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Differential placental CpG methylation is associated with chronic lung disease of prematurity
Wesley M Jackson1, Hudson P Santos2,3, Hadley J Hartwell2
1Department of Pediatrics, School of Medicine, The University of North Carolina, Chapel Hill, NC, USA. wesley.jackson@unc.edu.
Insights
Placental DNA methylation patterns are linked to chronic lung disease (CLD) in extremely preterm infants. These epigenetic associations differ by infant sex, suggesting distinct biological pathways influencing CLD risk.
Area of Science:
- Perinatal epigenetics
- Neonatal respiratory health
- Developmental origins of disease
Background:
- Chronic lung disease (CLD) is a major complication in extremely preterm infants.
- The role of prenatal exposures, particularly placental epigenetic variation, in CLD risk is not fully understood.
- Sex-specific effects on CLD risk and its underlying mechanisms require further investigation.
Purpose of the Study:
- To investigate the association between placental DNA methylation and CLD in extremely preterm infants.
- To explore whether these associations are influenced by fetal sex.
- To identify potential epigenetic mechanisms contributing to CLD development.
Main Methods:
- Epigenome-wide association study on placental DNA methylation in 423 extremely preterm infants.
- Robust linear regression analysis adjusted for covariates.
- Stratified analyses by fetal sex to assess differential associations.
Main Results:
- 49 CpG sites (46 genes) in placental DNA methylation were significantly associated with CLD.
- Associated genes are involved in fetal lung development pathways (e.g., p53 signaling, myo-inositol biosynthesis).
- Methylation-CLD associations showed significant differences between male and female infants.
Conclusions:
- Differential placental methylation in key fetal lung development genes may mediate CLD risk via placenta-fetus signaling.
- These epigenetic pathways appear to be sex-specific, potentially explaining dimorphic CLD phenotypes.
- Further research into placental epigenetics could inform strategies to prevent or reduce CLD in preterm infants.
Background:
Chronic lung disease (CLD) is the most common pulmonary morbidity in extremely preterm infants. It is unclear to what extent prenatal exposures influence the risk of CLD. Epigenetic variation in placenta DNA methylation may be associated with differential risk of CLD, and these associations may be dependent upon sex.
Methods:
Data were obtained from a multi-center cohort of infants born extremely preterm (<28 weeks' gestation) and an epigenome-wide approach was used to identify associations between placental DNA methylation and CLD (n = 423). Associations were evaluated using robust linear regression adjusting for covariates, with a false discovery rate of 0.05. Analyses stratified by sex were used to assess differences in methylation-CLD associations.
Results:
CLD was associated with differential methylation at 49 CpG sites representing 46 genes in the placenta. CLD was associated with differential methylation of probes within genes related to pathways involved in fetal lung development, such as p53 signaling and myo-inositol biosynthesis. Associations between CpG methylation and CLD differed by sex.
Conclusions:
Differential placental methylation within genes with key roles in fetal lung development may reflect complex cell signaling between the placenta and fetus which mediate CLD risk. These pathways appear to be distinct based on fetal sex.
Impact:
In extremely preterm infants, differential methylation of CpG sites within placental genes involved in pathways related to cell signaling, oxidative stress, and trophoblast invasion is associated with chronic lung disease of prematurity. DNA methylation patterns associated with chronic lung disease were distinctly based on fetal sex, suggesting a potential mechanism underlying dimorphic phenotypes. Mechanisms related to fetal hypoxia and placental myo-inositol signaling may play a role in fetal lung programming and the developmental origins of chronic lung disease. Continued research of the relationship between the placental epigenome and chronic lung disease could inform efforts to ameliorate or prevent this condition.
