Abstract
BACKGROUND: Accumulating evidence indicates that elevated maternal glucose concentrations during pregnancy are associated with adverse birth outcomes, but the mechanistic underpinnings remain unclear. This study aimed to evaluate the associations between maternal glucose concentrations and DNA methylation levels in genes related to the peroxisome proliferator-activated receptor (PPAR) signaling pathway in the human placenta and explore the potential mediating role of placental DNA methylation in the relationship between maternal glucose concentrations and neonatal anthropometric measures. METHODS: Maternal glucose concentrations were obtained from medical records, and neonatal anthropometric parameters were measured in 335 mother-infant pairs. DNA methylation levels of 14 genes related to the PPAR signaling pathway were analyzed in placental samples. Multiple linear regression models and mediation analyses were used to examine the associations and potential mediation effects. RESULTS: Higher maternal fasting plasma glucose (FPG) concentrations were generally associated with hypomethylation of genes related to the PPAR signaling pathway, with stronger effects in male neonates. Maternal 1-h plasma glucose concentrations after the glucose challenge test exhibited weaker but consistent patterns. Mediation analyses indicated that hypomethylation of ACAA1 mediated 29.00% (Indirect effect [IE]: β = 0.07; 95% confidence interval [CI] 0.02, 0.14) and 21.75% (IE: β = 0.07; 95% CI 0.00, 0.18) of the effects of FPG concentrations on increased neonatal abdominal and back skinfold thickness, respectively, while ACADM hypomethylation mediated 15.39% (IE: β = 0.03; 95% CI 0.00, 0.08) and 17.69% (IE: β = 0.06; 95% CI 0.00, 0.13) of these effects. CONCLUSIONS: Elevated Maternal glucose concentrations were associated with hypomethylation of genes related to the PPAR signaling pathway. Specifically, hypomethylation of ACAA1 and ACADM may partially mediate the impact of maternal glucose concentrations on increased neonatal anthropometric measures. These findings provide mechanistic insights into potential epigenetic pathways linking maternal glucose concentrations to neonatal anthropometric outcomes.