Natural disaster stress during pregnancy is linked to reprogramming of the placenta transcriptome in relation to anxiety and stress hormones in young offspring

Abstract

Prenatal stress can lead to long-term adverse effects that increase the risk of anxiety and other emotional disorders in offspring. The in utero underpinnings contributing to such phenotypes remain unknown. We profiled the transcriptome of placental specimens from women who lived through Hurricane Sandy during pregnancy compared to those pregnant during non-Sandy conditions. Following birth, longitudinal assessments were conducted in their offspring during childhood (~3-4 years old) to measure steroid hormones (in hair) and behavioral and emotional problems. This revealed a significant link between prenatal Sandy stress (PNSS) and child HPA dysfunction, evident by altered cortisol, dehydroepiandrosterone (DHEA), and cortisol:DHEA levels. In addition, PNSS was associated with significantly increased anxiety and aggression. These findings coincided with significant reorganization of the placental transcriptome via vascular, immune, and endocrine gene pathways. Interestingly, many of the most prominently altered genes were known to be uniquely expressed in syncytiotrophoblast (STB)-subtype of placental cells and harbored glucocorticoid response elements in promoter regions. Finally, several vascular development- and immune-related placental gene sets were found to mediate the relationship between PNSS and childhood phenotypes. Overall, these findings suggest that natural disaster-related stress during pregnancy reprograms the placental molecular signature, potentially driving long-lasting changes in stress regulation and emotional health. Further examination of placental mechanisms may elucidate the environment's contribution to subsequent risk for anxiety disorders later in life.

Figure 1:. Prenatal Sandy stress (PNSS) is associated with robust differential gene expression across critical functional pathways in placenta.

(a-b) Gene expression alterations (blue points, q<0.05) in PNSS(+) placentas with many endocrine and pregnancy-specific gene regulators among the most differentially expressed genes (DEGs) (red points, q<0.05 & |log₂ fold change (FC)|>1). (c) PNSS(+) DEGs (q<0.05) were enriched for vascular and immune-related functions. (d) The most robustly altered DEGs associated with endocrine and glucocorticoid signaling functions (p<0.05).

Figure 2:. PNSS(+) is associated with reduced expression of trophoblast-subtype specific genes and targets of glucocorticoid signaling.

(a) Diagram depicting major placental cell-types contributing to the placental villi. (b) Several placental cell type specific genes were differentially expressed in PNSS(+) placentas, especially syncytiotrophoblast (STB)-specific markers. Bars = µ, blue points = differentially expressed, red points = differentially expressed with |log2FC| >1. (c) Heatmap of STB-enriched genes with unsupervised clustering of rows annotated for PNSS(−) (blue) and PNSS(+) placentas (red). (d) Several transcription factor motifs (represented by gene name) are enriched in the promoter of STB-specific genes. (e) Expression of NR3C1 was significantly increased in PNSS(+) placentas. (f) Significant negative correlation between NR3C1 and all STB-specific genes in placenta (lines represent regressions for each STB-gene and NR3C1 (normalized expression). ***=p<0.001 for each spearman correlation analyzed.

Figure 3:. Placental genes related to immune activation and vascular development mediate the relationship between PNSS(+) and offspring HPA/neurobehavioral phenotypes.

(a) Heatmap showing correlation coefficients between cortisol or cortisol:DHEA and PNSS+ DEGS with dot bar annotation representing log₂ fold change (FC) of each PNSS(+) DEG (blue=log₂FC<0, red=log₂FC>0). (b) Genes mediating increased cortisol:DHEA in PNSS(+) children were related to adaptive immune response pathways. (c) Correlation coefficients for child aggression or anxiety and PNSS(+) DEGs with dot bar and log₂FC annotation bar. (d) Genes mediating PNSS(+)-linked child aggression were nominally significant for VEGF, B-cell, and Ras signaling pathways. * = significant mediation (p<0.05).