The Placental Epigenome as a Molecular Link Between Prenatal Exposures and Fetal Health Outcomes Through the DOHaD Hypothesis

Abstract

Purpose of Review The developmental origins of health and disease (DOHaD) hypothesis posits that the perinatal environment can impact fetal and later life health. The placenta is uniquely situated to assess prenatal exposures in the context of DOHaD because it is an essential ephemeral fetal organ that manages the transport of oxygen, nutrients, waste, and endocrine signals between the mother and fetus. The purpose of this review is to summarize recent studies that evaluated the DOHaD hypothesis in human placentas using epigenomics, including DNA methylation and transcriptomic studies of mRNA, lncRNA, and microRNAs. Recent Findings Between 2016 and 2021, 28 articles evaluated associations between prenatal exposures and placental epigenomics across broad exposure categories including maternal smoking, psychosocial stressors, chemicals, air pollution, and metals. Sixteen of these studies connected exposures to health outcome such as birth weight, fetal growth, or infant neurobehavior through mediation analysis, identification of shared associations between exposure and outcome, or network analysis. These aspects of infant and childhood health serve as a foundation for future studies that aim to use placental epigenetics to understand relationships between the prenatal environment and perinatal complications (such as preterm birth or fetal growth restriction) or later life childhood health. Summary Placental DNA methylation and RNA expression have been linked to numerous prenatal exposures, such as PM2.5 air pollution, metals, and maternal smoking, as well as infant and childhood health outcomes, including fetal growth and birth weight. Placental epigenomics provides a unique opportunity to expand the DOHaD premise, particularly if research applies novel methodologies such as multi-omics analysis, sequencing of non-coding RNAs, mixtures analysis, and assessment of health outcomes beyond early childhood.

Placental transcriptomic signatures of spontaneous preterm birth

“…Our findings stand apart as a large transcriptome-wide assessment of sPTBe related differences in the placenta, 28 quantified using RNA sequencing. We collected detailed covariate data, which was harmonized across both cohorts, allowing us to exclude PTBs with other pathologies and to adjust for potential confounding variables that were not addressed in our previous analyses of PTB, including key variables such as labor status.…”

“…27 The goal of our study was to identify genes whose placental expression is associated with sPTB and different gestational age subgroups (early preterm, late preterm, early term, and late term vs full term) in a retrospective cohort analysis with detailed covariate data that allow for enhanced control of confounding variables. This was a large retrospective cohort analysis, 28 and Our combined cohort was representative of a diverse group of participants from different parts of the country and includes under-represented populations. Importantly, our selection criteria were designed using established clinical guidelines to capture an important subgroup of spontaneously premature births by excluding PTBs due to medical conditions (eg, induced labor, chorioamnionitis, preeclampsia, and multifetal pregnancy).…”

A Genome Scale Transcriptional Regulatory Model of the Human Placenta

“…62 Many researchers studying the placenta have used omics data to generate lists of genes which are associated with prenatal exposures as well as infant or child health outcomes, as summarized in our recent review. 63 These genes are often contextualized using pathway analysis approaches within KEGG or Gene Ontology (GO) gene sets. The TF enrichment analysis we have performed using regulons is complementary to using other defined gene sets such as KEGG or GO.…”

miRNA-150_R-1 mediates the HIF-1/ErbB signaling pathway to regulate the adhesion of endometrial epithelial cells in cows experiencing retained placenta

“…miRNAs are endogenous non-coding RNAs ∼18-25 nucleotides (nt) in length and exert regulatory functions (5). miRNAs bind to the 3 ′ -untranslated (UTR) region complementary to the mRNA sequence and correspondingly inhibit or repress mRNA translation (6). Recent studies showed that various miRNAs play major roles in the molecular mechanism of placental development (5)(6)(7).…”