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. 2025 Jul 18;20(7):e0313705.
doi: 10.1371/journal.pone.0313705. eCollection 2025.

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

Can Liu  1   2 , Hongya Liu  3   1 , Hongyu Li  1   2 , Deguang Yang  1   2 , Ye Li  1   2 , Rui Wang  1   2 , Jiashu Zhu  1   2 , Shuqin Ma  4 , Suzhen Guan  1   2
Affiliations

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

Can Liu et al. PLoS One. .

Abstract

This study aimed to investigate the association between prenatal stress (PS) and corticosterone levels, and its influence on DNA methylation of genes related to the placental glucocorticoid (GC) barrier, including 11β-HSD2, ABCB1 (P-gp), NR3C1, and FKBP5. The PS model was established through chronic unpredictable mild stress (CUMS). DNA methylation of GC-related genes was analyzed by 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 were 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 exhibited down-regulation in both mRNA and protein expression of DNA methyltransferases (DNMT 3A and DNMT 3B), while up-regulation was observed in the expression of DNMT1. RRBS analyses identified ABCB1 and FKBP5 as hypermethylated genes, including a total of 43 differentially methylated sites (DMS) and 2 differentially methylated regions (DMR). MethylTarget™ sequencing further confirmed 15 differentially methylated CpG sites in these genes. 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.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Plasma corticosterone concentration in the PC and PS group.
This figure presents the comparison of plasma corticosterone concentrations between the PC (control) group and the PS (experimental) group at different stress time. Data are expressed as mean± SD (N = 6 per group). Statistically significant differences are indicated by *, P < 0.05.
Fig 2
Fig 2. Effects of PS on offspring’s body weight and plasma corticosterone.
(A) Plasma corticosterone concentrations in offspring on postnatal day 28 (PND28) and postnatal day 42 (PND42). (B) Body weight in offspring on PND28 and PND42. Data are represented as mean ± SD (N = 10 per group). *Statistically significant difference compared with the OPC group (P < 0.05).
Fig 3
Fig 3. Effects of PS on DNMTs in the placenta.
(A-C) Relative mRNA expression, (D) representative western blot images, and (E-G) statistical results of relative protein expression of DNMT1, DNMT3A, and DNMT3B. Three biological replicates were performed. All data are shown as mean ± SD (N = 3 per group). *Statistically significant difference compared with the OPC group (P < 0.05).
Fig 4
Fig 4. Effects of PS on DMRs methylation and total methylation levels of offspring placental GC barrier genes.
(A) The methylation levels of DMRs and (B) the total methylation levels of FKBP5 were increased by PS on offspring. (C) The methylation levels of DMRs in ABCB1 were increased by PS on offspring, whereas (D) the total methylation levels of ABCB1 showed no significant change. Data are represented as mean ± SD (N = 6 per group). *Statistically significant difference compared with the OPC group (P < 0.05).
Fig 5
Fig 5. Effects of PS on mRNA and protein expression levels of placental GC barrier genes.
(A-D) The mRNA levels of 11β-HSD2, ABCB1(abcb1a, abcb1b), NR3C1 and FKBP5. (F) Representative western blot images. (G-J) Relative protein levels of 11β-HSD2, ABCB1, NR3C1 and FKBP5. Data are represented as mean ± SD (N = 3 per group). *Statistically significant difference compared with the OPC group (P < 0.05).
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