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. 2024 Apr;29(4):1179-1191.
doi: 10.1038/s41380-023-02403-6. Epub 2024 Jan 11.

Placental transcriptomic signatures of prenatal and preconceptional maternal stress

Affiliations

Placental transcriptomic signatures of prenatal and preconceptional maternal stress

Brennan H Baker et al. Mol Psychiatry. 2024 Apr.

Abstract

Prenatal exposure to maternal psychological stress is associated with increased risk for adverse birth and child health outcomes. Accumulating evidence suggests that preconceptional maternal stress may also be transmitted intergenerationally to negatively impact offspring. However, understanding of mechanisms linking these exposures to offspring outcomes, particularly those related to placenta, is limited. Using RNA sequencing, we identified placental transcriptomic signatures associated with maternal prenatal stressful life events (SLEs) and childhood traumatic events (CTEs) in 1 029 mother-child pairs in two birth cohorts from Washington state and Memphis, Tennessee. We evaluated individual gene-SLE/CTE associations and performed an ensemble of gene set enrichment analyses combing across 11 popular enrichment methods. Higher number of prenatal SLEs was significantly (FDR < 0.05) associated with increased expression of ADGRG6, a placental tissue-specific gene critical in placental remodeling, and decreased expression of RAB11FIP3, an endocytosis and endocytic recycling gene, and SMYD5, a histone methyltransferase. Prenatal SLEs and maternal CTEs were associated with gene sets related to several biological pathways, including upregulation of protein processing in the endoplasmic reticulum, protein secretion, and ubiquitin mediated proteolysis, and down regulation of ribosome, epithelial mesenchymal transition, DNA repair, MYC targets, and amino acid-related pathways. The directional associations in these pathways corroborate prior non-transcriptomic mechanistic studies of psychological stress and mental health disorders, and have previously been implicated in pregnancy complications and adverse birth outcomes. Accordingly, our findings suggest that maternal exposure to psychosocial stressors during pregnancy as well as the mother's childhood may disrupt placental function, which may ultimately contribute to adverse pregnancy, birth, and child health outcomes.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Inclusion criteria flowchart.
Study flowchart for inclusion of participants shows analytic sample sizes remaining from the implementation of each exclusion criterion. Participants come from two US pregnancy cohorts in the ECHO-PATHWAYS Consortium: CANDLE (Conditions Affecting Neurocognitive Development and Learning in Early Childhood) and GAPPS (Global Alliance to Prevent Prematurity and Stillbirth).
Fig. 2
Fig. 2. Associations of prenatal SLEs with placental gene expression.
Volcano plot depicts log2-adjusted fold-changes in 14 047 genes for each one number increase in prenatal stressful life events (SLEs), from multiple imputation analyses adjusting for maternal age, race, ethnicity, pre-pregnancy BMI, gravidity, tobacco and alcohol use during pregnancy, household income adjusted for region and inflation, household size, maternal education, neighborhood deprivation index, fetal sex, labor type, delivery method, study site, and sequencing batch (A). Horizontal line at P = 0.05. Limma-voom linear model trends (lines) for ADGRG6 (B), RAB11FIP3 (C), and SMYD5 (D). For each gene, one point per participant (gray points) and means (red diamonds) summarize the distributions of log2-counts per million (CPM) normalized to library size at each level of prenatal SLEs.
Fig. 3
Fig. 3. Ensemble of Gene Set Enrichment Analyses for Prenatal SLEs and Maternal CTEs.
Associations of mutation signatures database (MSigDB) hallmarks and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways with prenatal SLEs and maternal CTEs. Log2 adjusted fold-changes (LogFC) and P-values come from ensemble of gene set enrichment analyses combining across 11 popular gene set testing methods. All terms with false discovery rate (FDR) adjusted P-value < 0.05 in association with prenatal SLEs and/or maternal CTEs shown.
Fig. 4
Fig. 4. Ensemble of Gene Set Enrichment Analyses for Prenatal SLEs Stratified by Sex.
Associations of mutation signatures database (MSigDB) hallmarks and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways with prenatal SLEs stratified by sex. Log2 adjusted fold-changes (LogFC) and P-values come from ensemble of gene set enrichment analyses combining across 11 popular gene set testing methods. All terms with false discovery rate (FDR) adjusted P-value < 0.05 in either stratum shown.
Fig. 5
Fig. 5. Ensemble of Gene Set Enrichment Analyses for Maternal CTEs Stratified by Sex.
Associations of mutation signatures database (MSigDB) hallmarks and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways with prenatal SLEs stratified by sex. Log2 adjusted fold-changes (LogFC) and P-values come from ensemble of gene set enrichment analyses combining across 11 popular gene set testing methods. All terms with false discovery rate (FDR) adjusted P-value < 0.05 in either stratum shown.

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