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

BMC Medicine

Man Fang¹  Caiyun Ge¹  Hui Wang²  Dan Xu³  Juanjuan Guo³  Yuanzhen Zhang³  Yuan Qiao³  Pengxia Yu⁴  Sijia Chen⁴ 

[1] Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang District, 430071, Wuhan, China;Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang District, 430071, Wuhan, China;Department of Pharmacology, Basic Medical School of Wuhan University, 185 Donghu Road, Wuchang District, 430071, Wuhan, China;Hubei Provincial Key Laboratory of Developmentally Originated Diseases, 185 Donghu Road, Wuchang District, 430071, Wuhan, China;Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang District, 430071, Wuhan, China;Hubei Provincial Key Laboratory of Developmentally Originated Diseases, 185 Donghu Road, Wuchang District, 430071, Wuhan, China;Department of Pharmacology, Basic Medical School of Wuhan University, 185 Donghu Road, Wuchang District, 430071, Wuhan, China;Department of Pharmacology, Basic Medical School of Wuhan University, 185 Donghu Road, Wuchang District, 430071, Wuhan, China;Hubei Provincial Key Laboratory of Developmentally Originated Diseases, 185 Donghu Road, Wuchang District, 430071, Wuhan, China;

关键词: Intrauterine growth retardation;    P-glycoprotein;    Placental glucocorticoid barrier;    Prenatal caffeine exposure;    Histone acetylation;   

DOI  :  10.1186/s12916-021-02173-4

来源: Springer

【 摘 要 】

BackgroundPrenatal 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.MethodsHuman 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.ResultsThe 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.ConclusionsThis 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.

【 授权许可】

CC BY