Human Placental Transcriptome Reveals Critical Alterations in Inflammation and Energy Metabolism with Fetal Sex Differences in Spontaneous Preterm Birth.

Yu-Chin Lien,Marni J Falk,Laura Sillers,Samuel Parry,Erzsebet Polyak,Rebecca A Simmons,Yi Cheng,Zhe Zhang,Harry Ischiropoulos

doi:10.3390/ijms22157899

Abstract

A well-functioning placenta is crucial for normal gestation and regulates the nutrient, gas, and waste exchanges between the maternal and fetal circulations and is an important endocrine organ producing hormones that regulate both the maternal and fetal physiologies during pregnancy. Placental insufficiency is implicated in spontaneous preterm birth (SPTB). We proposed that deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy may ultimately result in SPTB. To explore our hypothesis, we performed a RNA-seq study in male and female placentas from women with SPTB (<36 weeks gestation) compared to normal pregnancies (≥38 weeks gestation) to assess the alterations in the gene expression profiles. We focused exclusively on Black women (cases and controls), who are at the highest risk of SPTB. Six hundred and seventy differentially expressed genes were identified in male SPTB placentas. Among them, 313 and 357 transcripts were increased and decreased, respectively. In contrast, only 61 differentially expressed genes were identified in female SPTB placenta. The ingenuity pathway analysis showed alterations in the genes and canonical pathways critical for regulating inflammation, oxidative stress, detoxification, mitochondrial function, energy metabolism, and the extracellular matrix. Many upstream regulators and master regulators important for nutrient-sensing and metabolism were also altered in SPTB placentas, including the PI3K complex, TGFB1/SMADs, SMARCA4, TP63, CDKN2A, BRCA1, and NFAT. The transcriptome was integrated with published human placental metabolome to assess the interactions of altered genes and metabolites. Collectively, significant and biologically relevant alterations in the transcriptome were identified in SPTB placentas with fetal sex disparities. Altered energy metabolism, mitochondrial function, inflammation, and detoxification may underly the mechanisms of placental dysfunction in SPTB.

Highlights

IntroductionPreterm birth (delivery before or at 37 weeks of gestation) is the leading cause of morbidity and mortality in newborn infants worldwide [1]
Preterm birth is the leading cause of morbidity and mortality in newborn infants worldwide [1]
There were no differences in maternal ages between term and spontaneous preterm birth (SPTB) placenta samples (Table 1)

Summary

Introduction

Preterm birth (delivery before or at 37 weeks of gestation) is the leading cause of morbidity and mortality in newborn infants worldwide [1]. Fifteen million babies are born prematurely annually, resulting in an excess of one million deaths. Infants who survive preterm birth often have serious and lifelong health problems, including lung disease, vision loss, and neurodevelopmental disorders. Spontaneous preterm birth (SPTB) remains a significant and poorly understood perinatal complication. SPTB includes the preterm spontaneous rupture of membranes, cervical insufficiency, and preterm labor. While the exact etiology remains unknown, many factors may contribute to SPTB, including placental dysfunction, abnormal cervical remodeling, uterine distension, vascular disorders, and chorioamnionitis [2,3]

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