Maternal Gestational Diabetes Influences DNA Methylation in the Serotonin System in the Human Placenta

Abstract

The offspring of mothers with gestational diabetes mellitus (GDM) are at a higher risk for metabolic dysregulation and neurodevelopmental impairment. Evidence suggests that serotonin, which is present in both the placenta and the brain, programs the development and growth of the fetal brain. In the current study, we tested the hypothesis that GDM affects the methylation of the serotonin transporter gene (SLC6A4) and serotonin receptor gene (HTR2A) in the placenta. Ninety pregnant women were included in this study. Thirty mothers were diagnosed with GDM, and sixty mothers served as controls in a 1:2 ratio. Ten CpG sites within the promoter regions of SLC6A4 and HTR2A were analyzed using pyrosequencing. The relative expression of genes involved in DNA methylation was evaluated using real-time PCR. The average DNA methylation of placental SLC6A4 was higher in the GDM group than in the control group (2.29 vs. 1.16%, p < 0.001). However, the average DNA methylation level of HTR2A did not differ between the two groups. SLC6A4 methylation showed a positive correlation with maternal plasma glucose level and neonatal birth weight percentile and a negative correlation with the neonatal head circumference percentile. This finding suggests that epigenetic modification of the placental serotonin system may affect placental adaptation to a harmful maternal environment, thereby influencing the long-term outcome in the offspring.