Amer J Perinatol 2018; 35(08): 721-728
DOI: 10.1055/s-0037-1613682
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Epigenetic Regulation of the Nitric Oxide Pathway, 17-α Hydroxyprogesterone Caproate, and Recurrent Preterm Birth

Tracy A. Manuck
1  Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
,
Lisa Smeester
2  Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
,
Elizabeth M. Martin
2  Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
,
Martha S. Tomlinson
2  Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
,
Christina Smith
1  Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
,
Michael W. Varner
3  Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah
4  Intermountain Healthcare Women and Newborns Clinical Program, Salt Lake City, Utah
,
Rebecca C. Fry
2  Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
› Author Affiliations
Funding This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development 5K23HD067224 (Dr. Manuck), NIMHD 1R01MD011609 (Dr. Manuck) and a H.A. and Edna Benning Endowed Professorship (Dr. Varner). This study was also supported by the Translational and Clinical Sciences Institute grant support (ULTR001111 from the Clinical and Translational Science Award program of the National Center for Advancing Translational Sciences, National Institutes of Health) and the NIEHS (T32ES007018).
Further Information

Publication History

03 November 2017

10 November 2017

Publication Date:
14 December 2017 (eFirst)

Abstract

Objective We sought to evaluate nitric oxide pathway placental gene expression and the epigenome (CpG methylation) among women receiving 17-α hydroxyprogesterone caproate (17-OHPC) with and without recurrent preterm birth (PTB).

Study Design This was a case–control study. We prospectively recruited women with ≥ 1 prior singleton spontaneous PTB <34 weeks receiving 17-OHPC. DNA and RNA were isolated from placentas. RNA abundance (gene expression) and the methylome were analyzed for 84 genes in nitric oxide pathways. Women with recurrent PTB <34 weeks (cases) were compared with those delivering at term (controls). Statistical analysis included multivariable models with Bonferroni's corrected p-values.

Results In this study, 17 women met inclusion criteria; 7 preterm cases (delivered at 22.6 ± 2.9 weeks) and 10 term controls (delivered at 38.5 ± 0.8 weeks). Groups had similar PTB history, race/ethnicity, and socioeconomic risk factors for PTB. Twenty-seven nitric oxide genes displayed differential expression (p < 0.05 and q < 0.10) when comparing placentas from preterm cases and term controls; all were downregulated in preterm cases. Eight hundred sixty corresponding CpG sites were differentially methylated between the preterm cases and term controls (Bonferroni's p-value <0.05).

Conclusion CpG methylation and gene expression patterns in nitric oxide pathway genes differ among placentas from recurrent PTB compared with term birth following 17-OHPC exposure.

Note

This study was presented in part at the Society for Maternal Fetal Medicine's 37th Annual Meeting (Las Vegas, NV), January 26, 2017, as a poster presentation, final abstract ID# 379.