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01-12-2021 | Glucocorticoid | Research article

P-gp expression inhibition mediates placental glucocorticoid barrier opening and fetal weight loss

Authors: Caiyun Ge, Dan Xu, Pengxia Yu, Man Fang, Juanjuan Guo, Dan Xu, Yuan Qiao, Sijia Chen, Yuanzhen Zhang, Hui Wang

Published in: BMC Medicine | Issue 1/2021

Abstract

Background

Prenatal adverse environments can cause fetal intrauterine growth retardation (IUGR) and higher susceptibility to multiple diseases after birth, related to multi-organ development programming changes mediated by intrauterine overexposure to maternal glucocorticoids. As a glucocorticoid barrier, P-glycoprotein (P-gp) is highly expressed in placental syncytiotrophoblasts; however, the effect of P-gp on the occurrence of IUGR remains unclear.

Methods

Human placenta and fetal cord blood samples of IUGR fetuses were collected, and the related indexes were detected. Pregnant Wistar rats were administered with 30 mg/kg·d (low dose) and 120 mg/kg·d (high dose) caffeine from gestational day (GD) 9 to 20 to construct the rat IUGR model. Pregnant mice were administered with caffeine (120 mg/kg·d) separately or combined with sodium ferulate (50 mg/kg·d) from gestational day GD 9 to 18 to confirm the intervention target on fetal weight loss caused by prenatal caffeine exposure (PCE). The fetal serum/placental corticosterone level, placental P-gp expression, and related indicator changes were analyzed. In vitro, primary human trophoblasts and BeWo cells were used to confirm the effect of caffeine on P-gp and its mechanism.

Results

The placental P-gp expression was significantly reduced, but the umbilical cord blood cortisol level was increased in clinical samples of the IUGR neonates, which were positively and negatively correlated with the neonatal birth weight, respectively. Meanwhile, in the PCE-induced IUGR rat model, the placental P-gp expression of IUGR rats was decreased while the corticosterone levels of the placentas/fetal blood were increased, which were positively and negatively correlated with the decreased placental/fetal weights, respectively. Combined with the PCE-induced IUGR rat model, in vitro caffeine-treated placental trophoblasts, we confirmed that caffeine decreased the histone acetylation and expression of P-gp via RYR/JNK/YB-1/P300 pathway, which inhibited placental and fetal development. We further demonstrated that P-gp inducer sodium ferulate could reverse the inhibitory effect of caffeine on the fetal body/placental weight. Finally, clinical specimens and other animal models of IUGR also confirmed that the JNK/YB-1 pathway is a co-regulatory mechanism of P-gp expression inhibition, among which the expression of YB-1 is the most stable. Therefore, we proposed that YB-1 could be used as the potential early warning target for the opening of the placental glucocorticoid barrier, the occurrence of IUGR, and the susceptibility of a variety of diseases.

Conclusions

This study, for the first time, clarified the critical role and epigenetic regulation mechanism of P-gp in mediating the opening mechanism of the placental glucocorticoid barrier, providing a novel idea for exploring the early warning, prevention, and treatment strategies of IUGR.

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Title: P-gp expression inhibition mediates placental glucocorticoid barrier opening and fetal weight loss
Authors: Caiyun Ge
Dan Xu
Pengxia Yu
Man Fang
Juanjuan Guo
Dan Xu
Yuan Qiao
Sijia Chen
Yuanzhen Zhang
Hui Wang
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Glucocorticoid
Published in: BMC Medicine / Issue 1/2021
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-021-02173-4

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

P-gp expression inhibition mediates placental glucocorticoid barrier opening and fetal weight loss

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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