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Abstract
We tested the hypothesis that gestational diabetes mellitus (GDM) alters the DNA methylation pattern of the fetal serotonin transporter gene (SLC6A4), and examined the functional relevance of DNA methylation for regulation of the SLC6A4 expression in the human placenta. The study included 50 mother-infant pairs. Eighteen mothers were diagnosed with GDM and 32 had normal glucose tolerance (NGT). All neonates were of normal birth weight and born at term by planned Cesarean section. DNA and RNA were isolated from samples of tissue collected from the fetal side of the placenta immediately after delivery. DNA methylation was quantified at 7 CpG sites within the SLC6A4 distal promoter region using PCR amplification of bisulfite treated DNA and subsequent DNA sequencing. SLC6A4 mRNA levels were measured by reverse transcription—quantitative PCR (RT-qPCR). Functional SLC6A4 polymorphisms (5HTTLPR, STin2, rs25531) were genotyped using standard PCR-based procedures. Average DNA methylation across the 7 analyzed loci was decreased in the GDM as compared to the NGT group (by 27.1%, p = 0.037) and negatively correlated, before and after adjustment for potential confounder/s, with maternal plasma glucose levels at the 24th to 28th week of gestation (p<0.05). Placental SLC6A4 mRNA levels were inversely correlated with average DNA methylation (p = 0.010) while no statistically significant association was found with the SLC6A4 genotypes (p>0.05). The results suggest that DNA methylation of the fetal SLC6A4 gene is sensitive to the maternal metabolic state in pregnancy. They also indicate a predominant role of epigenetic over genetic mechanisms in the regulation of SLC6A4 expression in the human placenta. Longitudinal studies in larger cohorts are needed to verify these results and determine to which degree placental SLC6A4 changes may contribute to long-term outcomes of infants exposed to GDM.
Highlights
Serotonin (5-hydroxyptamine, 5HT) is a multifunctional signaling molecule, best known for its role in the etiopathogenesis of depression, autism and other mental health conditions [1]
Numerical results of oral glucose tolerance test (OGTT) performed in the 24th to 28th week of pregnancy were available for 40 participants
We investigated the relationship between gestational diabetes mellitus (GDM), the most common cause of maternal hyperglycemia in pregnancy, and placental DNA methylation of the SLC6A4 gene
Summary
Serotonin (5-hydroxyptamine, 5HT) is a multifunctional signaling molecule, best known for its role in the etiopathogenesis of depression, autism and other mental health conditions [1]. Alterations in 5HT homeostasis during the prenatal or early postnatal period, caused by either genetic or environmental influences, affect developmental processes, which may in turn lead to increased disease susceptibility later in life [5,6]. Studying these alterations is of major importance for better understanding of 5HT-related conditions. The placenta is an organ that plays a key role in maintaining homeostasis of the intrauterine environment and is highly responsive to environmental changes [8]. It was suggested that the placental 5HT system might be a key link between early environmental perturbations and their impact on developmental outcomes [9,10]
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