Endogenous oxytocin levels in children with autism: Associations with cortisol levels and oxytocin receptor gene methylation

Background. Alterations in the oxytocinergic system of the brain have been suggested to play an important role in the pathophysiology of autism spectrum disorder (ASD), but insights from pediatric populations are sparse. Methods. We examined salivary oxytocin in school-aged children with (n=80) and without (n=40) ASD (boys/girls 4/1), as well as characterizations of DNA methylation (DNAm) of the oxytocin receptor gene (OXTR). Cortisol levels were also assessed to examine links between the oxytocinergic system and hypothalamic-pituitary-adrenal (HPA) axis signaling. Results. Children with ASD displayed altered (diminished) oxytocin levels in the morning, but not in the afternoon, after a mildly stress-inducing social interaction session. Notably, in the control group, higher oxytocin levels were predictive of lower stress-induced cortisol, likely reflective of a protective stress-regulatory mechanism for buffering HPA stress activity. In children with ASD, on the other hand, a more reactive stress regulatory mechanism was evident, involving a significant rise in oxytocin levels from the morning to the afternoon upon stress-induced cortisol release, i.e., to reactively cope with heightened HPA activity. Regarding epigenetic modifications, no overall pattern of OXTR hypo- or hypermethylation was evident in ASD. In control children, a notable association between OXTR methylation and levels of cortisol was evident, likely indicative of a compensatory downregulation of OXTR methylation (higher oxytocin receptor expression) in children with heightened HPA axis activity. Conclusion. Together, these observations bear important insights into altered oxytocinergic signaling in ASD, which may aid in establishing relevant biomarkers for diagnostic and/or treatment evaluation purposes targeting the oxytocinergic system in ASD.