胎盘发育机制的研究进展

胎盘是母体与胎儿之间重要的交流器官,其正常发育对胎儿的生长发育至关重要。胎盘的形成和发育受性别、表观遗传学及外界环境等诸多因素的影响,如不同性别胚胎会影响不同的性激素基因在各自胎盘中的表达,X染色体连锁基因中的性激素合成基因STS倾向于在女性胎儿的胎盘中表达;LHB-CGB基因簇的表达也倾向于女性胎儿的胎盘,其表达产物黄体生成激素、人绒毛膜促性腺激素(hCG)与胎盘的生长、侵袭、血管生成等密切相关。表观遗传学甲基化的重建过程影响胎盘的早期发育,如在胚胎发育早期抑制DNA的甲基化过程会破坏胎盘滋养层的增殖和迁移。另外,胎盘的生长需要充足的有氧环境,氧含量的下降会通过诱导缺氧诱导因子(HIF)活性的增加直接影响胎盘的体积、发育及成熟。综述胎盘发育过程中的一系列变化及这些变化对胎盘功能的影响,可为阐明胚胎发育机制提供必要的理论基础,同时也为母婴安全提供重要保障。     

生殖道发育异常对女性生育的影响及其结局

正女性生殖道发育异常从简单到复杂多种多样。在女性胚胎发育时期,如受到某些内源性(如基因或染色体异常)或外源性因素(如使用性激素类药物)的影响,副中肾管或中肾旁管在形成、融合、再吸收过程中出现障碍,就可导致各种生殖道发育异常。生殖道发育异常对女性生育功能及妊娠结局都有重要影响,可能导致不孕、流产、胎位异常、胎儿发育异常、胎儿生长受限、胎盘早剥、产程异常、产后出血、胎盘滞留等一系列不良妊娠事件。其中子宫发育     

胎盘的表观遗传学与小于胎龄儿的关系

胎盘对子宫内胎儿的生长和发育起着至关重要的作用,其形态或功能的异常都可能会导致母体和胎儿一些疾病的发生,例如先兆子痫、妊娠滋养层病变、胎儿生长受限等。越来越多的研究表明,表观遗传调控在胎盘的发育中占据重要的地位,并与小于胎龄儿(SGA)的发生有关。表观遗传调控主要从DNA甲基化、组蛋白修饰和非编码RNAs调控这几个方面来改变胎盘基因的表达。     

利用母胎间基因甲基化的差异性检测母血中微量胎儿DNA方法的建立

随着表观遗传学方法 在无创性产前诊断中的逐步应用,第一个普通应用的胎儿表观遗传学标记低甲基化maspin基因突破了胎儿性别和基因多态性的局限,为母血中胎儿DNA应用于临床开辟了新的领域,象征着非创伤性产前诊断的研究向前迈进了一大步[1].甲基化特异的聚合酶链反应(polymerase chain reaction,PCR)技术是低甲基化maspin序列检测的重要手段,然而该方法 操作复杂且造成大量DNA降解,给微量胎儿DNA的定量分析带来困难.有研究者发现,RASSF1A基因启动子区在母血细胞中处于低甲基化状态,而在胎盘细胞中处于超甲基化状态[2-3];同时发现母血浆中超甲基化的RASSF1A序列中存在胎儿SNP基因型.     

组蛋白甲基化修饰与哺乳动物生殖

组蛋白甲基化是表观遗传学研究的热点和难点,研究表明,组蛋白甲基化修饰在哺乳动物配子的发生、胚胎着床和发育以及胎盘的发育过程中有着特殊作用,这些修饰可影响基因的表达,从而动态调节哺乳动物生殖过程中许多生物学进程。但目前研究的组蛋白甲基化修饰相关基因位点多而杂,且多停留在广泛的探索和描述这一层面,这些甲基化修饰发生动态变化的机制,以及相互作用等一系列过程还有待深入研究。     

