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

Livio Provenzi,Monica Fumagalli,Ida Sirgiovanni,Giorgia Menozzi,Renato Borgatti,Silvana Beri,Roberto Giorda,Uberto Pozzoli,Rosario Montirosso,Fabio Mosca,Francesco Morandi

doi:10.3389/fnbeh.2015.00099

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.

Highlights

Preterm birth represents a major health care issue worldwide with the rate of preterm birth ranging from about 5% in some European countries to 18% in several African countries (Blencowe et al, 2013)
Post-hoc tests revealed that full-term infants had higher birth weight than low pain-exposure (LPE) and high pain-exposure (HPE) very preterm (VPT) infants, whereas LPE and HPE VPT infants did not differ for gestational age and birth weight
The current study aimed at assessing DNA methylation at 20 CpG sites within the promoter region of the SLC6A4 gene in relation to different levels of pain-related stress during Neonatal Intensive Care Unit (NICU) stay in VPT infants

Summary

Introduction

Preterm birth represents a major health care issue worldwide with the rate of preterm birth ranging from about 5% in some European countries to 18% in several African countries (Blencowe et al, 2013). Even in absence of major post-natal morbidities and brain injuries, very preterm (VPT) infants are neuro-behaviorally immature and require long-lasting hospitalization in the Neonatal Intensive Care Unit (NICU) (Lester et al, 2011a; Grunau, 2013). Higher levels of pain-related stress (e.g., numbers of neonatal skin-breaking procedures) have been associated with reduced development of white matter and subcortical gray matter (Brummelte et al, 2012), motor and cognitive development in preschoolers (Grunau et al, 2009), altered activity of hypothalamic-pituitary-adrenal (HPA) axis (Grunau et al, 2013) and internalizing behavioral symptoms during school age (Ranger et al, 2013) in VPT infants, after adjusting for specific medical confounders

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