Intrauterine Inflammation Alters the Transcriptome and Metabolome in Placenta.

Yu-Chin Lien,Amy Green-Brown,Rebecca A Simmons,Zhe Zhang,Michal A Elovitz,Guillermo Barila

doi:10.3389/fphys.2020.592689

Abstract

Placental insufficiency is implicated in spontaneous preterm birth (SPTB) associated with intrauterine inflammation. We hypothesized that intrauterine inflammation leads to deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy ultimately resulting in SPTB. Using a mouse model of intrauterine inflammation that leads to preterm delivery, we performed RNA-seq and metabolomics studies to assess how intrauterine inflammation alters gene expression and/or modulates metabolite production and abundance in the placenta. 1871 differentially expressed genes were identified in LPS-exposed placenta. Among them, 1,149 and 722 transcripts were increased and decreased, respectively. Ingenuity pathway analysis showed alterations in genes and canonical pathways critical for regulating oxidative stress, mitochondrial function, metabolisms of glucose and lipids, and vascular reactivity in LPS-exposed placenta. Many upstream regulators and master regulators important for nutrient-sensing and mitochondrial function were also altered in inflammation exposed placentae, including STAT1, HIF1α, mTOR, AMPK, and PPARα. Comprehensive quantification of metabolites demonstrated significant alterations in the glucose utilization, metabolisms of branched-chain amino acids, lipids, purine and pyrimidine, as well as carbon flow in TCA cycle in LPS-exposed placenta compared to control placenta. The transcriptome and metabolome were also integrated to assess the interactions of altered genes and metabolites. Collectively, significant and biologically relevant alterations in the placenta transcriptome and metabolome were identified in placentae exposed to intrauterine inflammation. Altered mitochondrial function and energy metabolism may underline the mechanisms of inflammation-induced placental dysfunction.

Highlights

Preterm birth is the leading cause of neonatal morbidity and mortality worldwide (March of Dimes, 2015). 15 million babies are born prematurely annually resulting in an excess of 1 million deaths
Principal component analysis (PCA) showed a strong confounding impact of treatment but not of fetal sex (Figure 1A). This suggests that LPS-induced transcriptome changes in placenta are not affected by sex hormones or sex chromosomes at this gestational age
Using a model of intrauterine inflammation that is similar to human pregnancies complicated by acute chorioamnionitis (Elovitz and Mrinalini, 2005; Elovitz et al, 2011; Hester et al, 2018; Brown et al, 2019), we demonstrated that intrauterine LPS injection alters the placenta metabolome and is associated with marked changes in expression of genes involved in key pathways including vascular function and reactivity, mitochondria function and nutrient sensing, glucose and lipid metabolism, and ceramide and sphingosine-1phosphate signaling

Summary

Introduction

Preterm birth (delivery before or at 37 weeks of gestation) is the leading cause of neonatal morbidity and mortality worldwide (March of Dimes, 2015). 15 million babies are born prematurely annually resulting in an excess of 1 million deaths. Intrauterine Inflammation Transcriptome and Metabolome birth (SPTB) remains a significant and poorly understood perinatal complication. SPTB includes preterm spontaneous rupture of membranes, cervical weakness, and preterm labor. While the exact etiology of SPTB remains unknown, many factors may contribute, including placental dysfunction, cervical insufficiency, uterine distension, vascular disorders, and chorioamnionitis (Romero et al, 2014; Manuck et al, 2015). How intrauterine infection/inflammation precisely induces parturition is unknown, emerging evidence supports the concept that preterm births complicated by chorioamnionitis are associated with placental insufficiency (Kourtis et al, 2014; Morgan, 2016; do Imperio et al, 2018). Elucidating underlying mechanisms for placental dysfunction may lead to a better understanding of the etiology of prematurity and the development of preventative treatment

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