重度子痫前期胎盘中的双特异性磷酸酶9表达下调

目的：胎儿生长受限（FGR）和子痫前期（PE）是胎盘功能不全严重的、重要的临床表现。在小鼠中,双特异性磷酸酶9（DUSP9）是胎盘发育的关键。本研究旨在观察DUSP9在正常妊娠者以及胎盘功能不全患者中的表达特性。研究设计：应用反转录聚合酶链反应（RT—PCR）、免疫组化法以及蛋白印迹技术检测重度FGR和（或）重度子痫前期的妊娠妇女中DUSP9的基因表达及蛋白水平。应用DUSP9启动子甲基化来探索在病理性及早产胎盘中的潜在表观遗传学调控,应用沉默RNA的DUSP9干扰早孕期绒毛及BeWo细胞来研究其下游通路。胎盘缺氧是子痫前期的标志,因此,通过低氧培养环境中的胎盘培养来确定氧气对DUSP9体外表达的影响。结果：在发育过程中,DUSP9绒毛滋养层中的表达显著下降。重度子痫前期患者胎盘中的DUSP9蛋白水平显著低于重度FGR者。从表观遗传学角度,这并不是由启动子的高甲基化介导的,且下游通路细胞外信号调节激酶（ERK）1／2并未受显著影响。低氧（3％氧浓度）培养环境中培养的妊娠早期胎盘中,DUSP9表达显著降低[（74＋20）％]。利用DUSP9沉默RNA处理的BeWo细胞及体外培养的胎盘绒毛中,DUSP9的表达分别降低了61％和62％。在DUSP9下调的细胞及体外培养的绒毛中,其下游靶蛋白ERK1／2的磷酸化有增强的趋势。结论：DUSP9蛋白的表达在重度子痫前期患者胎盘中被显著抑制,但在严重的FGR患者中却没有。这种抑制可能是由子痫前期中的持续低氧环境所导致的。     

胎盘源性母儿并发症研究进展

胎盘是哺乳类动物妊娠期特有的器官,具有物质交换、代谢、屏障防御以及合成功能,对于维持胎儿健康发育具有重要作用.近年来,随着基因组学、蛋白组学和表观遗传学等的迅猛发展以及对胎盘研究的不断深入,胎盘医学应运而生.目前已认识到,胎盘正常的发生、发育受一系列精确的分子调控,胎盘印迹基因表达具有时间和空间特异性,随着孕周不同可发生较大的变化[1].胎盘发生发育不同时期印迹基因缺失或过度表达,可引起胎盘形态、重量异常和滋养细胞浸润功能障碍,最终影响胎盘整体功能的发挥[2].面对宫内外各种不良环境因素时,胎盘并非仅仅被动适应.相反,胎盘可主动通过表观遗传修饰等方式对营养物质转运、自身和胎儿生长速度进行可塑性调整,确保胎儿在宫内不利环境因素下尽可能正常发育.     

DNA甲基化在子宫内膜癌中的研究进展

DNA甲基化是表观遗传学研究的重要内容之一,并与多种肿瘤的发生、发展密切相关.其中子宫内膜癌是女性生殖道常见的恶性肿瘤之一,DNA异常甲基化在其发生、发展过程中也起着重要作用,如使雌激素受体(ER)、孕激素受体(PR)表达沉默、增加基因组DNA的不稳定性、原癌基因激活和抑癌基因及肿瘤负相关基因失活等.了解DNA异常甲基化在子宫内膜癌发生机制中的作用将有助于患者早期预防、早期诊断和改善预后.     

