Leptin DNA Methylation and Maternal and Infant Pregnancy Outcomes in the Rhode Island Child Health Study

In utero exposure to maternal malnutrition is associated with increase offspring susceptibility to cardiometabolic and neuropsychiatric disease. Epigenetic mechanisms mediate, at least in part, fetal adaptations to adverse in utero environments because these integrate environmental signals into gene expression control without genetic sequence changes. Leptin is a pleiotropic hormone, pivotal for energy homeostasis and epigenetically regulated by DNA methylation. During pregnancy, leptin is produced by the placenta, maternal and fetal adipose tissues and participates in pregnancy-related metabolic adaptations and fetal development, consequently is a plausible player in fetal programming. Using the resources of the Rhode Island Child Health Study, we sought to explore the hypothesis that epigenetic variation of the leptin promoter (LEP) in pregnancy-related tissues is associated with adverse maternal and infant outcomes. In cord blood and maternal blood, we observed associations with birth size and prepregnancy BMI, respectively, suggestive of an inverse association between blood LEP DNA methylation and adiposity. Importantly, maternal blood LEP DNA methylation is positively associated with cord blood methylation and consequently infants born to prepregnancy obese mothers have lower cord blood LEP methylation. In contrast, placentas from infants born to obese mothers have higher LEP DNA methylation, and this effect in partially mediated by gestational diabetes. Placental epigenetic variation was also influenced by infant sex and the relation between DNA methylation and gene expression is different between sexes. Consistently, in placental tissue, we observed that higher LEP methylation levels are associated with a neurobehavioral profile characterized by lethargy and hypotonicity only in male infants. Moreover, we observed that genetic variation influences LEP promoter methylation in fetal tissues. In summary, we observed that maternal prepregnancy obesity influences LEP DNA methylation marks of maternal and fetal tissues, and placental methylation is associated with infant intrinsic factors (sex and genotype) and neurobehavior. Taken together, our observations suggest that the maternal metabolic environment and infant factors influence LEP methylation in a tissue-specific and sequence-dependent manner and in turn this methylation is associated with infant behavior at birth. It remains to be determined if methylation of this promoter relates to metabolic or neurobehavioral risk during childhood or adult life.