Division of Neonatology, Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Health Sciences, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Early Hum Dev. 2023 Nov;186:105868. doi: 10.1016/j.earlhumdev.2023.105868. Epub 2023 Sep 29.
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.
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.
We included 45 extremely preterm infants in this prospective cohort study, gestational age 24-30 weeks.
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.
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.
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.
新生儿重症监护病房（NICU）住院期间的应激暴露可能对极早产儿的神经发育结果产生持久影响。应激相关和神经发育相关基因的 DNA 甲基化改变可能是其潜在机制。
本探索性研究旨在调查新生儿应激暴露与这些基因的 DNA 甲基化之间的关联，分别在两个不同的时间点：NICU 住院期间早期（出生后 7-14 天）和之后的 NICU 出院时。
我们纳入了本前瞻性队列研究中的 45 名极早产儿，胎龄 24-30 周。
我们在第 7-14 天（n=44）和出院时（n=28）收集粪便样本，并使用焦磷酸测序确定 NR3C1、SLC6A4、HSD11B2、OPRM1、SLC7A5、SLC1A2、IGF2、NNAT、BDNF 和 GABRA6 中预设区域的 DNA 甲基化状态。由于一些粪便样本中的 DNA 浓度较低，我们只能在 25-50%的收集样本中进行检测。我们使用新生儿应激量表（NISS）前瞻性地量化每日新生儿应激暴露，并探索累积 NISS 评分与平均 DNA 甲基化状态之间的关联。
除 OPRM1 外，大多数基因在第 7-14 天和出院时的甲基化率没有统计学差异。我们发现，在出院时，NR3C1、SLC6A4、SLC1A2、IGF2、BDNF 和 OPRM1 基因的累积 NISS 与 DNA 甲基化状态之间存在中等强度且大多为负相关系数，但无统计学意义。
研究结果表明，应激相关和神经发育相关基因的表达可能在受到更高水平的新生儿应激暴露后受到不同的调控。更大规模的研究应挑战本研究的结果，并理想地测试其对基因表达的影响。
