Influence Of Choline Intake During Pregnancy On Maternal And Fetal Genomic Markers In Humans
Choline is an essential nutrient, which functions in cellular membrane structure, neurotransmission and methyl group donation. The need for choline increases substantially during pregnancy. An Adequate Intake (AI) for choline has been established at 450mg/d for pregnant women. This thesis was focused on assessing the influence of choline intake exceeding the current AI during the third trimester of pregnancy on maternal and fetal genomic readouts in humans. A 12-week choline controlled feeding study was conducted among third trimester pregnant and nonpregnant control women. The participants were randomized to either 480mg choline/d, which is slightly above the AI, or 930mg/d. Maternal blood samples were retrieved at the study beginning (wk-0) and end (wk-12). Placental biopsies, and maternal and cord blood samples were retrieved at delivery. Epigenetic marks and transcriptomes were assessed. Genomic markers in fetal derived tissues were responsive to maternal choline intake. Specifically, the higher maternal choline intake group (930 vs 480 mg/d) had higher placental global DNA and histone methylation (P=0.02). The placental promoter DNA methylation of cortisol regulating genes corticotropin releasing hormone (CRH) (P=0.05) and glucocorticoid receptor (NR3C1) (P=0.002) were also higher among women consuming 930 vs 480 mg choline/d, which was consistent with decreased CRH gene expression (P=0.05) in the placenta and lower cortisol in cord blood (P=0.07) in the 930 mg choline/d group. Analysis of the placental transcriptome revealed that the higher maternal choline intake group had lower expression of the anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFLT1) (P=0.05), a marker that predicts preeclampsia. Similar decreases (P=0.04) were detected in maternal blood sFLT1 protein concentrations. The effect of choline on decreasing sFLT1 was confirmed in a trophoblast cell line HTR-8/SVneo. Additionally, in this cell line, suboptimal choline concentrations in the culture medium induced apoptosis, elevated oxidative stress, increased expression of angiogenic and inflammatory genes, and impaired in vitro angiogenesis. Inhibition of protein kinase C rescued the effects of low choline on angiogenesis and apoptosis indicating that choline deficiency perturbs this signaling pathway. In sum, a maternal choline intake exceeding current recommendations may beneficially program offspring stress reactivity and mitigate the production of proteins associated with preeclampsia.
choline; genomics; epigenetics
Caudill, Marie A.
O'Brien, Kimberly O; Soloway, Paul; Cassano, Patricia Ann
Ph.D. of Nutrition
Doctor of Philosophy
dissertation or thesis