遗传风险作简要探讨,以评估这些技术的安全性。     

基因组印迹与生殖疾病

表观遗传修饰中印迹基因对胎儿的发育具有重要的作用,对式分个体的生长与行为也有深远影响,特别是对胎盘发育极为重要.印迹基因的异常和失调不仅影响胚胎和胎盘发育,还可诱发出生后的发育异常而导致多种疾病发生.大量证据表明,许多肿瘤的发生都与其相应基因组印迹丢失有关.许多研究工作分析了辅助生殖技术和印迹失调之间的联系.对印迹基因和各种表观遗传疾病做文献,并对辅助生殖技术所致的遗传风险作简要探讨,以评估这些技术的安全性.     

生殖安全研究进展

生殖安全的理念在2005年中华医学会生殖医学分会成立大会上提出至今,受到了国内外学者前所未有的关注。胚胎源性疾病的新概念已在国家重大基础研究计划———＂ART致胚胎源性疾病机制研究＂中立项开篇探索。辅助生殖技术（ART）涉及的超促排卵、体外受精、体外培养、配子/胚胎冻融、卵裂球活检等非生理性的过程,引发了相应的＂生殖安全性问题＂。其可能与高流产率、早产、先天畸形、低出生体质量等不良健康风险、遗传病、染色体异常、表观遗传修饰异常、神经系统发育异常、肿瘤等成年期疾病发生有联系。除了ART本身,亲代生殖障碍相关疾病可通过干扰分子表达、信号通路等影响配子发生、受精、胚胎发育及着床。亲代妊娠期并发症引起的宫内环境异常可能通过干扰基因、蛋白表达导致子代迟发性疾病的发生。亲代感染性疾病则可通过配子垂直传播给子代,影响子代健康。生殖安全还依赖于环境安全,环境中各种有害因素包括物理和化学因素均可能对生物生殖行为产生不良影响。     

辅助生殖技术与胚胎DNA甲基化

表观遗传修饰,尤其DNA甲基化在控制细胞表达中发挥重要作用。高甲基化的DNA与基因沉默有关,低甲基化的DNA可以激活基因的转录,哺乳动物中70%~80%的Cp G位点被甲基化。DNA的甲基化状态并不像基因组那样稳定,在原始生殖细胞(primordial germ cells,PGCs)和早期胚胎阶段发生了一系列重组,即甲基化模式擦除、甲基化模式重新建立和甲基化模式维持。发达国家通过辅助生殖技术(assisted reproductive technology,ART)出生的婴儿已占1%~3%,并不断增长。ART方案的多样性和基因组印迹疾病的罕见性导致ART过程与印迹障碍发病率间的因果关系复杂化。除早产的发生率增加外,ART过程可导致配子及胚胎发生异常的表观遗传修饰和重组。脐疝-巨舌-巨体综合征(Beckwith-Wiedemann syndrome,BWS)、普达-威利综合征(Prader-Willi syndrome,PWS)等均为最具有代表性的基因组印迹疾病。     

辅助生殖技术中基因印迹分析

人类辅助生殖临床数据已经显示,辅助生殖技术（ART）与自发流产、早产和围生期死亡、低体质量儿以及一些印迹疾病有关。在配子及胚胎早期发育过程中,基因印迹需经历印迹擦除、重建和维持过程,其中任何一个环节出错都可能导致胚胎发育缺陷,甚至死亡。ART恰施于这一表观遗传重编程的关键时期。因此,这些异常结局可能与ART导致的印迹基因的异常表达有关。而ART中主要的治疗手段有促排卵、体外受精、胞浆内单精子注射（ICSI）和体外培养。这些操作通过干扰基因印迹的重建和维持,影响基因表达和表型,进而影响配子和早期胚胎的发育,从而影响子代的生长发育潜能。     

生殖安全研究进展

生殖安全的理念在2005年中华医学会生殖医学分会成立大会上提出至今,受到了国内外学者前所未有的关注。胚胎源性疾病的新概念已在国家重大基础研究计划———"ART致胚胎源性疾病机制研究"中立项开篇探索。辅助生殖技术(ART)涉及的超促排卵、体外受精、体外培养、配子/胚胎冻融、卵裂球活检等非生理性的过程,引发了相应的"生殖安全性问题"。其可能与高流产率、早产、先天畸形、低出生体质量等不良健康风险、遗传病、染色体异常、表观遗传修饰异常、神经系统发育异常、肿瘤等成年期疾病发生有联系。除了ART本身,亲代生殖障碍相关疾病可通过干扰分子表达、信号通路等影响配子发生、受精、胚胎发育及着床。亲代妊娠期并发症引起的宫内环境异常可能通过干扰基因、蛋白表达导致子代迟发性疾病的发生。亲代感染性疾病则可通过配子垂直传播给子代,影响子代健康。生殖安全还依赖于环境安全,环境中各种有害因素包括物理和化学因素均可能对生物生殖行为产生不良影响。     