子痫前期的表观遗传学研究进展

子痫前期是一种严重的产科并发症,可导致母体多系统不可逆损伤以及胎儿生长受限。子痫前期在临床上一经诊断,终止妊娠、娩出胎盘是唯一的根治方法。国内外学者关于子痫前期发病机制有很多学说,但是具体病因至今未明。表观遗传学是相对于传统的遗传学而被研究者所认识,重点阐述DNA序列不变的情况下机体所发生的可遗传改变。最近表观遗传学在子痫前期发病中的研究方兴未艾,表观遗传的各种机制在子痫前期发生中的作用主要涉及DNA甲基化、微小RNA（miRNA）以及基因印迹三个方面。     

DNA甲基化在子宫内膜癌中的研究进展

DNA甲基化是表观遗传学研究的重要内容之一，并与多种肿瘤的发生、发展密切相关。其中子宫内膜癌是女性生殖道常见的恶性肿瘤之一，DNA异常甲基化在其发生、发展过程中也起着重要作用，如使雌激素受体（ER）、孕激素受体（PR）表达沉默、增加基因组DNA的不稳定性、原癌基因激活和抑癌基因及肿瘤负相关基因失活等。了解DNA异常甲基化在子宫内膜癌发生机制中的作用将有助于患者早期预防、早期诊断和改善预后。     

Maternal Asthma as a Model for Examining Fetal Sex-specific Effects on Maternal Physiology and Placental Mechanisms that Regulate Human Fetal Growth

Studying the effect of maternal asthma during pregnancy on placental function and fetal development has highlighted that there is a strong interaction between mother, placenta and fetus and these interactions appear to be sex-specific. This work has found that the female fetus alters maternal asthma during pregnancy by upregulating maternal inflammatory pathways. When asthma-associated inflammatory pathways are not treated with inhaled steroids during pregnancy, the female fetus has reduced growth and adrenal function due to alterations in placental glucocorticoid metabolism. When the mother uses inhaled steroid for the treatment of her asthma during pregnancy, female fetal growth and placental function are comparable to the control population. The growth of the male fetus appears to be unaffected by asthma or inhaled steroid use. These findings indicate there may be different mechanisms regulating placental glucocorticoid and immune mechanisms depending on fetal sex in both asthmatic and non-asthmatic pregnancies.     

Review: Nutrient sulfate supply from mother to fetus: Placental adaptive responses during human and animal gestation

Nutrient sulfate has numerous roles in mammalian physiology and is essential for healthy fetal growth and development. The fetus has limited capacity to generate sulfate and relies on sulfate supplied from the maternal circulation via placental sulfate transporters. The placenta also has a high sulfate requirement for numerous molecular and cellular functions, including sulfate conjugation (sulfonation) to estrogen and thyroid hormone which leads to their inactivation. Accordingly, the ratio of sulfonated (inactive) to unconjugated (active) hormones modulates endocrine function in fetal, placental and maternal tissues. During pregnancy, there is a marked increase in the expression of genes involved in transport and generation of sulfate in the mouse placenta, in line with increasing fetal and placental demands for sulfate. The maternal circulation also provides a vital reservoir of sulfate for the placenta and fetus, with maternal circulating sulfate levels increasing by 2-fold from mid-gestation. However, despite evidence from animal studies showing the requirement of maternal sulfate supply for placental and fetal physiology, there are no routine clinical measurements of sulfate or consideration of dietary sulfate intake in pregnant women. This is also relevant to certain xenobiotics or pharmacological drugs which when taken by the mother use significant quantities of circulating sulfate for detoxification and clearance, and thereby have the potential to decrease sulfonation capacity in the placenta and fetus. This article will review the physiological adaptations of the placenta for maintaining sulfate homeostasis in the fetus and placenta, with a focus on pathophysiological outcomes in animal models of disturbed sulfate homeostasis.     

Placental adaptations to the maternal–fetal environment: implications for fetal growth and developmental programming

