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Background: Sex-specific differences in DNA methylation of the oxytocin receptor gene (OXTR) have been shown in adults and are related to several mental disorders. Negative affectivity early in life is a trans-diagnostic risk marker of later psychopathology and is partly under genetic control. However, sex-specific variations in OXTR methylation (OXTRm) in infants and their associations with negative affectivity are still unknown. Aims: Here, we explored sex differences in the association between infant OXTRm at birth and negative affectivity at 3 months of age. Methods: Infants and their mothers (N = 224) were recruited at delivery. Infants’ methylation status was assessed in 13 CpG sites within the OXTR gene intron 1 region (chr3: 8810654–8810919) in buccal cells at birth while 3-month-old infants’ negative affectivity was assessed by mothers using a well-validated temperament questionnaire. Results: OXTRm at 12 CpG sites was higher in females than in males. Moreover, higher infants’ OXTRm at 6 specific CpG sites was associated with greater negative affectivity in males, but not in females. Conclusions: These results provide new insights into the role of sex-dependent epigenetic mechanisms linking OXTRm with early infants’ emotional development. Understanding the degree to which epigenetic processes relate to early temperamental variations may help inform the etiology of later childhood psychopathological outcomes.

Background: The coronavirus disease of 2019 (Covid-19) represents an unprecedented threat for human health worldwide that may have profound stress effects Pregnancy is a sensitive period for adverse parenting effects on infants’ development and epigenetic mechanisms (DNA methylation) may play a pivotal role Here we present the study protocol of the MOM-COPE project Methods: Mothers and infants will be enrolled in twelve neonatal units in Northern Italy, a dramatic hotspot for Covid-19 contagion in Europe Maternal covid-related stress will be assessed with an ad-hoc questionnaire At birth, newborns and mothers’ salivary samples will be obtained to estimate target genes’ methylation (BDNF, FKBP5, NR3C1, SLC6A4, and OXTR) Post-natal bonding and infants’ temperament will be assessed through maternal reports at 3, 6 and 12 months Maternal sensitivity and infants’ emotional regulation will be assessed during remote videotaped mother-infant interaction at 12 months Results: The study has obtained approval of the Ethics Committee and is going to start by May 15th Hypotheses and anticipated results will be discussed according to the available behavioral epigenetic literature on parenting, pregnancy and large-scale disasters Discussion: This multi-centric study will provide evidence about the effect of pandemic-related prenatal stress exposure on the health and well-being of mothers and infants from birth to 12 months of age Moreover, the longitudinal nature of the study will allow to assess the relative role of epigenetic regulation of specific target genes in mediating the effect of this precocious adverse exposure on short- and long-term outcomes