Neonatal stress exposure and DNA methylation of stress-related and neurodevelopmentally relevant genes: An exploratory study

Nienke H. van Dokkum*, Mian Bao, Rikst Nynke Verkaik-Schakel, Sijmen A. Reijneveld, Arend F. Bos, Marlou L.A. de Kroon, Torsten Plösch

*Corresponding author for this work

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Background: Stress exposure during Neonatal Intensive Care Unit (NICU) stay may have long-lasting effects on neurodevelopmental outcomes in extremely preterm infants. Altered DNA methylation of stress-related and neurodevelopmentally relevant genes may be an underlying mechanism.

Aims: This exploratory study aimed to investigate the association between neonatal stress exposure and DNA methylation in these genes at two different time points: early during the NICU stay (7–14 days after birth) and later, at discharge from the NICU.

Subjects: We included 45 extremely preterm infants in this prospective cohort study, gestational age 24–30 weeks.

Outcome measures: We collected fecal samples at days 7–14 (n = 44) and discharge (n = 28) and determined DNA methylation status in predefined regions of NR3C1, SLC6A4, HSD11B2, OPRM1, SLC7A5, SLC1A2, IGF2, NNAT, BDNF and GABRA6 using pyrosequencing. Because of low DNA concentrations in some fecal samples, we could do so in 25–50 % of collected samples. We prospectively quantified daily neonatal stress exposure using the Neonatal Infant Stressor Scale (NISS) and explored associations between cumulative NISS scores and average DNA methylation status.

Results: Rates of methylation of most genes were not statistically different between day 7–14 and discharge, except for OPRM1. We found moderately high and mostly negative correlation coefficients upon discharge with the cumulative NISS for the NR3C1, SLC6A4, SLC1A2, IGF2, BDNF and OPRM1 genes, albeit not statistically significant.

Conclusions: Findings suggest that expression of stress-related and neurodevelopmentally relevant genes may be differently regulated following higher neonatal stress exposure. Larger studies should challenge the findings of this study and ideally test the effects on gene expression.

Original languageEnglish
Article number105868
Number of pages8
JournalEarly Human Development
Publication statusPublished - Nov-2023


  • DNA methylation
  • Extremely preterm infants
  • Neonatal stress exposure

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