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Updated: Sep 6, 2025
A Murine Model of Fetal Exposure to Maternal Inflammation to Study the Effects of Acute Chorioamnionitis on Newborn Intestinal Development
Published on: June 24, 2020
CpG methylation patterns in placenta and neonatal blood are differentially associated with neonatal inflammation
Lauren A Eaves1,2, Adam E Enggasser1,2, Marie Camerota3
1Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Insights
Placental DNA methylation is linked to sustained inflammation in preterm infants, while blood DNA methylation is associated with early inflammation. This highlights tissue-specific epigenetic patterns influencing infant health outcomes.
Area of Science:
- Epigenetics
- Neonatal Medicine
- Developmental Biology
Background:
- Infants born extremely premature face heightened risks for long-term health issues, with neonatal inflammation as a potential driver.
- Placental CpG methylation offers insights into prenatal epigenetic programming, prematurity, neonatal inflammation, and future health.
- Understanding these links is crucial for mitigating adverse outcomes in extremely preterm infants.
Purpose of the Study:
- To investigate the relationship between placental and neonatal blood CpG methylation and neonatal inflammation in extremely preterm infants.
- To determine if epigenetic patterns in different tissues are specifically associated with distinct types of neonatal inflammation.
- To explore the role of placental epigenetic programming in the context of neonatal inflammation and later-life health.
Main Methods:
- Compared CpG methylation in 354 placental and 318 neonatal blood samples from the Extremely Low Gestational Age Newborn (ELGAN) cohort.
- Assessed neonatal inflammation based on the expression of six inflammation-related proteins, categorizing it as day-one inflammation (DOI) or intermittent or sustained systemic inflammation (ISSI).
- Utilized epigenome-wide association studies to identify specific CpG sites associated with inflammation markers.
Main Results:
- Placental CpG methylation showed a strong association with ISSI (48 CpG sites) but not with DOI.
- Neonatal blood spot CpG methylation was associated with DOI (111 CpG sites) but not with ISSI (1 CpG site).
- These findings indicate distinct tissue-specific epigenetic associations with different inflammation patterns.
Conclusions:
- Placental CpG methylation is significantly linked to sustained inflammation (ISSI), which is associated with later-life cognitive impairment.
- Neonatal blood spot CpG methylation is associated with early-onset inflammation (DOI).
- The study supports the framework of placental origins of disease, suggesting placental epigenetic patterns predict a propensity for sustained neonatal inflammation.
Background:
Infants born extremely premature are at increased risk for health complications later in life for which neonatal inflammation may be a contributing biological driver. Placental CpG methylation provides mechanistic information regarding the relationship between prenatal epigenetic programming, prematurity, neonatal inflammation, and later-in-life health.
Methods:
We contrasted CpG methylation in the placenta and neonatal blood spots in relation to neonatal inflammation in the Extremely Low Gestational Age Newborn (ELGAN) cohort. Neonatal inflammation status was based on the expression of six inflammation-related proteins, assessed as (1) day-one inflammation (DOI) or (2) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 postnatal weeks). Epigenome-wide CpG methylation was assessed in 354 placental samples and 318 neonatal blood samples.
Results:
Placental CpG methylation displayed the strongest association with ISSI (48 CpG sites) but was not associated with DOI. This was in contrast to CpG methylation in blood spots, which was associated with DOI (111 CpG sites) and not with ISSI (one CpG site).
Conclusions:
Placental CpG methylation was strongly associated with ISSI, a measure of inflammation previously linked to later-in-life cognitive impairment, while day-one neonatal blood methylation was associated with DOI.
Impact:
Neonatal inflammation increases the risk of adverse later-life outcomes, especially in infants born extremely preterm. CpG methylation in the placenta and neonatal blood spots were evaluated in relation to neonatal inflammation assessed via circulating proteins as either (i) day-one inflammation (DOI) or (ii) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 weeks). Tissue specificity was observed in epigenetic-inflammatory relationships: placental CpG methylation was associated with ISSI, neonatal blood CpG methylation was associated with DOI. Supporting the placental origins of disease framework, placental epigenetic patterns are associated with a propensity for ISSI in neonates.
