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Antenatal Steroids and Cord Blood T-cell Glucocorticoid Receptor DNA Methylation and Exon 1 Splicing

  • Maternal Fetal Medicine/Biology: Original Article
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Abstract

Antenatal administration of glucocorticoids such as betamethasone (BMZ) during the late preterm period improves neonatal respiratory outcomes. However, glucocorticoids may elicit programming effects on immune function and gene regulation. Here, we test the hypothesis that exposure to antenatal BMZ alters cord blood immune cell composition in association with altered DNA methylation and alternatively expressed Exon 1 transcripts of the glucocorticoid receptor (GR) gene in cord blood CD4+ T-cells. Cord blood was collected from 51 subjects in the Antenatal Late Preterm Steroids Trial: 27 BMZ, 24 placebo. Proportions of leukocytes were compared between BMZ and placebo. In CD4+ T-cells, methylation at CpG sites in the GR promoter regions and expression of GR mRNA exon 1 variants were compared between BMZ and placebo. BMZ was associated with an increase in granulocytes (51.6% vs. 44.7% p = 0.03) and a decrease in lymphocytes (36.8% vs. 43.0% p = 0.04) as a percent of the leukocyte population vs. placebo. Neither GR methylation nor exon 1 transcript levels differed between groups. BMZ is associated with altered cord blood leukocyte proportions, although no associated alterations in GR methylation were observed.

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Acknowledgements

The authors thank the following for their contributions to the original trial: Felecia Ortiz, RN, BSN and Sabine Bousleiman, RNC, MSN, MPH for protocol development and coordination between clinical research centers and Ronald Wapner, MD, Elizabeth A. Thom, PhD, Carol Blaisdell, MD, Catherine Spong, MD, and Uma M. Reddy, MD, MPH for protocol development and oversight.

In addition to the authors, other members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network contributing centers are as follows:

University of Utah Health Sciences Center, Salt Lake City, UT — K. Hill, A. Sowles, S. Timothy, P. Reed (deceased; Intermountain Healthcare), M. Varner

Columbia University, New York, NY — S. Bousleiman, R. Wapner, M. DiVito, M. Talucci, L. Plante (Drexel University), C. Tocci (Drexel University), M. Hoffman (Christiana Care Health Systems), S. Lynch (Christiana Care Health Systems), A. Ranzini (St. Peter’s University Hospital), M. Lake (St. Peter’s University Hospital), J. Smulian (Lehigh Valley Health Network), D. Skupski (New York Hospital Queens)

The George Washington University Biostatistics Center, Washington, D.C. — E. Thom, V. Momirova, G. Heinrich, T. Spangler

National Heart, Lung, and Blood Institute, Bethesda, MD — C. Blaisdell

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD — C. Spong, U. Reddy, S. Tolivaisa

Funding

This study was supported by grants (HL098554 and HL098354) from the NHLBI, by grants (HD34208, HD40485, and HD36801) from the NICHD, and by a grant (UL1 TR000040) from the National Center for Advancing Translational Sciences, National Institutes of Health. This study was also supported in part through the University of Utah Flow Cytometry Facility and National Cancer Institute (5P30CA042014-24) and the Divisions of Maternal Fetal Medicine and Neonatology at the University of Utah. The comments and views expressed in this article are those of the authors and do not necessarily represent the views of the National Institutes of Health. National Heart,Lung,and Blood Institute,HL098554,Cynthia Gyamfi-Bannerman ,HL098354,Kathleen A Jablonski ,Eunice Kennedy Shriver National Institute of Child Health and Human Development,HD34208,HD40485,HD36801

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Authors and Affiliations

  1. Obstetrics & Gynecology, University of Utah, Salt Lake City, UT, USA

    Jeanette R. Carpenter & Michael W. Varner

  2. Milken School of Public Health, Biostatistics Center, George Washington University, Washington, D.C, USA

    Kathleen A. Jablonski

  3. Department of Pediatrics, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA

    Jordan Koncinsky & Lisa A. Joss-Moore

  4. Obstetrics & Gynecology, Columbia University, New York, NY, USA

    Cynthia Gyamfi-Bannerman

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  1. Jeanette R. Carpenter
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Correspondence to Lisa A. Joss-Moore.

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Cord blood was collected under IRB approved protocol IRB_00056274 at the University of Utah and Columbia University in accordance with local and federal Protection of Human Subjects law 45 CFR 46 and the Health Insurance Portability and Accountability Act (HIPAA).

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All maternal donors consented to participate and gave HIPPA authorization for data collection and use in research.

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Carpenter, J.R., Jablonski, K.A., Koncinsky, J. et al. Antenatal Steroids and Cord Blood T-cell Glucocorticoid Receptor DNA Methylation and Exon 1 Splicing. Reprod. Sci. 29, 1513–1523 (2022). https://doi.org/10.1007/s43032-022-00859-5

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