Sex-specific placental gene expression signatures of small for gestational age at birth

Suvo Chatterjee; Xuehuo Zeng; Marion Ouidir; Markos Tesfaye; Cuilin Zhang; Fasil Tekola-Ayele

doi:10.1016/j.placenta.2022.03.004

Sex-specific placental gene expression signatures of small for gestational age at birth

Placenta. 2022 Apr:121:82-90. doi: 10.1016/j.placenta.2022.03.004. Epub 2022 Mar 12.

Authors

Suvo Chatterjee¹, Xuehuo Zeng¹, Marion Ouidir¹, Markos Tesfaye², Cuilin Zhang¹, Fasil Tekola-Ayele³

Affiliations

¹ Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892, MD, USA.
² Section of Sensory Science and Metabolism (SenSMet), National Institute on Alcohol Abuse and Alcoholism & National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, 20814, USA.
³ Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892, MD, USA. Electronic address: ayeleft@mail.nih.gov.

Abstract

Introduction: Small for gestational age at birth (SGA), often a consequence of placental dysfunction, is a risk factor for neonatal morbidity and later life cardiometabolic diseases. There are sex differences in placental gene expression and fetal growth. Here, we investigated sex-specific associations between gene expression in human placenta measured using RNA sequencing and SGA status using data from ethnic diverse pregnant women in the NICHD Fetal Growth Studies cohort (n = 74).

Methods: Gene expression measures were obtained using RNA-Sequencing and differential gene expression between SGA (birthweight <10th percentile) and appropriate for gestational age (AGA: ≥10th and <90th percentile) was tested separately in males (12 SGA and 27 AGA) and females (9 SGA and 26 AGA) using a weighted mean of log ratios method with adjustment for mode of delivery and ethnicity.

Results: At 5% false discovery rate (FDR), we identified 40 differentially expressed genes (DEGs) related to SGA status among males (95% up- and 5% down-regulated) and 314 DEGs among females (32.5% up- and 67.5% down-regulated). Seven female-specific DEGs overlapped with known imprinted genes (AXL, CYP24A1, GPR1, PLAGL1, CMTM1, DLX5, LY6D). The DEGs in males were significantly enriched for immune response and inflammation signaling pathways whereas the DEGs in females were enriched for organ development signaling pathways (FDR<0.05). Sex-combined analysis identified no additional DEGs, rather 98% of the sex-specific DEGs were no longer significant and the remaining 2% were attenuated.

Discussion: This study revealed sex-specific human placental gene expression changes and molecular pathways associated with SGA and underscored that unravelling the pathogenesis of SGA warrants consideration of fetal sex as a biological variable.

Trial registration: https://www.

Clinicaltrials: gov, Unique identifier: NCT00912132.

Keywords: Developmental origins of health and disease; Human placenta; Pregnancy; Sexual dimorphism; Small for gestational age.

Published by Elsevier Ltd.

Publication types

Research Support, American Recovery and Reinvestment Act
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural

MeSH terms

Birth Weight / genetics
Female
Fetal Growth Retardation / pathology
Gestational Age
Humans
Infant, Newborn
Infant, Newborn, Diseases*
Infant, Small for Gestational Age
Male
Placenta / metabolism
Pregnancy
Transcriptome*

Associated data

ClinicalTrials.gov/NCT00912132

Abstract

Publication types

MeSH terms

Associated data

Grants and funding