engleski

Placental DNA methylation of the serotonin transporter gene is associated with maternal gestational diabetes

Epigenetic alterations occurring in response to various prenatal exposures are considered to play a role in fetal programming of lifelong health outcomes, and the placenta, being capable to adapt to various environmental conditions, is considered to be a central organ in fetal programming (1). Intrauterine exposure to maternal hyperglycemia has been linked to increased risk for later-life obesity, metabolic disorders and cardiovascular diseases, however, underlying mechanisms are poorly understood (2). The biogenic amine serotonin (5HT) is increasingly being recognized as an important contributor to obesity and related metabolic disorders (3). The serotonin transporter gene (SLC6A4), encoding a transmembrane protein responsible for extracellular serotonin bioavailability, plays a central role in the regulation of the intensity and duration of 5HT signaling. Here we hypothesized that the SLC6A4 gene might be a candidate gene implicated in fetal programing in infants exposed to intrauterine hyperglycemia. Hence, we investigated potential association between the SLC6A4 DNA methylation in human term placenta and maternal gestational diabetes mellitus (GDM). The study included 50 mother-infant dyads enrolled at the Department of Obstetrics and Gynecology, Clinical Hospital Center Zagreb, School of Medicine, University of Zagreb. Eighteen mothers were diagnosed with GDM and 32 were normoglycemic (control group). All infants were healthy, of normal birth weight and born at term by planned Cesarean section. Tissue samples were collected from the fetal side of the placenta immediately after delivery and DNA methylation was quantified at seven CpG sites within the SLC6A4 promoter region using bisulfite sequencing. In addition, all placental samples were genotyped for common SLC6A4 polymorphisms (5-HTTLPR, rs25531, In2- VNTR) and analyzed for SLC6A4 mRNA levels. Methylation levels at the investigated loci were highly correlated with each other (P<0.0001 for all combinations). Average methylation across all seven CpG sites showed no association with infant sex, genotype, gestational age, birth weight, maternal age at delivery, pre-gestational body mass index, gestational weight gain, parity, and nicotine, alcohol and vitamins use (P>0.05). On the other hand, average methylation (P=0.0365), as well as methylation at three individual CpG sites, was significantly decreased in the GDM as compared to the control group. Between group differences were further supported by negative correlation between SLC6A4 methylation levels and maternal gestational glucose levels (P=0.0343 for average methylation). In addition, a significant negative correlation was observed between placental SLC6A4 methylation and mRNA levels (P=0.0104 for average methylation). The obtained results provide the first evidence for a potential role of SLC6A4 epigenetic alterations in mechanisms underlying fetal programming in infants exposed to intrauterine hyperglycemia.

fetal programming ; gestational diabetes ; placenta ; DNA methylation ; serotonin transporter

nije evidentirano