Maternal Nutrition, Placenta Function and Offspring Health

Diabetes mellitus has become a global health concern during past decades. Consequently, diabetic pregnancies were affected in an increasing amount of population. As the one of the major factors during diabetes, maternal hyperglycemia is considered to have great adverse influences on fetal development. As a transient organ connecting the mother and the fetus, the placenta plays many important roles in fetal development. Placental development is affected in diabetes related pregnancy, which further promotes diabetic pregnancy related complications. FOXO1, a transcriptional factor in the forkhead family, plays important roles in fetal cardiovascular and placental development, as well as glucose metabolism. The aim of the project is to understand the molecular mechanism underlying how hyperglycemia disrupts placenta function and promotes birth defects of the fetus, focusing on maternal overnutrition, diabetes and the transcription factor FOXO1. Therefore, three distinct but interconnected studies are involved in this PhD project. In study 1, in ovo hyperglycemia was generated in a chicken egg model to study the impact of “hyperglycemia” on the embryonic development. We reported that high dose of glucose was embryonic lethal and lower dose of glucose resulted in heart and limb defects. We further demonstrated that the limb defects induced by “hyperglycemia” were an outcome of disrupted proliferation and apoptosis of the limb mesenchymal cells, associated with down-regulation of Hedgehog signaling. In study 2, wild-type (WT) or FOXO1 heterozygous mice with diabetic pregnancy were generated by streptozotocin (STZ) injections. The placental function and the embryonic heart development were examined to understand the interaction between diabetic pregnancy and FOXO1 deficiency. The results demonstrated that diabetic pregnancy affected the placental growth and promoted angiogenesis of the placental labyrinth layer, which was further associated with the fetal overgrowth. But those effects were not observed when FOXO1 was downregulated. In study 3, we discovered the influence of maternal diet interventions on the offspring pancreatic β-cell function while the offspring were exposed to postnatal high-fat (HF) diet. The results suggested that proliferation defects and degranulation of the β-cells induced by maternal HF diet were rescued by a pre-gestational diet transition. This study could provide evidence for potential strategies to reduce the detrimental effects of maternal overnutrition. Taken together, this PhD project explored the impacts of maternal factors such as diabetes and overnutrition on placental and fetal development, and further investigated the mechanisms behind them. It provides important information that will lead to health care strategies to improve health outcomes of mothers and children