The placenta is a transient organ found in eutherian mammals that evolved primarily to provide nutrients for the developing fetus. The placenta exchanges a wide array of nutrients, endocrine signals, cytokines and growth factors with the mother and the fetus, thereby regulating intrauterine development. Recent studies show that the placenta is not just a passive organ mediating maternal–fetal exchange. It can adapt its capacity to supply nutrients in response to intrinsic and extrinsic variations in the maternal–fetal environment. These dynamic adaptations are thought to occur to maximize fetal growth and viability at birth in the prevailing conditions in utero. However, some of these adaptations may also affect the development of individual fetal tissues, with patho-physiological consequences long after birth. Here, this review summarizes current knowledge on the causes, possible mechanisms and consequences of placental adaptive responses, with a focus on the regulation of transporter-mediated processes for nutrients. This review also highlights the emerging roles that imprinted genes and epigenetic mechanisms of gene regulation may play in placental adaptations to the maternal–fetal environment.The placenta regulates intrauterine development in mammals by performing the function of several adult organs for the growing fetus. These tasks are achieved by a multitude of specialized cell types. Recent work suggests the placenta has the ability to ‘sense’ the maternal and fetal environment and respond to changes in a dynamic fashion. These placental adaptations are particularly important when dealing with suboptimal conditions for growth and development. In this paper, we review the current knowledge on what triggers these adaptations, how the placenta responds to maternal and fetal signals, what these signals might be and what the long-term consequences are for the function of adult organs if the placenta fails to fully adapt. We argue that a special class of genes, so-called imprinted genes, are key regulators of placental adaptive responses to physiological stressors. These genes are different from the rest because they retain information about their parental origin and because they have evolved to be ‘selfish’. They play special roles in the placenta, as we will describe, which include controlling the amounts of maternal nutrients that go across to the fetus and the manipulation of maternal physiology, sometimes in conflict with the mother’s own interests.     

Intrauterine growth restriction and genetic determinants - existing findings,problems, and further direction

Fetal growth is determined largely by the nutrient supply, placental transport function, and growth hormones. Recently, gene mutation and expression, especially of those genes associated with the proteins that are related to the fetal growth, have been reported to play an important role in the development of intrauterine growth restriction (IUGR). Fetal growth epigenetics, a new concept in fetal growth, has resulted from studies on fetal programing. This paper outlines the findings of our serial studies on IUGR, and summarizes data on IUGR animal models, placental function in transferring nutrients, cell proliferation dynamics in IUGR, and experimental treatment of IUGR. We review genetic approaches to IUGR, especially those relating to growth factor genes, angiotensinogen genes and other gene mutations. We also discuss the epigenetics of fetal growth and future study directions on fetal growth restriction. These should be valuable in elucidating the mechanisms employed by the fetus and in helping to develop interventional strategies that might prevent the development of IUGR.     

Review: Sex and the Human Placenta: Mediating Differential Strategies of Fetal Growth and Survival

There are known sex specific differences in fetal and neonatal morbidity and mortality. There are also known differences in birthweight centile with males generally being larger than females at birth. These differences are generally ignored when studying obstetric complications of pregnancy and the mechanisms that confer these differences between the sexes are unknown. Current evidence suggests sex specific adaptation of the placenta may be central to the differences in fetal growth and survival. Our research examining pregnancies complicated by asthma has reported sexually dimorphic differences in fetal growth and survival with males adapting placental function to allow for continued growth in an adverse maternal environment while females reduce growth in an attempt to survive further maternal insults. We have reported sex differences in placental cytokine expression, insulin-like growth factor pathways and the placental response to cortisol in relation to the complication of asthma during pregnancy. More recently we have identified sex specific alterations in placental function in pregnancies complicated by preterm delivery which were associated with neonatal outcome and survival. We propose the sexually dimorphic differences in growth and survival of the fetus are mediated by the sex specific function of the human placenta. This review will present evidence supporting this hypothesis and will argue that to ignore the sex of the placenta is no longer sound scientific practice.     

Review: The blood-brain barrier; protecting the developing fetal brain

While placental function is fundamental to normal fetal development, the blood-brain barrier provides a second checkpoint critical to protecting the fetal brain and ensuring healthy brain development. The placenta is considered the key barrier between the mother and fetus, regulating delivery of essential nutrients, removing waste as well as protecting the fetus from potentially noxious substances. However, disturbances to the maternal environment and subsequent adaptations to placental function may render the placenta ineffective for providing a suitable environment for the developing fetus and to providing sufficient protection from harmful substances. The developing brain is particularly vulnerable to changes in the maternal/fetal environment. Development of the blood-brain barrier and maturation of barrier transporter systems work to protect the fetal brain from exposure to drugs, excluding them from the fetal CNS. This review will focus on the role of the ‘other’ key barrier during gestation – the blood-brain barrier – which has been shown to be functional as early as 8 weeks' gestation.     

