Maternal Choline Supplementation Modulates Maternal and Fetal Choline Metabolism and Downregulates Inflammatory Gene Expression in a Mouse Model of Placental Insufficiency

A properly functioning placenta allows efficient transfer of nutrients from mother to fetus and promotes fetal growth. Decreased placental efficiency is commonly associated with intrauterine growth restriction, preeclampsia, and miscarriage. Choline is an essential nutrient that is a precursor for several molecules with crucial roles in fetal development: betaine, an osmolyte and methyl donor; acetylcholine, a neurotransmitter and signaling molecule; and phosphatidylcholine (PC), the most prevalent membrane phospholipid. We previously showed that maternal choline supplementation (MCS) in the Dlx3+/ − mouse, a model of placental insufficiency, increases fetal growth in early gestation and lowers expression of pro‐angiogenic genes implicated in preeclampsia. To explore the mechanisms contributing to these effects, we measured choline metabolites in the maternal liver and placentas of Dlx3+/ − female mice consuming 1X (control), 2X or 4X the recommended intake levels of choline during gestation. Additionally, we measured expression of inflammatory genes that are elevated in preeclampsia and indicative of placental dysfunction. Dams were sacrificed at embryonic days E10.5, E12.5, E15.5, and E18.5. Data were analyzed using linear mixed models with dam as a random factor. MCS increased betaine concentrations in the maternal liver at all four time points (p<.01) and prevented a decline in maternal hepatic betaine stores in late pregnancy. 4X choline also increased phosphocholine, a precursor of PC, at E15.5 (p=.014), and decreased glycerophosphocholine, a product of PC breakdown, at E12.5 (p=.025). In the placenta, MCS increased betaine concentrations at E10.5 and 12.5 (p=.005 and .041, respectively). These data suggest that effects of MCS may be primarily driven by betaine, potentially through increased supply of methyl groups for one‐carbon reactions including DNA methylation. This is supported by data demonstrating widespread effects of choline on gene expression. In Dlx3+/ − placentas, choline decreased (p<0.05) expression of pro‐inflammatory genes Il1b (at E12.5, 15.5 and 18.5), Tnf‐α (at E12.5) and NfκB (at E15.5). Further studies are ongoing to identify downstream effects of increased betaine on placental DNA methylation and growth factor signaling pathways. Support or Funding Information Funding provided by USDA‐NIFA 2012‐67017‐30176