CpG methylation patterns in placenta and neonatal blood are differentially associated with neonatal inflammation

• Authors: Lauren A Eaves, University of North Carolina; Adam E Enggasser, University of North Carolina; Marie Camerota, Brown University; Semsa Gogcu, Wake Forest School of Medicine; William A Gower, University of North Carolina; Hadley Hartwell, University of North Carolina; Wesley M Jackson, University of North Carolina; Elizabeth Jensen, Wake Forest School of Medicine; Robert M Joseph, Boston University; Carmen Marsit, Emory University; Kyle Roell, University of North Carolina; Hudson P Santos, University of North Carolina; Jeffrey S Shenberger, Wake Forest School of Medicine; Lisa Smeester, University of North Carolina; Diana Yanni, Harvard Medical School; Karl CK Kuban, Boston University; Michael T O'Shea, University of North Carolina; Rebecca C Fry, University of North Carolina
• Journal Title: PEDIATRIC RESEARCH
• Volume: Volume 93, Number 4
• Publisher: SPRINGERNATURE | 2022-06-28, Pages 1072-1084
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/s41390-022-02150-4
• Subjects: Environmental Sciences; Biology, Anatomy; Health Sciences, Public Health; Health Sciences, Mental Health; Health Sciences, Nursing; Health Sciences, Epidemiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Pediatrics; MATERNAL IMMUNE ACTIVATION; FETAL-BRAIN DEVELOPMENT; SYSTEMIC INFLAMMATION; DNA METHYLATION; CHILDREN BORN; 28TH WEEK; COGNITIVE IMPAIRMENT; PRETERM NEWBORNS; AGE; PROTEINS

Abstract

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.