Physiologie der Plazenta

The placenta is a complex organ with a limited lifespan. It sustains its own as well as fetal development and in doing so interacts with the mother and fetus. The interaction with the mother is particularly pronounced in the first half of gestation during which placental hormones promote the adaptation of maternal physiology and metabolism. Moreover, locally produced cytokines and growth factors induce immunological tolerance for the semiallogenic fetus. During the course of gestation fetal signals gain increasing influence on placental development and mediate adaptation of the placenta to fetal requirements. The specialization of the placenta during pregnancy mostly serves to optimize the supply of nutrients and oxygen to the fetus. Impaired maternal-fetal transport is often associated with pregnancy problems, such as fetal growth restriction.     

Review: Placental adaptations to the presence of maternal asthma during pregnancy

Asthma is a highly prevalent chronic medical condition affecting an estimated 12% of pregnant, women each year, with prevalence of asthma greatest (up to 16%) among the socially disadvantaged. Maternal asthma is associated with significant perinatal morbidity and mortality including preterm births, neonatal hospitalisations and low birthweight outcomes each year. We have identified that the placenta adapts to the presence of chronic, maternal asthma during pregnancy in a sex specific manner that may confer sex differences in fetal outcome. The male fetus was at greater risk of a poor outcome than a female fetus in the presence of maternal asthma and an acute inflammatory event such as an asthma exacerbation. This review will examine the role of sex specific differences in placental function on fetal growth and survival.     

Morphological variability and placental function

In mammals, the blastocyst defines with the maternal organism, a structure which allows embryonic development during gestation: the placenta. The structure of this organ varies remarkably across species. In this review the different type of placentation have been described in a comparative manner using terms of classification such as: placental materno-fetal interdigitation, matemofetal blood flow interrelationships, layers of the placental interhemal barrier, trophoblast invasiveness and decidual cell reaction, formation of syncytiotrophoblast. The human hemomonochorial placenta is characterized by a strong decidualization of the uterus and a major invasiveness of the extravillous trophoblast. Furthermore, there is a spectrum of placental endocrine activities across species. In some mammals (e.g., mouse and rat) the placenta eclipses the pituitary in the maintenance of ovarian function. In the human and in the sheep, horse, cat and guinea pig, the placenta acquires the ability to substitute for the ovaries in the maintenance of gestation at various time during pregnancy. The human placenta is characterized by a high rate of stero?dogenesis (progesterone and estrogens) and by the production of a primate specific trophoblastic hormone: human chorionic gonadotropin (hCG). Recently, it was demonstrated that mutation of many genes in mice results in embryonic mortality or fetal growth restriction, due to defects in placental development. Furthermore, distinct molecular pathways regulate the differentiation of various trophoblast cell subtype of the mouse placenta. An important question is whether or not placental differentiation in other mammals is regulated by the same molecular mechanisms. Due to the striking diversity in placental structure, endocrine function and gene expression, caution must be exercised in extrapolating findings regarding placental function and development from one species to another.     

胎盘中传递甲状腺激素的转运蛋白研究

甲状腺激素对机体各组织的新陈代谢起着重要的作用,也是人类妊娠期重要的内分泌激素。研究证实,在胎儿自身甲状腺激素 分泌前,母体甲状腺激素能通过胎盘并参与胎儿内分泌系统的调节。这个过程中需要一些特殊的转运蛋白,有关人胎盘中的这些重要的转运蛋白 相关研究很少,已证实的有人类胎盘中氨基酸转运载体、有机阴离子转运肽、单羧酸转运肽、Na+/I-同向转运蛋白等。但仍需进一步研究胎盘中 转运甲状腺激素的一些蛋白作用,以了解导致胎儿生长受限、流产、胚芽种植失败、胎儿死亡等不良妊娠结局的发生机制。