人类辅助生殖技术子代安全性研究进展

随着辅助生殖技术（ART）子代人数的增加和生存时间的延长，人们对其围生期结局、出生缺陷、基因印迹改变和远期发育等方面的健康风险有了较以往更深入的研究和了解。亲代的不孕背景及胚胎操作导致的子代表观遗传修饰改变可能是导致 ART 子代健康风险增加的基础。全面的评估尚需要大样本、高质量、前瞻性的对照研究和流行病学调查，有利于今后对 ART 方案进行针对性地改善和优化，降低子代风险。     

胎源性疾病发生中表观遗传学变化的研究进展

近年来,多项针对"健康与疾病的发育起源(DOHa D)"学说展开的动物实验及流行病学调查研究发现,DNA甲基化、组蛋白修饰及非编码RNA的转录调控等表观遗传修饰可能是引发胎源性疾病的重要机制之一,如nr3c1和11β-hsd-2基因的异常甲基化可影响胎儿神经系统的发育,导致其出生后神经行为的异常即抑郁症、精神分裂症等精神障碍的发生;而组蛋白脱乙酰酶3(HDAC3)可引起胎儿第二心室发育过程中的形态缺陷及细胞外基质异常,与人类先天性心脏病的发病直接相关。现就胎源性疾病发生中表观遗传学变化的研究进展进行综述,可为部分胎源性疾病的预防及临床诊断与治疗提供重要的理论基础及可靠的实验依据。     

宫内高雄激素环境与子代多囊卵巢综合征

近年研究认为,多囊卵巢综合征(polycystic ovary syndrome,PCOS)是一种胎源性疾病.胎儿暴露于宫内高雄激素环境,可能引起多个组织内基因表观遗传修饰状态的改变,如基因DNA甲基化、子代基因印迹的改变,干扰胎儿下丘脑-垂体-卵巢轴和内脏靶器官的生理发育过程,导致下丘脑对类固醇激素的负反馈调节敏感性下降和胰腺功能受损,造成青春期或成年后出现各种PCOS症状.明确PCOS的早期发病机制,对预防高危人群PCOS的发生与发展具有临床意义.     

辅助生殖技术与基因印迹异常

基因印迹指某些基因来源于不同亲代的一对等位基因发生的差异性表达.关于辅助生殖技术(ART)与基因印迹异常的相关研究已成为生殖安全研究的前沿和热点.ART包括控制性超排卵、体外受精/胞浆内单精子注射、胚胎体外成熟和胚胎移植等,而究竟哪个环节造成、如何造成基因印迹异常,乃至引起基因印迹疾病目前尚未明确.诸多研究显示,在患者...     

子宫内膜异位症不孕的表观遗传学研究进展

子宫内膜异位症是生育年龄妇女不孕的主要原因之一,其机制仍不清楚.最新研究发现,子宫内膜异位症可能是一种表观遗传性疾病.DNA甲基化异常和印记功能紊乱是表现遗传异常的主要形式.在子宫内膜异位症中存在DNA的异常甲基化,这种异常甲基化与子宫内膜异位症不孕有关;印记基因对胎儿及胎盘的发育具有十分重要的作用,子宫内膜异位症相关的印记功能紊乱可能影响胚胎着床和发育.该文就DNA甲基化、基因印记与子宫内膜异位症不孕的研究进展作以综述,为子宫内膜异位症不孕新治疗方法的提出提供理论依据.     

辅助生殖技术与出生缺陷

辅助生殖技术（ART）是否增加或引发出生缺陷目前尚无定论，但ART婴儿出生缺陷的原因可能是多因素的，与自然妊娠或许不同。目前研究主要关注于ART助孕过程如促排卵、胚胎培养液、培养时长等对子代的不利影响。ART与印迹疾病的风险近年来也受到很多关注。此外，引发不孕的疾病本身也可能导致出生缺陷。应当强调，大多数ART婴儿是健康的。未来应更好地探索ART出生缺陷的分子机制，改进现有ART治疗方法，降低出生缺陷的发生风险，提高出生人口的素质。     

Preconception Care and Treatment with Assisted Reproductive Technologies

Couples with fertility problems seeking treatment with assisted reproductive technologies (ART) such as in vitro fertilization should receive preconception counseling on all factors that are provided when counseling patients without fertility problems. Additional counseling should address success rates and possible risks from ART therapies. Success rates from ART are improving, with the highest live birth rates averaging about 40% per cycle among women less than 35 years old. A woman’s age lowers the chance of achieving a live birth, as do smoking, obesity, and infertility diagnoses such as hydrosalpinx, uterine leiomyoma, or male factor infertility. Singletons conceived with ART may have lower birth weights. Animal studies suggest that genetic imprinting disorders may be induced by certain embryo culture conditions. The major risk from ovarian stimulation is multiple gestation. About one-third of live-birth deliveries from ART have more than one infant, and twins represent 85% of these multiple-birth children. There are more complications in multiple gestation pregnancies, infants are more likely to be born preterm and with other health problems, and families caring for multiples experience more stress. Transferring fewer embryos per cycle reduces the multiple birth rate from ART, but the patient may have to pay for additional cycles of ART because of a lower likelihood of pregnancy.

