Programming of stress regulation in 5 - 7 year old children by maternal gestational mood and antidepressant use

Of particular importance to mental health across the life span is our capacity to regulate neuroendocrine responses to stressful events via the hypothalamic pituitary adrenal (HPA) axis. Prenatal exposure to maternal depression/anxiety may be among the earliest adverse experiences shown to influence the developing HPA system, possibly via changes in fetal serotonergic signaling. In addition, the developmental impact of prenatal exposure to serotonin reuptake inhibitor (SRI) antidepressants is often undistinguishable from prenatal maternal mood. The molecular mechanisms underlying how serotonin (5-HT) influences the development of the HPA stress system remain unclear, but may involve epigenetic mechanisms such as DNA methylation. This thesis explored whether prenatal exposure to SRIs and maternal depressed/anxious mood are associated with altered HPA stress reactivity, characterized by variable basal and stress-induced cortisol concentrations in 5 - 7 year-old children. Furthermore, the methylation status in promoter regions of NR3C1 1F (encodes the glucocorticoid receptor) and SLC6A4 (encodes the serotonin transporter) at birth and at 5 - 7 years of age was evaluated and the relationship to children’s cortisol patterns was assessed. Prenatal exposure to SRIs and higher 3rd trimester maternal depressed/anxious mood were associated with reduced cortisol stress responses at 5 - 7 years. Higher NR3C1 1F methylation at 5 - 7 years was associated with higher diurnal cortisol concentrations and a reduced cortisol stress response. Children exposed to mothers with higher 3rd trimester and concurrent anxious mood exhibited lower SLC6A4 methylation, compared to children exposed to higher 3rd trimester maternal anxious mood alone. Furthermore, children with higher SLC6A4 methylation at birth exhibited a reduced cortisol stress response. These findings suggest that the relationship between early life experiences and altered stress responses in early childhood may be moderated by epigenetic mechanisms involving the serotonergic and HPA regulatory systems. In addition, an interactive relationship between pre- and postnatal maternal mood with cortisol stress responses and methylation status at 5 - 7 years suggests that an early adverse environment may confer sensitivity toward altered HPA activity and regulation, and that the postnatal environment may shift the HPA stress response towards vulnerability or resilience to stress-related disorders across the lifespan.Medicine, Faculty ofObstetrics and Gynaecology, Department ofGraduat