Abstract
BackgroundTo investigate the relationship between early-life stress and glucocorticoid receptor (GR) gene methylation, which may result in long-lasting neurodevelopmental impairment, we performed a longitudinal analysis of the methylation ratio within the GR gene promoter 1F region using next-generation sequencing in preterm infants.Cell-free DNA was extracted from the frozen serum of 19 preterm birth infants at birth and at 1 and 2 months after birth. All were admitted to the neonatal intensive care unit of Juntendo University Shizuoka Hospital between August 2014 and May 2016 and suffered from chronic lung disease (CLD).Through bisulfite amplicon sequencing using an Illumina Miseq system and Bismark-0.15.0 software, we identified the rate of cytosine methylation.ResultsPatients’ sex and body weight standard deviation were extracted as the associated independent variables at birth. Sex, glucocorticoid administration for treating CLD, and postnatal invasive procedures (surgical operation and blood sampling) were extracted as the associated independent variables at 1 month. Methylation rates increased significantly between postnatal 1 and 2 months at 9 of the 39 CpG sites. Postnatal glucocorticoid administration to treat circulatory collapse was the most-associated independent variable with a positive regression coefficient for a change in methylation rate at these nine CpG sites. It also influenced the methylation ratio at 22 of the 39 CpG sites at 2 months of age. The standard deviation (SD) score at birth was extracted as an independent variable, with a negative regression coefficient at 9 of the 22 CpG sites together with glucocorticoid administration.ConclusionsThe results of this study indicate that a prenatal environment that results in intrauterine growth restriction and postnatal relative adrenal insufficiency requiring glucocorticoid administration leads to GR gene methylation. That, in turn, may result in neurodevelopmental disabilities.
Highlights
To investigate the relationship between early-life stress and glucocorticoid receptor (GR) gene methylation, which may result in long-lasting neurodevelopmental impairment, we performed a longitudinal analysis of the methylation ratio within the GR gene promoter 1F region using next-generation sequencing in preterm infants
Infants born with a birth weight < 10th percentile or small for gestational age (SGA) [3, 4] and infants with chronic lung disease (CLD) characterized by prolonged inflammation of lung tissue are at increased risk for neonatal mortality, and preterm infants suffer from both short- and long-term morbidities [5, 6]
We showed that a postnatal environment that includes the need for acute care and prolonged physical separation under neonatal intensive care affects epigenetic programming of GR expression through methylation of the NR3C1 promoter in premature infants, which might result in glucocorticoid resistance later in life [19]
Summary
To investigate the relationship between early-life stress and glucocorticoid receptor (GR) gene methylation, which may result in long-lasting neurodevelopmental impairment, we performed a longitudinal analysis of the methylation ratio within the GR gene promoter 1F region using next-generation sequencing in preterm infants. Infants born with a birth weight < 10th percentile or small for gestational age (SGA) [3, 4] and infants with chronic lung disease (CLD) characterized by prolonged inflammation of lung tissue are at increased risk for neonatal mortality, and preterm infants suffer from both short- and long-term morbidities [5, 6]. The most commonly implicated mechanism of these long-term effects is the dysregulation of the hypothalamus–pituitary–adrenal (HPA) axis. Dysregulation of this axis has been noted in extremely low birth weight and very low birth weight (VLBW) survivors across their lifespan [7, 8]. Activity of the HPA axis is regulated by the hypothalamic glucocorticoid receptor (GR) encoded by the nuclear receptor subfamily 3 group C member 1 (NR3C1) gene, which mediates a negative feedback loop [11]
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