Lauren A Eaves1,2, Adam E Enggasser1,2, Marie Camerota3, Semsa Gogcu4, William A Gower5, Hadley Hartwell1, Wesley M Jackson5, Elizabeth Jensen6, Robert M Joseph7, Carmen J Marsit8, Kyle Roell1,2, Hudson P Santos2,9, Jeffrey S Shenberger4, Lisa Smeester1,2, Diana Yanni10, Karl C K Kuban11, T Michael O'Shea5, Rebecca C Fry12,13,14. 1. Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 2. Institute for Environmental Health Solutions, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 3. Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA. 4. Division of Neonatology, Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC, USA. 5. Department of Pediatrics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA. 6. Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA. 7. Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, USA. 8. Gangarosa Department of Environmental Health, Emory University Rollins School of Public Health, Atlanta, GA, USA. 9. School of Nursing & Health Studies, University of Miami, Miami, FL, USA. 10. Department of Neonatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 11. Division of Pediatric Neurology, Department of Pediatrics, School of Medicine, Boston University Medical Center, Boston, MA, USA. 12. Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. rfry@unc.edu. 13. Institute for Environmental Health Solutions, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. rfry@unc.edu. 14. Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. rfry@unc.edu.
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.
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.
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