Sex differences in the risk of autistic-related traits in toddlers born to mothers with perinatal depression: Evidence from human cohort and mouse study

Maternal perinatal depression (MPD) is associated with reduced maternal plasma oxytocin (OXT) levels and an increased risk of autism spectrum disorder (ASD) in offspring. Using data from 23,218 Japanese mother-child pairs, we evaluated the relationship between MPD-assessed with the Kessler Psychological Distress Scale (K6) and the Edinburgh Postnatal Depression Scale (EPDS)-and autistic-related traits (ART) in toddlers, measured by the Tokyo Autistic Behavior Scale (TABS). We also tested the potential causal relationship of maternal stress exposure on OXT, its receptor (OXTR), and offspring outcomes using a prenatal stress-exposed mouse model. In the human cohort study, higher K6 or EPDS scores during pregnancy and postpartum were significantly associated with increased TABS scores in toddlers. Offspring of mothers with MPD (K6 or EPDS score ≥ 9) during pregnancy or postpartum exhibited a higher risk of ART (TABS score ≥ 15; P < 0.05). This risk was particularly pronounced in female toddlers exposed to MPD during pregnancy and postpartum (ORs: 5.805-9.367; P < 0.05). Female toddlers born to mothers with MPD also had lower birth weight, and their ART were positively correlated with K6 scores during mid-gestation and with impaired maternal bonding postpartum. In the mouse model, chronically stressed dams displayed depressive-like behaviors, and their female juveniles exhibited increased self-grooming and impaired social interaction. Furthermore, OXTR mRNA levels were significantly reduced in the prefrontal cortex of female juveniles from stressed dams. These findings suggest that MPD increases the risk of ART, particularly in females, highlighting potential sex-specific mechanisms underlying ASD susceptibility.