Glucocorticoid programming of placental nutrient transport capacity

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.

Many epidemiological and experimental studies have shown that environmental conditions during pregnancy produce a specific offspring epigenome with phenotypical consequences long after the original insult. Glucocorticoids (GCs) have an important role in this process of developmental programming but little is known about the epigenetic regulation of placental phenotype, despite the placenta's importance in supplying nutrients for fetal growth. Thus, the aim of the project is to establish the role of GCs in programming the placental nutrient transport capacity. Using chronically catheterised sheep, the study will determine whether maternal and fetal GCs alter the placental nutrient transport capacity differentially and the extent to which these effects persist after treatment and are sex-linked. In vivo measurements of placental clearance, consumption and net transfer of nutrients will be made in male and females fetuses during and after treatment of the mother and/or fetus with cortisol for 5 days during late gestation at doses known to impair fetal growth. These measurements will be compared to saline infused controls and related to in vitro analyses of placental morphology and expression for growth regulatory, GC bioavailability and nutrient supply genes quantified using stereological and molecular biology techniques. The study, therefore, provides a comprehensive integrated assessment of placental nutrient transfer by simple and faciltated diffusion and active transport. The results will establish whether the placental epigenome provides a mechanism of transmitting memories of early events to fetuses later in development and the importance of placental phenotype as an index of conditions experienced during prenatal development. This has implications for the outcome of pregnancies treated clinically with glucocoticoids or compromised by maternal or fetal stress. The long term goal is to identify novel placental biomarkers of the offspring's future health.

Who will benefit from this research? This is a basic science application with potential for impact on a number of beneficaries in addition to academic and clinical research communities. The primary beneficiaries from the proposed research will include (a) researchers in fetal and placental physiology, intrauterine programming and epigenetics (b) obstetricians and paediatricians caring for compromised pregnancies and infants and women receiving clinical treatment with glucocorticoids antenatally, (c) compromised babies and mothers at risk of preterm delivery and other chronic condition requiring glucocorticoid treatment, (d) pharmaceutical organisations who may translate the findings into clinical practice, e) other health professionals and public policy makers involved in the care of pregnant women eg midwives, health visitors and finally f) farmers dealing with the consequences of unexpected stresses to their livestock during pregnancy (eg floods, unseasonal weather, environmental change). Furthermore, the economic and social consequences of poor intrauterine development mean that the research has wider implications for society in both the short and longer term with implications for future health strategies. How will they benefit from the research? Although there is increasing acceptance that the early life environment can influence adult health, the concept that the placenta is important in determining the offspring's future quality of life is foreign to many, primarily because the placenta is seen as a passive conduit of nutrients to the fetus. By highlighting the role of the glucocorticoid stress hormones in the developmental plasticity of the placenta, the study will increase awareness of the dynamic role of the placenta in determining the health outcomes of environmental challenges during pregnancy. Understanding the mechanisms of placental programming at the systemic, cellular and molecular levels will inform intervention strategies and life style choices during pregnancy to minimize adult disease risk associated with poor early life environments. The data generated will also help meet the growing need for life style advice during pregnancy, particularly with the anticipated environmental and economic changes impacting on diet, perceived wellbeing and actual stress during pregnancy. The data also contribute to the public and political understanding of the importance of early developmental influences on health and the inherent inequalities this brings to different population sectors, irrespective of subsequent levels of public health care. The training received by the staff employed on this grant will increase their effectiveness and employability in a range of different spheres. Past postdoctoral research associates have gone onto secondary school education, legal science consultancy, science policy, medicine and the civil service as well as into academia. What will be done to ensure they have the opportunity to benefit from this research? Realisation of potential impacts will occur through a range of media including dissemination of results at meetings, workshops and wider bioscience forums and in peer reviewed publications and reviews, industrial partnerships, engagement with policy bodies, as appropriate, and outreach activities like school visits and public Science Week events. In addition, the results will be used through the University's Development office to leverage benefactions in the field of Reproductive Biology and Medicine to further underpin our research activities.