Prenatal stress increases corticosterone levels in offspring by impairing placental glucocorticoid barrier function

Abstract

Abstract Background: Exposure to high cortisol levels in fetus of prenatal stress (PS) has adverse effects on growth, which is related to placental glucocorticoid (GC) barrier. DNA methylation is a potential prenatal planning mechanism in embryonic stage, however, the epigenetic regulation of placental GC barrier related genes on the PS resulting higher GC is unclear. This study was to test the hypothesis that PS would elevate cortisol which was associated with GC-related placenta genes (11β-HSD2, P-gp, NR3C1, and FKBP5) based on the DNA methylation. Method: PS model was established by chronic unpredictable mild stress (CUMS). DNA methylation in GC-related genes was analyzed using reduced representation bisulfite sequencing (RRBS) and confirmed results using MethylTarget™ sequencing. The genes expression were subjected to qRT-PCR and Western blot. Results: Offspring of PS had increased plasma corticosterone levels. GC-related gene (P-gp(abcb1a) and FKBP5) were identified by RRBS. We further verified DNA methylation and gene expression, including 43 differentially methylated sites and 2 differentially methylated regions. We found P-gp was hypermethylation and low expression, FKBP5 was hypermethylation low translational and high transcriptional levels. The expressions of 11β-HSD2 decreased, the NR3C1 mRNA expression was inhibited, and the protein expression increased. Discussion:This study provides an exploratory result: PS disrupts the placental GC barrier through hypermethylation and aberrant expression of GC-related genes, resulting in high corticosterone level in offspring, affecting growth and development. However, the molecular mechanism by which PS regulates the placental GC barrier remains to be further determined.