Pain-related stress during the Neonatal Intensive Care Unit stay and SLC6A4 methylation in very preterm infants

Abstract

Very preterm (VPT) infants need long-lasting hospitalization in the Neonatal Intensive Care Unit (NICU) during which they are daily exposed to pain-related stress. Alterations of DNA methylation at the promoter region of the SLC6A4 have been associated with early adverse experiences in infants. The main aim of the present work was to investigate the association between level of exposure to pain-related stress during hospitalization and changes in SLC6A4 DNA methylation at NICU discharge in VPT infants. In order to exclude the potential effect of birth status (i.e., preterm vs. full-term birth) on SLC6A4 methylation, we preliminarily assessed SLC6A4 epigenetic differences between VPT and full-term (FT) infants at birth. Fifty-six VPT and thirty-two FT infants participated in the study. The level of exposure to pain-related stress was quantified on the basis of the amount of skin-breaking procedures to which they were exposed. VPT infants were divided in two sub-groups: low-pain exposure (LPE, N = 25) and high-pain exposure (HPE, N = 31). DNA methylation was evaluated at birth for both VPT and FT infants, assessing 20 CpG sites within the SLC6A4 promoter region. The same CpG sites were re-evaluated for variations in DNA methylation at NICU discharge in LPE and HPE VPT infants. No differences in SLC6A4 CpG sites' methylation emerged between FT and VPT infants at birth. Methylation at CpG sites 5 and 6 significantly increased from birth to NICU discharge only for HPE VPT infants. Findings show that preterm birth per se is not associated with epigenetic alterations of the SLC6A4, whereas higher levels of pain-related stress exposure during NICU stay might alter the transcriptional functionality of the serotonin transporter gene.

Serotonin Transporter Gene (SLC6A4) Methylation Associates With Neonatal Intensive Care Unit Stay and 3‐Month‐Old Temperament in Preterm Infants

“…Overall, this evidence is consistent with previous studies on humans indicating that the serotonergic system is highly sensitive to early adverse events (Devlin et al., ). At a more specific level, our finding is consistent with recent studies documenting the association between pain‐related stress during NICU stay and SLC6A4 methylation status in preterm infants (Provenzi et al., ) and children (Chau et al., ). However, as noted earlier, their study had no data on further infants' experience that might well affect NICU‐related epigenetic changes.…”

Maternal caregiving and DNA methylation in human infants and children: Systematic review

“…More specifically, rat pups of mothers that showed reduced amount of licking and grooming presented greater Nr3c1 methylation in the hippocampus and higher stress reactivity in adulthood . Similar findings have been reported in other stress‐ and behavior‐related genes, such as Bdnf (brain‐derived neurotropic factor gene), Slc6a4 (serotonin transporter gene) and Oxtr (oxytocin receptor gene).…”

“…(serotonin transporter gene 20 ) and Oxtr (oxytocin receptor gene 21 ). Impact of early adverse experience on DNA methylation has also been reported in humans.…”

Respiratory sinus arrhythmia in the fourth decade of life depends on birth weight and the DRD4 gene: Implications for understanding the development of emotion regulation

“…Although the presented analyses attempted to control for covariates such as age, sex, and BMI that might influence RSA, it is possible that unmeasured confounding variables may at least partially account for the observed associations. Additionally, an emerging body of evidence suggests that neonatal exposure to pain and stress (as when receiving NICU care) might alter gene expression, potentially influencing parasympathetic nervous system development and function (Provenzi et al, ). As well, ELBW survivors were exposed to numerous perinatal stressors, and although ELBW status is a marker of early life stress exposure, we cannot assess the effect of each of its contributing stressors individually.…”