Epigenetic associations in HPA axis genes related to bronchopulmonary dysplasia and antenatal steroids

Kenyaita M Hodge; Vasyl Zhabotynsky; Amber A Burt; Brian S Carter; Rebecca C Fry; Jennifer Helderman; Julie A Hofheimer; Elisabeth C McGowan; Charles R Neal; Steven L Pastyrnak; Lynne M Smith; Sheri A DellaGrotta; Lynne M Dansereau; Barry M Lester; Carmen J Marsit; T Michael O'Shea; Todd M Everson; program collaborators for Environmental influences on Child Health Outcomes

doi:10.1038/s41390-024-03116-4

Epigenetic associations in HPA axis genes related to bronchopulmonary dysplasia and antenatal steroids

Pediatr Res. 2024 Mar 13. doi: 10.1038/s41390-024-03116-4. Online ahead of print.

Authors

Kenyaita M Hodge¹, Vasyl Zhabotynsky², Amber A Burt¹, Brian S Carter³, Rebecca C Fry^{4

5}, Jennifer Helderman⁶, Julie A Hofheimer⁵, Elisabeth C McGowan⁷, Charles R Neal⁸, Steven L Pastyrnak⁹, Lynne M Smith¹⁰, Sheri A DellaGrotta¹¹, Lynne M Dansereau¹¹, Barry M Lester^{7

11

12}, Carmen J Marsit^{1

13}, T Michael O'Shea⁵, Todd M Everson^{14

15}; program collaborators for Environmental influences on Child Health Outcomes

Collaborators

program collaborators for Environmental influences on Child Health Outcomes:
P B Smith, L K Newby, L P Jacobson, D J Catellier, R Gershon, D Cella, R Vaidya, R Obeid, C Rollins, K Bear, M Lenski, R Singh, M Msall, J Frazier, S Gogcu, A Montgomery, K Kuban, L Douglass, H Jara, R Joseph

Affiliations

¹ Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, 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 Pediatrics-Neonatology, Children's Mercy Hospital, Kansas City, MO, USA.
⁴ Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
⁶ Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁷ Department of Pediatrics, Warren Alpert Medical School of Brown University and Women and Infants Hospital, Providence, RI, USA.
⁸ Department of Pediatrics, University of Hawaii John A. Burns School of Medicine, Honolulu, HI, USA.
⁹ Department of Pediatrics, Spectrum Health-Helen Devos Hospital, Grand Rapids, MI, USA.
¹⁰ Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
¹¹ Brown Center for the Study of Children at Risk, Women and Infants Hospital, Providence, RI, USA.
¹² Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI, USA.
¹³ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
¹⁴ Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA. todd.m.everson@emory.edu.
¹⁵ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA. todd.m.everson@emory.edu.

PMID: 38480856
DOI: 10.1038/s41390-024-03116-4

Abstract

Background: Bronchopulmonary dysplasia (BPD), a common morbidity among very preterm infants, is associated with chronic disease and neurodevelopmental impairments. A hypothesized mechanism for these outcomes lies in altered glucocorticoid (GC) activity. We hypothesized that BPD and its treatments may result in epigenetic differences in the hypothalamic-pituitary-adrenal (HPA) axis, which is modulated by GC, and could be ascertained using an established GC risk score and DNA methylation (DNAm) of HPA axis genes.

Methods: DNAm was quantified from buccal tissue (ECHO-NOVI) and from neonatal blood spots (ELGAN ECHO) via the EPIC microarray. Prenatal maternal characteristics, pregnancy complication, and neonatal medical complication data were collected from medical record review and maternal interviews.

Results: The GC score was not associated with steroid exposure or BPD. However, six HPA genes involved in stress response regulation demonstrated differential methylation with antenatal steroid exposure; two CpGs within FKBP5 and POMC were differentially methylated with BPD severity. These findings were sex-specific in both cohorts; males had greater magnitude of differential methylation within these genes.

Conclusions: These findings suggest that BPD severity and antenatal steroids are associated with DNAm at some HPA genes in very preterm infants and the effects appear to be sex-, tissue-, and age-specific.

Impact: This study addresses bronchopulmonary dysplasia (BPD), an important health outcome among preterm neonates, and interrogates a commonly studied pathway, the hypothalamic-pituitary-adrenal (HPA) axis. The combination of BPD, the HPA axis, and epigenetic markers has not been previously reported. In this study, we found that BPD itself was not associated with epigenetic responses in the HPA axis in infants born very preterm; however, antenatal treatment with steroids was associated with epigenetic responses.