PMID- 34876109 OWN - NLM STAT- MEDLINE DCOM- 20220124 LR - 20220716 IS - 1741-7015 (Electronic) IS - 1741-7015 (Linking) VI - 19 IP - 1 DP - 2021 Dec 8 TI - P-gp expression inhibition mediates placental glucocorticoid barrier opening and fetal weight loss. PG - 311 LID - 10.1186/s12916-021-02173-4 [doi] LID - 311 AB - 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. CI - (c) 2021. The Author(s). FAU - Ge, Caiyun AU - Ge C AD - Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang District, Wuhan, 430071, China. FAU - Xu, Dan AU - Xu D AD - Department of Pharmacology, Basic Medical School of Wuhan University, 185 Donghu Road, Wuchang District, Wuhan, 430071, China. AD - Hubei Provincial Key Laboratory of Developmentally Originated Diseases, 185 Donghu Road, Wuchang District, Wuhan, 430071, China. FAU - Yu, Pengxia AU - Yu P AD - Department of Pharmacology, Basic Medical School of Wuhan University, 185 Donghu Road, Wuchang District, Wuhan, 430071, China. FAU - Fang, Man AU - Fang M AD - Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang District, Wuhan, 430071, China. FAU - Guo, Juanjuan AU - Guo J AD - Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang District, Wuhan, 430071, China. AD - Hubei Provincial Key Laboratory of Developmentally Originated Diseases, 185 Donghu Road, Wuchang District, Wuhan, 430071, China. FAU - Xu, Dan AU - Xu D AD - Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang District, Wuhan, 430071, China. AD - Hubei Provincial Key Laboratory of Developmentally Originated Diseases, 185 Donghu Road, Wuchang District, Wuhan, 430071, China. FAU - Qiao, Yuan AU - Qiao Y AD - Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang District, Wuhan, 430071, China. AD - Hubei Provincial Key Laboratory of Developmentally Originated Diseases, 185 Donghu Road, Wuchang District, Wuhan, 430071, China. FAU - Chen, Sijia AU - Chen S AD - Department of Pharmacology, Basic Medical School of Wuhan University, 185 Donghu Road, Wuchang District, Wuhan, 430071, China. FAU - Zhang, Yuanzhen AU - Zhang Y AD - Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang District, Wuhan, 430071, China. zhangyuanzhen@vip.sina.com. AD - Hubei Provincial Key Laboratory of Developmentally Originated Diseases, 185 Donghu Road, Wuchang District, Wuhan, 430071, China. zhangyuanzhen@vip.sina.com. FAU - Wang, Hui AU - Wang H AUID- ORCID: 0000-0001-5300-8661 AD - Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang District, Wuhan, 430071, China. wanghui19@whu.edu.cn. AD - Department of Pharmacology, Basic Medical School of Wuhan University, 185 Donghu Road, Wuchang District, Wuhan, 430071, China. wanghui19@whu.edu.cn. AD - Hubei Provincial Key Laboratory of Developmentally Originated Diseases, 185 Donghu Road, Wuchang District, Wuhan, 430071, China. wanghui19@whu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211208 PL - England TA - BMC Med JT - BMC medicine JID - 101190723 RN - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1) RN - 0 (Glucocorticoids) SB - IM EIN - BMC Med. 2022 Mar 27;20(1):126. PMID: 35346196 MH - ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics MH - Animals MH - Epigenesis, Genetic MH - Female MH - Fetal Growth Retardation/chemically induced MH - *Fetal Weight MH - *Glucocorticoids MH - Mice MH - Placenta MH - Pregnancy MH - Rats MH - Rats, Wistar PMC - PMC8653610 OTO - NOTNLM OT - Histone acetylation OT - Intrauterine growth retardation OT - P-glycoprotein OT - Placental glucocorticoid barrier OT - Prenatal caffeine exposure COIS- The authors declare that they have no competing interests. EDAT- 2021/12/09 06:00 MHDA- 2022/01/27 06:00 PMCR- 2021/12/08 CRDT- 2021/12/08 05:37 PHST- 2021/06/20 00:00 [received] PHST- 2021/10/26 00:00 [accepted] PHST- 2021/12/08 05:37 [entrez] PHST- 2021/12/09 06:00 [pubmed] PHST- 2022/01/27 06:00 [medline] PHST- 2021/12/08 00:00 [pmc-release] AID - 10.1186/s12916-021-02173-4 [pii] AID - 2173 [pii] AID - 10.1186/s12916-021-02173-4 [doi] PST - epublish SO - BMC Med. 2021 Dec 8;19(1):311. doi: 10.1186/s12916-021-02173-4.