CHOLINE AS A MODULATOR OF PLACENTAL FUNCTION FOR IMPROVING FETAL DEVELOPMENT
Kwan, Sze Ting
The placenta is a fetal-derived tissue responsible for providing nutrients to the fetus to support its growth and development. Any abnormal variation in its size, morphology or functional capacity can adversely impact placental nutrient supply, consequently altering the development of the fetus and its risk of diseases. As such, the placenta is positioned to play a crucial role in programming offspring health in later life. A growing body of data indicates that suboptimal prenatal conditions impair aspects of placental development that affect nutrient supply, and that these placental phenotypes correlate with higher disease susceptibility in the offspring. The overarching goal of this dissertation research is to characterize the impact of maternal choline supplementation (MCS) on factors that determine placental nutrient supply. To accomplish this research goal, pregnant wild-type non Swiss Albino (NSA) mice were randomized to receive a diet containing 1X, 2X or 4X the recommended choline level and were sacrificed at one of four gestational days (E10.5, 12.5, 15.5 or 18.5). Maternal liver, serum, placentas and fetuses were collected for the following studies. Study 1 examined the impact of MCS on biomarkers of placental inflammation, apoptosis and angiogenesis as well as placental morphological and vascular indicators in mice during normal pregnancy. This study demonstrates that MCS modulates the abundance of inflammatory, apoptotic and angiogenic markers in the mouse placenta in a fetal sex- and gestational day-dependent manner. In addition, this study provides evidence of enhanced placental perfusion in response to MCS through increased luminal area of the maternal spiral arteries. Study 2 investigated the impact of MCS on placental nutrient transporter abundance and placental nutrient metabolism during late gestation of the mouse pregnancy when fetal growth is maximal. This study indicates that MCS modulates the placental nutrient metabolism and the placental abundance of nutrient transporters. More importantly, this study provides evidence showing that these choline-induced changes in the placenta alter nutrient availability in the fetal brain, suggesting that these placental changes may influence the development of the fetus and the normal functioning of its organs. Study 3 explored the impact of MCS on placental epigenetic markers during late gestation of mouse pregnancy. This study shows that MCS affects several placental epigenetic markers, including the amount of global DNA methylation, the expression of imprinted genes, as well as the abundance of microRNAs and the expression of their mRNA targets. Although these changes occur in a sexually-dimorphic manner, they all have similar downstream consequences on placental vascular development and nutrient supply system. In sum, this dissertation research shows a wide-range of effects of MCS on factors that influence placental nutrient supply and ultimately fetal development and its long term health.
Choline; Placenta; Nutrition
Caudill, Marie A.
Strupp, Barbara Jean; Clark, Andrew; Roberson, Mark Stephen
PHD of Nutrition
Doctor of Philosophy
dissertation or thesis