Sex-dimorphic pathways in the associations between maternal trait anxiety, infant BDNF methylation and negative emotionality

Maternal antenatal anxiety is an emerging risk factor for child emotional development. Both sex and epigenetic mechanisms, such as DNA methylation, may contribute to the embedding of maternal distress into emotional outcomes. Here, we investigated sex-dependent patterns in the association between antenatal maternal trait anxiety, methylation of the brain-derived neurotrophic factor gene (BDNFm) and infant negative emotionality (NE). Mother-infant dyads (N=276) were recruited at delivery. Maternal trait anxiety, as a marker of antenatal chronic stress exposure, was assessed soon after delivery using the Stait-Trait Anxiety Inventory (STAI-Y). Infants’ BDNFm at birth was assessed in 11 CpG sites in buccal cells whereas infants’ NE was assessed at 3 (N=225) and 6 months (N=189) using the Infant Behavior Questionnaire-Revised (IBQ-R). Hierarchical linear analyses showed that higher maternal antenatal anxiety was associated with greater 6-month-olds’ NE. Furthermore, maternal antenatal anxiety predicted greater infants’ BNDFm in 5 CpG sites in males but not in females. Higher methylation at these sites was associated with greater 3-to-6-month NE increase, independently of infants’ sex. Maternal antenatal anxiety emerged as a risk factor for infant’s NE. BNDFm might mediate this effect in males. These results may inform the development of strategies to promote mothers and infants’ emotional well-being.