Pain exposure in human newborns affects telomere length regulation

Preterm human newborns are known to be at high risk for detrimental developmental outcomes, including behavioral problems, neuroendocrine dysregulation, neurobehavioral maladjustment and socio-emotional issues (Montagna and Nosarti, 2016; Zeitlin et al., 2008). Among the major risk factors for preterm newborns, the early exposure to painful stimulations (e.g., mechanical ventilation, skin-breaking procedures) during the hospitalization in the Neonatal Intensive Care Unit (NICU) has been associated to such altered developmental trajectories (Grunau, 2013). Nonetheless, the mechanisms linking NICU-related pain and developmental outcomes are only partially known.

Recently, we have applied principles of behavioral epigenetics to the study of how early NICU stress exposures end up in altered phenotype in preterm infants (i.e., Preterm Behavioral Epigenetics, PBE; for a systematic review of PBE literature so far, see: Provenzi et al., 2018a). Our previous research focused mainly on one specific epigenetic mechanism, DNA methylation, occurring at stress-related genes (e.g., SLC6A4, the serotonin transporter gene) (Fumagalli et al., 2018; Montirosso et al., 2016; Provenzi et al., 2015). In this recent paper, we report on a different epigenetic mechanism, namely telomere length regulation.

Telomere length regulation is genetically instructed, but environmental adverse exposures might contribute to increase the erosion rate with detrimental consequences for developmental outcomes

Telomeres are the end caps of chromosomes and protect genomic DNA from damage during cell replications. With each cell division, telomerres shorten until they reach a critical end-point. Nonetheless, telomere length shorening (or erosion) is highly affected by cumulative stress exposures (Price et al., 2013). Studies in humans show that adults reporting a history of childhood trauma and neglect have shorter telomeres in peripheral blood compared to controls and the association appears to be dose-dependent (Kiecolt-Glaser et al., 2011).

In our study, we measured telomere length (TL) at birth and at NICU discharge in a group of 46 very preterm (VPT) infants as well as at birth only in a group of 31 full-term (FT) counterparts (Provenzi et al., 2018b). Despite VPT infants showed longer TL at birth compared to FT controls (as they were "younger" than FT counterparts), the cumulative exposure to pain-related stress during NICU stay was associated with progressive and greater telomere erosion from birth to discharge (Fig. 1).

Fig. 1 - Dose-dependent association between cumulative exposure to NICU-related stress and progressive telomere length erosion in very preterm infants.

This study confirms previous retrospective evidence in humans and further suggests that the environmental regulation of TL during a critical period of post-natal life might contribute to the embedding of early adverse exposures into the developing biology of preterm infants.

Preterm infants might be at higher risk for less than optimal developmental outcomes, partly due to the NICU-related increased rate of telomere erosion

We are currently investigating the functional consequences of increased TL erosion on different phenotypic outcomes in preterms.

Stay tuned!


Keywords: #epigenetics #telomere #preterm #stress #NICU #programming

Project: The Preterm Behavioral Epigenetics (PBE) research project

Article citation: Provenzi L, Giorda R, Fumagalli M et al (2018) Pain exposure associates with telomere length erosion in very preterm infants. Psychoneuroendocrinology, 89, 113-119.

References in this post

  • Fumagalli M, Provenzi L, De Carli P et al (2018). From early stress to 12-month development in very preterm infants: Preliminary findings on epigenetic mechanisms and brain growth. Plos One, 13(1).

  • Grunau RE (2013). Neonatal pain in very preterm infants: long-term effects on brain, neurodevelopment and pain reactivity. Rambam Maimonides Med. J. 4 (4), e0025.

  • Kiecolt-Glaser JK, Gouin J-P, Weng N et al (2011). Childhood adversity heightens the impact of later-Life caregiving stress on telomere length and inflammation. Psychosom. Med. 73 (1), 16–22.

  • Montagna A, Nosarti C (2016). Socio-Emotional development following very preterm birth: Pathways to psychopathology. Front. Psychol. 7, 80.

  • Montirosso R, Provenzi L, Fumagalli M et al (2016). Serotonin transporter gene (SLC6A4) methylation associates with neonatal intensive care unit stay and 3-month-old temperament in preterm infants. Child Dev. 87 (1), 38–48.

  • Price LH, Kao H-T, Burgers DE et al (2013). Telomeres and early-life stress: an overview. Biol. Psychiatry 73 (1), 15–23.

  • Provenzi L, Fumagalli M, Sirgiovanni I et al (2015). Pain-related stress during the Neonatal Intensive Care Unit stay and SLC6A4 methylation in very preterm infants. Front. Behav. Neurosci., 9, 99.

  • Provenzi L, Giorda R, Fumagalli M et al (2018b). Pain exposure associates with telomere length erosion in very preterm infants. Psychoneuroendocrinology, 89, 113-119.

  • Provenzi L, Guida E, Montirosso R (2018a). Preterm behavioral epigenetics: a systematic review. Neurosci. Biobehav. Rev., 84, 262–271.

  • Zeitlin J, Draper ES, Kollee L et al (2008) Differences in rates and short-term outcome of live births before 32 weeks of gestation in europe in 2003: results from the MOSAIC cohort. Pediatrics, 121(4), e936–e944.

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