Project Details
Projekt
Maternal Overweight During Pregnancy (MODP) and perinatal programming – effects on placental function and the role of placental glucocorticoid receptors
Subject Area
Gynaecology and Obstetrics
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 428871172
Obesity, type II diabetes and its associated complications are a permanently increasing challenge for our health system. Even more important, a growing number of children and adolescents are overweight and suffer from chronic diseases. One way to address a major root of the causative pathway is to target early life, applying a developmental origins approach to disease prevention. Maternal excessive gestational weight gain and maternal overweight during pregnancy (MODP) are the strongest predictors of offspring obesity and metabolic syndrome in children. It has been proposed that the metabolic consequences of maternal obesity may contribute to HPA axis disruption, accompanied by elevated cortisol levels throughout the day, with fetal overexposure to maternal cortisol as a pathway linking obesity to chronic disease later in life. The placenta may play an important role in the cortisol-associated programming effects. Our understanding of how endogenous cortisol and/or HPA-disruption associated with MODP influences fetal and placental development begins with the glucocorticoid receptor (GR) and its isoforms. Cortisol-induced epigenomic modifications with hyper-/hypomethylation in specific promoter regions of GR and/or down-stream signaling pathways, such as the placental cortisol barrier and/or placental glucose transporters that are activated or repressed in the presence of elevated cortisol, finally contribute to altered placental GR sensitivity and function. We hypothesize that sex-specific cortisol sensitivity is regulated by GR distribution, expression and/or interaction of GRα as transduction stimulating GR vs. other placental GR isoforms and that maternal MODP changes these relationships. Different clusters of placental GR isoforms correlate sex-specifically with placental function, fetal and neonatal outcome parameters. We therefore propose studies in human placentas from normal weight and placentas from MODP pregnancies with the objective of sex- and gestational-age specific identification and localization of placental GR alpha vs. other GR-isoforms, the correlative evaluation of the physiological function (HPA, glucose transport, placental cortisol resistance) and impact of the GR isoforms for fetal development, and cortisol/MODP-induced epigenomic GR and other candidates-promotor changes as a possible mechanism of gender-specific placental cortisol resistance and fetal mal-programming. The combination of sensitive and quantitative technologies (e.g. pyrosequencing and Real-Time PCR) could enable assessment of epigenetic changes in a tissue and sex-specific manner. An enhanced appreciation of placental-mediated signaling pathways in determining long-term health in offspring will be crucial in the efforts to design interventional strategies in at-risk populations and will potentially allow us to identify biomarkers and targets for intervention trials in future studies.
DFG Programme
Research Grants
Co-Investigators
Rebecca Graebig-Rancourt, Ph.D.; Professor Dr. Wolfgang Henrich