     

Ex vivo early embryo development and effects on gene expression and imprinting

The environment to which the mammalian embryo is exposed during the preimplantation period of development has a profound effect on the physiology and viability of the conceptus. It has been demonstrated that conditions that alter gene expression, and in some instances the imprinting status of specific genes, have all previously been shown to adversely affect cell physiology. Thus, questions are raised regarding the aetiology of abnormal gene expression and altered imprinting patterns, and whether problems can be averted by using more physiological culture conditions. It is also of note that the sensitivity of the embryo to its surroundings decreases as development proceeds. Post compaction, environmental conditions have a lesser effect on gene function. This, therefore, has implications regarding the conditions used for IVF and the culture of the cleavage stage embryo. The developmental competence of the oocyte also impacts gene expression in the embryo, and therefore superovulation has been implicated in abnormal methylation and imprinting in the resultant embryo. Furthermore, the genetics and dietary status of the mother have a profound impact on embryo development and gene expression. The significance of specific animal models for human assisted reproductive technologies (ART) is questioned, given that most cattle data have been obtained from in vitro-matured oocytes and that genes imprinted in domestic and laboratory animals are not necessarily imprinted in the human. Patients treated with ART have fertility problems, which in turn may predispose their gametes or embryos to greater sensitivities to the process of ART. Whether this is from the drugs involved in the ovulation induction or from the IVF, intracytoplasmic sperm injection or culture procedures themselves remains to be determined. Alternatively, it may be that epigenetic alterations are associated with infertility and symptoms are subsequently revealed through ART. Whatever the aetiology, continued long-term monitoring of the children conceived through ART is warranted.     

基因印记与精子发生障碍的研究进展

基因印记是特定基因的一对等位基因发生差异性的表达,机体仅表达来自亲本一方的等位基因,而另一方保持沉默。精子发生是一个高度复杂的独特分化过程,包括精原细胞发育为精母细胞、单倍体精细胞的形成和精子成熟。本文通过探讨精子发生障碍与基因印记的关系,分析不育男性表观遗传缺陷的潜在风险,为临床男性不育的预防和治疗提供理论支持。     

Epigenetics in congenital diseases and pervasive developmental disorders

Epigenetics is an intrinsic mechanism that alters gene function – not by altering DNA sequences, but by chemically modifying the DNA and chromosomal histone proteins. Epigenetics is involved in genomic imprinting and X-chromosome inactivation in humans, and the failure of this mechanism causes a subset of congenital syndromes and cancers. Until recently, it has been believed that epigenetic modification is stable and that the pattern is faithfully preserved following DNA replication during cell division, leading to stable epigenomic patterns during one’s life-time. However, more recent reports of environmental stress altering the epigenomic patterns within a short time frame after birth, followed by alterations in gene expression and phenotype, indicate that epigenetics is not only involved in congenital neurodevelopmental diseases but also in acquired diseases, including pervasive developmental disorders, through gene–environmental interaction. In this review, I introduce the subject of congenital diseases with abnormalities in known epigenetic mechanisms and discuss possible epigenetic abnormalities in pervasive developmental disorders.     

Genomic imprinting and environmental disease susceptibility

Genomic imprinting is one of the most intriguing subtleties of modern genetics. The term "imprinting" refers to parent-of-origin-dependent gene expression. The presence of imprinted genes can cause cells with a full parental complement of functional autosomal genes to specifically express one allele but not the other, resulting in monoallelic expression of the imprinted loci. Genomic imprinting plays a critical role in fetal growth and behavioral development, and it is regulated by DNA methylation and chromatin structure. This paper summarizes the Genomic Imprinting and Environmental Disease Susceptibility Conference held 8-10 October 1998 at Duke University, Durham, North Carolina. The conference focused on the importance of genomic imprinting in determining susceptibility to environmentally induced diseases. Conference topics included rationales for imprinting: parental antagonism and speciation; methods for imprinted gene identification: allelic message display and monochromosomal mouse/human hybrids; properties of the imprinted gene cluster human 11p15.5 and mouse distal 7; the epigenetics of X-chromosome inactivation; variability in imprinting: imprint erasure, non-Mendelian inheritance ratios, and polymorphic imprinting; imprinting and behavior: genetics of bipolar disorder, imprinting in Turner syndrome, and imprinting in brain development and social behavior; and aberrant methylation: methylation and chromatin structure, methylation and estrogen exposure, methylation of tumor-suppressor genes, and cancer susceptibility. Environmental factors are capable of causing epigenetic changes in DNA that can potentially alter imprint gene expression and that can result in genetic diseases including cancer and behavioral disorders. Understanding the contribution of imprinting to the regulation of gene expression will be an important step in evaluating environmental influences on human health and disease.