Glucocorticoid programming of placental nutrient transport capacity

在怀孕期间，营养和母亲压力等环境因素会影响胎儿的生长发育，对出生时和以后生命中的死亡率和发病率产生影响。新生儿越小，出生时存活的可能性就越小，成年后心血管和代谢异常的可能性就越大，这可能导致人类出现明显的疾病，如高血压和2型糖尿病。因此，在宫内发育期间的环境条件会产生特定的表观基因组，在最初的侮辱之后很长时间内对后代产生表型后果。糖皮质激素在这一发育规划过程中起着重要作用。它们在母亲和胎儿中都是逆境的信号，也永久性地改变了胎儿的组织增生和分化。这对新生儿生存能力有好处，但当糖皮质激素过度暴露发生早产时，对成年后代的心血管和代谢功能有更多的不良后遗症。胎盘在妊娠期间亚理想条件的表型结果中也起着关键作用，因为它形成了母体和胎儿环境之间的界面，是胎儿生长的主要营养来源。然而，迄今为止，对胎盘表型的表观遗传调控知之甚少，尽管它对后代随后的生活质量很重要。最近的研究表明，胎盘不仅是一个被动的管道营养物质到胎儿，但可以动态调整其营养运输能力，以帮助支持胎儿在不利的营养条件下生长。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到何种程度，从而改变胎盘在发育后期的营养转运特性，目前尚不清楚。因此，本研究的总体目的是确定糖皮质激素在规划羊胎盘的营养供应能力方面的作用。具体的可测量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？它们在多大程度上与母体和胎儿过度暴露不同？2. 停止治疗后糖皮质激素的这些作用是否持续？3. 糖皮质激素的这些作用与性别有关吗？这项研究的结果对那些因压力而怀孕的孕妇和用糖皮质激素治疗的临床病症（如哮喘和风湿性疾病），以及那些在早产迫在眉睫时服用糖皮质激素以提高婴儿存活率的妇女都有影响。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一种机制，将妊娠早期事件的记忆传递给发育后期的胎儿，从而确定胎盘表型在多大程度上是宫内发育过程中所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，以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，以改善宫内发育过程中恶劣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.