Maternal Choline Supplementation in a Mouse Model of Placental Insufficiency
King, Julia Heather
Placental insufficiency is commonly associated with intrauterine growth restriction, preeclampsia, and spontaneous abortion. The essential nutrient choline may mitigate some of these impairments, as suggested by data in humans and trophoblast cell culture. Choline is a precursor for several molecules with crucial roles during pregnancy: the methyl donor betaine, the neurotransmitter acetylcholine, and the phospholipid phosphatidylcholine. Through betaine, it participates in the metabolic network referred to as one-carbon metabolism which is essential for many biochemical processes including nucleotide synthesis, DNA methylation, and amino acid metabolism. Demand for one-carbon (methyl) nutrients, including choline, folate, and vitamin B-12, is high during pregnancy when cells of the placenta and fetus undergo rapid division. This dissertation research sought to examine the effects of choline supplementation during pregnancy in the Dlx3+/- mouse, a model of placental insufficiency. Study 1 investigated the effects of maternal choline supplementation (MCS) on pregnancy outcomes in Dlx3+/- mice. This study demonstrated that maternal choline supplementation led to a marked increase in fetal growth by mid-gestation, which resulted in compensatory mechanisms to slow growth by downregulating Igf1. Placental betaine concentrations were strongly predictive of fetal weights, suggesting betaine supply may be a determinant of fetal growth. Study 2 explored the effects of MCS on aspects of placental function in the Dlx3+/- mouse. The main findings indicate that a higher maternal choline intake can alter placental labyrinth size, modulate expression of angiogenic and inflammatory genes in the placenta, and decrease placental apoptosis; and that these effects occur in a fetal sex-dependent manner. Study 3 assessed the effects of MCS on vitamin B-12 status in mice with and without placental insufficiency. In addition, data from a human feeding study was used to further explore this relationship. MCS increased the active form of vitamin B-12 in pregnant women; genetic variants that increase choline requirements were also shown to alter vitamin B-12 markers. Taken together, these studies suggest that higher levels of choline intake during pregnancy may be beneficial for the mother and fetus, and provide support for further research on the use of choline for improving placental function and mitigating placental insufficiency.
Choline; Dlx3; Fetal Growth; Pregnancy; Placenta; vitamin B12; Nutrition
Caudill, Marie A.
Soloway, Paul; Roberson, Mark Stephen; Stipanuk, Martha Harney
Ph. D., Nutrition
Doctor of Philosophy
dissertation or thesis