Abstract
OBJECTIVES: We examined associations between maternal methyl donor status with lymphocytic epigenetic markers at third trimester, fetal fuel metabolism in placenta and neonatal birth weight (BW). METHODS: This study included seventy-eight healthy mother-newborn pairs with placenta samples and newborn growth data from the Taiwan Pregnancy-Newborn Epigenetics cohort. Maternal plasma methyl donors (folate/free choline/betaine) and lymphocytic epigenetic marks (DNA methylation of LINE1 and H19 imprinted gene) at the third trimester were measured. Placenta fuel metabolites (glucose/lactate/folate), expressions of glycolytic enzymes (hexokinase II: HK-II and lactate dehydrogenase: LDH) and the metabolic signaling AMP-activated protein kinase (AMPK) were assayed. Associations with BW were analyzed by multiple linear regression. RESULTS: Both maternal LINE1 methylation (β: −0.289, P = 0.044) and placenta lactate level (β: −0.262, P = 0.034) predicted neonatal BW variance. Maternal RBC folate level predicted LINE1 methylation (β: 0.300, P = 0.048). The significance of fetal lactate-prediction on neonatal BW variance was negated by adjustment for placenta glucose, maternal methyl donor status (folate/free choline/betaine), and maternal prepregnancy BMI. Further adjustment for maternal epigenetic marks (LINE1 and H19 methylation) resumed the prediction power (β: −0.366, P = 0.039). By stratification of maternal and fetal methyl donor status, the significant fetal lactate-BW prediction only displayed in mothers with high plasma folate levels (>10.2 ng/mL) (β: −0.371, P = 0.037), low free choline levels (<12.9 μM) (β: −0.444, P = 0.038) and low betaine levels (<13.4 μM) (β: −0.536, P = 0.010). As maternal plasma folate significantly predicted placenta folate (β: 0.283, P = 0.014), high placenta folate levels (>17.5 ng/g) markedly strengthen the fetal lactate-BW prediction (β: −0.657, P = 0.001), which coincided with higher expression of placenta AMPK levels. CONCLUSIONS: Our data highlights the inverse association between placenta lactate and birth weight. Maternal third trimester and placental methyl donor status may affect neonatal birth weight variance through their threshold effects on fetal lactate metabolism. FUNDING SOURCES: This study was supported by a grant from the Ministry of Science and Technology, Taiwan.