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

To investigate the association between prenatal stress (PS) and corticosterone, and its influence on DNA methylation of genes related to the placental glucocorticoid (GC) barrier, including 11{beta}-HSD2, P-gp, NR3C1, and FKBP5. The PS model was established through chronic unpredictable mild stress (CUMS). DNA methylation of GC-related genes was analyzed using reduced representation bisulfite sequencing (RRBS), and the results were confirmed using MethylTarget sequencing. The mRNA and protein expression levels of these genes were detected through qRT-PCR and Western blotting, respectively. Plasma corticosterone levels are elevated in pregnant female rats exposed to PS conditions and their offspring. Compared to the offspring of the prenatal control (OPC) group, the offspring of the prenatal stress (OPS) group showed down-regulation in both mRNA and protein expression of DNMT 3A and DNMT 3B, while up-regulation was observed in the expression of DNMT1. RRBS analyses identified P-gp and FKBP5 as hypermethylated genes, including a total of 43 differentially methylated sites (DMS) and 2 differentially methylated regions (DMR). MethylTarget sequencing revealed that both genes had 15 differentially methylated CpG sites. This study provides preliminary evidence that PS disrupts the placental GC barrier through abnormal gene expression caused by hypermethylation of GC-related genes, resulting in elevated corticosterone levels in offspring and affecting their growth and development.