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

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.

Cholic acid exposure during late pregnancy causes placental dysfunction and fetal growth restriction by reactive oxygen species‐mediated activation of placental GCN2/eIF2α pathway

“…32,33 Despite these beneficial effects, accumulating evidence showed that exposure of the fetus to active was related to adverse pregnancy outcomes, such as placental dysfunction, FGR, and reprogramming fetal organ development. 21,34,35 Taken together, we infer that excessive exposure to active GC may be one of the main causes of FGR induced by CA.…”

“…During pregnancy, appropriate exposure to GC not only is pivotal to enable the mother to meet the metabolic demands, 31 but also is crucial to accelerate the maturation of fetal lung for pregnant women with ongoing risk of premature delivery 32,33 . Despite these beneficial effects, accumulating evidence showed that excessive exposure of the fetus to active GC was related to adverse pregnancy outcomes, such as placental dysfunction, FGR, and reprogramming fetal organ development 21,34,35 . Taken together, we infer that excessive exposure to active GC may be one of the main causes of FGR induced by CA.…”

“…Accumulating evidence in humans demonstrated that decreased placental weight and size, and placental insufficiency were associated with an increased risk for FGR 19 . Several studies in rodent models indicated that poor placental development and function were the major mechanism leading to FGR 20,21 . Bile acids can induce the production of a large number of reactive oxygen species (ROS) and oxidative stress 22,23 .…”

Multidrug Resistance of Cancer Cells and the Vital Role of P-Glycoprotein

“…The involvement of P-gp in the brain has evolved to the point where it fights the entrance of neurotoxic medicines into the brain and hence maintains the penetration of central nervous system (CNS) agent delivery in the brain [54]. P-gp also protects the foetus against foreign bodies and hazardous chemicals entering the placenta [55].…”

“…The binding effect of modulators such as cyclosporine and verapamil are used in chemotherapy to modulate P-gp activity. The P-gp binding pockets' considerable flexibility and low specificity might be used to overcome MDR-related difficulties during chemotherapy [55]. P-gp inhibitors are classified primarily based on their specificity, affinity, and toxicity [64].…”