Sex-specific associations between placental leptin promoter DNA methylation and infant neurobehavior

Abstract

Leptin (LEP) is a hormone central for energy homeostasis and has been implicated in neurodevelopment. This adipokine is produced by the placenta and is epigenetically regulated by promoter DNA methylation. Recent evidence has suggested a role for LEP in behavioral development. In this study, we investigated associations between profiles of human newborn neurobehavior and placental LEP DNA methylation. We determined LEP promoter methylation in 444 placental samples from healthy term infants and measured LEP gene expression in a random subset of these samples. Infant neurobehavior was assessed with the NICU Network Neurobehavioral Scales (NNNS) and we examined the relationship between LEP promoter methylation and profiles of infant neurobehavior derived from these scores generated using a hierarchical model-based clustering method. LEP methylation is negatively correlated with gene expression only in placentas from male infants (r=-0.6, P=0.006). A 10% increase in LEP DNA methylation was associated with membership in a profile of infant neurobehavior marked by increased lethargy and hypotonicity (OR=1.9; 95% CI: 1.07-3.4), and consistently with reduced risk of membership in a profile characterized by decreased lethargy and hypotonicity (OR=0.54; 95% CI: 0.3-0.94) only in male infants (n=223). No statistically significant associations were observed amongst female infants. These results suggest that increased placental LEP DNA methylation, related to reduced expression, may play a role in human newborn neurodevelopment, particularly in reactivity to various stimuli, but that these effects may be sexually dimorphic.