Pain‐related increase in serotonin transporter gene methylation associates with emotional regulation in 4.5‐year‐old preterm‐born children

Abstract

Aim. The main goal of this study was to assess the association between pain-related increase in serotonin transporter gene (SLC6A4) methylation and emotional dysregulation in 4.5-year-old preterm children compared to full-term matched counterparts.Methods. Preterm (n=29) and full-term (n=26) children recruited from two Italian hospitals were followed-up from October 2011 to December 2017. SLC6A4 methylation was assessed from cord blood at birth from both groups and peripheral blood at discharge for preterm ones. At 4.5 years, emotional regulation (i.e., anger, fear, sadness) was assessed through an observational standardized procedure.Results. Preterm children (18 females; mean age = 4.5, range = 4.3 -4.8) showed greater anger display compared to full-term controls (14 females; mean age = 4.5, range = 4.4 -4.9) in response to emotional stress. Controlling for adverse life events occurrence from discharge to 4.5 years and SLC6A4 methylation at birth, CpG-specific SLC6A4 methylation in the neonatal period was predictive of greater anger display in preterm children but not in full-term ones.Conclusion. These findings contribute to highlight how epigenetic regulation of serotonin transporter gene in response to NICU pain exposure contributes to long-lasting programming of anger regulation in preterm children. KEY POINTS• Early exposure to adverse events may contribute to the behavioural phenotype of preterm infants via epigenetic mechanisms.• Pain-related increase in serotonin transporter gene methylation associated with increased anger response to emotional stress at 4.5 years of age in preterm children.• These findings highlight the importance of limiting early pain exposure in preterm infants to reduce the risk of later emotional dysregulation.

Hidden pandemic: COVID-19-related stress, SLC6A4 methylation, and infants’ temperament at 3 months

“…The saliva was collected from both mothers and infants using the OraCollect for Pediatrics kit OC-175 (DNA Genotek, Ottawa, Canada) between 6 and 24 h from delivery. Methylation assessment was conducted according to previous validated procedures from this lab 27 , 28 . The genomic DNA was extracted following manufacturer’s protocols and its quality was assessed using a Qubit fluorometer Invitrogen, Thermo Fisher Scientific, Waltham, Massachusetts, USA).…”

The role of maternal touch in the association between SLC6A4 methylation and stress response in very preterm infants

“…Additionally, a recent study found that VPT children displayed greater anger in response to an emotional stress procedure at 4.5 years compared with full‐term age‐matched controls. Remarkably, in the VPT children sample, the degree of anger expression was significantly predicted by increased SLC6A4 methylation measured at NICU discharge (Provenzi, Fumagalli, et al., 2020). Furthermore, higher exposure to pain‐related stress during NICU stay predicted an increased SLC6A4 methylation in 7‐year‐old VPT children (Chau et al., 2014), which in turn was related to internalizing behaviors.…”

“…Epigenetic mechanisms, functional modifications of the DNA that regulate gene activity without changing the DNA sequence, may explain, at least partially, how early NICU‐related stressful experiences can affect the developmental trajectories of preterm infants (Maddalena, 2013). Emerging evidence suggests a link between variation in the serotonin transporter gene (i.e., SLC6A4 ) and altered developmental trajectories of stress responses in VPT infants (Montirosso, Provenzi, Fumagalli, et al., 2016; Provenzi, Fumagalli, et al., 2020). Research on human infants indicates that postnatal maternal touch may buffer the early epigenetic effects of less‐than optimal caregiving (Murgatroyd et al., 2015).…”

International Young Investigator Award 2020

“…He receives the award for his paper: Pain ‐ related increase in serotonin transporter gene methylation associates with emotional regulation in 4 . 5 ‐ year ‐ old preterm ‐ born children published in Acta Paediatrica 2020 1 . The paper reports that preterm infants exposed to pain showed increased anger response to emotional stress four years later.…”