Glucocorticoid programming of placental nutrient transport capacity

在怀孕期间，环境因素，如营养和母亲的压力，影响胎儿的生长和发育，造成出生时和以后生活中的死亡率和发病率。新生儿越小，出生时存活的可能性就越小，并且更容易发生成人心血管和代谢异常，这可能导致人类中的显性疾病，如高血压和2型糖尿病。因此，子宫内发育期间的环境条件会产生一种特定的表观基因组，在最初的损伤后很长时间对后代产生表型影响。糖皮质激素在这一发育过程中起着重要作用。它们作为母亲和胎儿逆境的信号，也永久地改变胎儿的组织增生和分化。这对新生儿的生存能力有有益的影响，但当糖皮质激素过量早产时，对成年后代的心血管和代谢功能有更不利的后遗症。胎盘在妊娠期间次优条件的表型结果中也具有关键作用，因为它形成母体和胎儿环境之间的界面，并且是胎儿生长的主要营养来源。然而，迄今为止，很少有人知道胎盘表型的表观遗传调控，尽管它的重要性，后代的后续生活质量。最近的研究表明，胎盘不仅仅是向胎儿输送营养的被动管道，而且可以动态地调整其营养运输能力，以帮助在不利的营养条件下支持胎儿生长。糖皮质激素是否会改变胎盘表型，以及这些适应在暴露后持续改变胎盘在发育后期的营养转运特征的程度仍然未知。因此，本研究的总体目的是确定糖皮质激素在规划羊胎盘营养供应能力中的作用。具体可衡量的目标是回答以下三个问题：1.糖皮质激素对胎盘营养供应能力的影响是什么？它们在母体和胎儿过度妊娠中有什么不同？2.糖皮质激素的这些作用在停止治疗后是否持续？3.糖皮质激素的这些作用与性别有关吗？这项研究的结果对妊娠并发压力和糖皮质激素治疗的临床疾病（如哮喘和风湿性疾病）以及给予糖皮质激素以改善早产时婴儿生存能力的妇女具有影响。通过回答上述问题，该研究还将确定胎盘表观基因组是否提供了将妊娠早期事件的记忆传递给发育后期胎儿的机制，从而确定胎盘表型在多大程度上是宫内发育期间经历的条件的良好指标。该项目的长期目标是确定新的胎盘生物标志物，用于预测后代的未来健康和福祉，并开发针对胎盘的治疗干预措施，以改善宫内发育期间不良环境条件的不良后果。

During pregnancy, environmental factors, such as nutrition and maternal stress, affect fetal growth and development with consequences for mortality and morbidity both at birth and later in life. The smaller the neonate the less likely it is to survive at birth and the more prone it is to adult cardiovascular and metabolic abnormalities, which can lead to overt diseases, such as hypertension and Type 2 diabetes, in human populations. Environmental conditions during intrauterine development, therefore, produce a specific epigenome with phenotypical consequences for the offspring long after the original insult. Glucocorticoids have an important role in this process of developmental programming. They act as signals of adversity in both the mother and fetus and also permanently alter tissue accretion and differentiation in the fetus. This has beneficial effects on neonatal viability but more adverse sequelae for cardiovascular and metabolic function in the adult offspring when glucocorticoid overexposure occurs preterm. The placenta also has a pivotal role in the phenotypical outcome of sub-optimal conditions during pregnancy as it forms the interface between the maternal and fetal environments and is the main source of nutrients for fetal growth. However, to date, little is known about the epigenetic regulation of placental phenotype, despite its importance to the offspring's subsequent quality of life. Recent studies have shown that the placenta is not just a passive conduit for nutrients to the fetus but can adapt its nutrient transport capacity dynamically to help support fetal growth during adverse nutritional conditions. Whether glucocorticoids alter placental phenotype and the extent to which these adaptations persist after exposure to alter the nutrient transport characteristics of the placenta later in development remains unknown. Thus, the overall aim of the study is to establish the role of glucocorticoids in programming the nutrient supply capacity of the ovine placenta. The specific measurable objectives are to answer the following three questions: 1. What are the effects of glucocorticoids on the placental nutrient supply capacity and to what extent do they differ with maternal and fetal overexposure? 2. Do these effects of glucocorticoids persist after cessation of treatment? 3. Are these effects of glucocorticoids sex-linked? The results of the study have implications for pregnancies complicated by stress and clinical conditions treated with glucocorticoids, such as asthma and rheumatic diseases, and for women given glucocorticoids to improve infant viability when preterm delivery looks imminent. By answering the above questions, the study will also establish whether the placental epigenome provides a mechanism of transmitting memories of events earlier in gestation to the fetus later in development and hence the extent to which placental phenotype is a good index of conditions experienced during intrauterine development. The long term goals of the project are to identify novel placental biomarker for predicting the offspring's future health and well being and to develop therapeutic interventions aimed at the placenta to ameliorate the adverse consequences of poor environmental conditions during intrauterine development.