The Placental Transcriptome in Late Gestational Hypoxia Resulting in Murine Intrauterine Growth Restriction Parallels Increased Risk of Adult Cardiometabolic Disease

Abstract

Intrauterine growth restriction (IUGR) enhances risk for adult onset cardiovascular disease (CVD). The mechanisms underlying IUGR are poorly understood, though inadequate blood flow and oxygen/nutrient provision are considered common endpoints. Based on evidence in humans linking IUGR to adult CVD, we hypothesized that in murine pregnancy, maternal late gestational hypoxia (LG-H) exposure resulting in IUGR would result in (1) placental transcriptome changes linked to risk for later CVD, and 2) adult phenotypes of CVD in the IUGR offspring. After subjecting pregnant mice to hypoxia (10.5% oxygen) from gestational day (GD) 14.5 to 18.5, we undertook RNA sequencing from GD19 placentas. Functional analysis suggested multiple changes in structural and functional genes important for placental health and function, with maximal dysregulation involving vascular and nutrient transport pathways. Concordantly, a ~10% decrease in birthweights and ~30% decrease in litter size was observed, supportive of placental insufficiency. We also found that the LG-H IUGR offspring exhibit increased risk for CVD at 4 months of age, manifesting as hypertension, increased abdominal fat, elevated leptin and total cholesterol concentrations. In summary, this animal model of IUGR links the placental transcriptional response to the stressor of gestational hypoxia to increased risk of developing cardiometabolic disease.

Sperm Histone H3 Lysine 4 tri-methylation serves as a metabolic sensor of paternal obesity and is associated with the inheritance of metabolic dysfunction

“…Given the sperm epigenome influences placental gene expression (Wang et al, 2013), we were interested in the prospect that diet-induced epimutations in sperm affect placenta gene expression that could influence metabolic phenotypes across generations. To investigate this possibility, we used existing H3K4me3 and transcriptomic datasets from mouse trophectoderm -the embryonic precursor of placenta lineage -and placenta (Shen et al, 2012;Wu et al, 2016;Chu et al, 2019). We compared the enrichment profiles of H3K4me3 in sperm, trophectoderm and placenta, at all H3K4me3-enriched regions in sperm (n=30,745) and at those sensitive to diet (n=2,836).…”

“…Raw files for 4-cell and morula (Liu et al, 2019) (NCBI SRA: SRP163205), TE (Liu et al, 2016) (GEO: GSE73952), and placenta (Chu et al, 2019) (NCBI SRA: SRP137723) RNA-Seq were downloaded from the National Centre for Biotechnology Information (NCBI) using the Sequencing Read Archive (SRA) Toolkit. Files were pre-processed as described above for the sperm H3K4me3 ChIP-Sequencing with slight modifications to adapt for datasets with paired-end reads and for different sequencing read lengths.…”

The CD94/NKG2A inhibitory receptor educates uterine NK cells to optimize pregnancy outcomes in humans and mice

“…The p values were corrected for multiple testing and finally sample clustering relationships (PCA) were analyzed using the R package DESeq2 (Love et al, 2014). Normalized expression values (CPM) were used as input data for SaVanT (Lopez et al, 2017) to produce enrichment scores on mouse gene expression signatures (http://biogps.org/), as previously described (Chu et al, 2019). The 10 genes with an FDR < 0.01, were considered to be DE and were entered for functional pathway enrichment using a gene annotation and analysis resource (http://metascape.org).…”

“…We aimed to characterize any differences resulting from the presence or absence of maternal NKG2A through matching fetal comparison groups by gestational age, weight, sex composition and genotype. Sample size was based on previous studies (Chu et al, 2016(Chu et al, , 2019. All E15.5 placentae were collected in RNALater (Thermofisher) and stored at 4 C for 3-4 days, after corresponding fetal weight was recorded.…”

Mechanisms Underlying Neurologic Injury in Intrauterine Growth Restriction

“…Numerous studies have shown that the risks of perinatal and long-term complications, such as intrauterine distress, asphyxia, hypoglycemia, physical retardation, neurodevelopmental disorders, obesity, hypertension, coronary heart disease, type 2 diabetes, and nephropathy were significantly increased in patients with intrauterine growth restriction as compared with those in patients without intrauterine growth restriction. 4 -8 Additionally, neurodevelopmental disorders can lead to changes in the structure and function of the nervous system and adversely affect quality of life. However, the mechanisms underlying neurologic injury in intrauterine growth restriction are not completely clear; therefore, further research should be conducted to prevent neurologic injuries associated with intrauterine growth restriction and identify treatments for this condition.…”