Department of Pharmacology, Basic Medical School of Wuhan University, 185 Donghu Road, Wuchang District, Wuhan 430071, China.
Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang District, Wuhan 430071, China.
Sci Total Environ. 2022 Jun 25;827:154396. doi: 10.1016/j.scitotenv.2022.154396. Epub 2022 Mar 5.
A variety of adverse environmental factors during pregnancy cause maternal chronic stress. Caffeine is a common stressor, and its consumption during pregnancy is widespread. Our previous study showed that prenatal caffeine exposure (PCE) increased maternal blood glucocorticoid levels and caused abnormal development of offspring. However, the placental mechanism for fetal development inhibition caused by PCE-induced high maternal glucocorticoid has not been reported. This study investigated the effects of PCE-induced high maternal glucocorticoid level on placental and fetal development by regulating placental 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) expression and its underlying mechanism. First, human placenta and umbilical cord blood samples were collected from women without prenatal use of synthetic glucocorticoids. We found that placental 11β-HSD2 expression was significantly correlated with umbilical cord blood cortisol level and birth weight in male newborns but not in females. Furthermore, we established a rat model of high maternal glucocorticoids induced by PCE (caffeine, 60 mg/kg·d, ig), and found that the expression of 11β-HSD2 in male PCE placenta was decreased and negatively correlated with the maternal/fetal/placental corticosterone levels. Meanwhile, we found abnormal placental structure and nutrient transporter expression. In vitro, BeWo cells were used and confirm that 11β-HSD2 mediated inhibition of placental nutrient transporter expression induced by high levels of glucocorticoid. Finally, combined with the animal and cell experiments, we further confirmed that high maternal glucocorticoid could activate the GR-C/EBPα-Egr1 signaling pathway, leading to decreased expression of 11β-HSD2 in males. However, there was no significant inhibition of placental 11β-HSD2 expression, placental and fetal development in females. In summary, we confirmed that high maternal glucocorticoids could regulate placental 11β-HSD2 expression in a sex-specific manner, leading to differences in placental and fetal development. This study provides the theoretical and experimental basis for analyzing the inhibition of fetoplacental development and its sex difference caused by maternal stress.
多种不利的环境因素会导致孕妇慢性应激。咖啡因是一种常见的应激源，孕妇广泛摄入咖啡因。我们之前的研究表明，孕期咖啡因暴露（PCE）会增加母体血液中的糖皮质激素水平，并导致后代发育异常。然而，PCE 诱导的高母体糖皮质激素引起胎儿发育抑制的胎盘机制尚未报道。本研究通过调节胎盘 11β-羟类固醇脱氢酶 2（11β-HSD2）的表达及其潜在机制，探讨了 PCE 诱导的高母体糖皮质激素水平对胎盘和胎儿发育的影响。首先，从未使用合成糖皮质激素进行产前治疗的女性中采集胎盘和脐带血样本。我们发现，胎盘 11β-HSD2 的表达与男性新生儿脐带血皮质醇水平和出生体重显著相关，但与女性无关。此外，我们建立了 PCE（咖啡因，60mg/kg·d，ig）诱导的高母体糖皮质激素大鼠模型，发现雄性 PCE 胎盘 11β-HSD2 的表达降低，与母体/胎儿/胎盘皮质酮水平呈负相关。同时，我们发现胎盘结构异常和营养转运体表达异常。在体外，我们使用 BeWo 细胞证实 11β-HSD2 介导了高水平糖皮质激素对胎盘营养转运体表达的抑制。最后，结合动物和细胞实验，我们进一步证实高母体糖皮质激素可激活 GR-C/EBPα-Egr1 信号通路，导致雄性 11β-HSD2 表达降低。然而，在雌性中，并没有明显抑制胎盘 11β-HSD2 的表达、胎盘和胎儿的发育。总之，我们证实高母体糖皮质激素可以以性别特异性的方式调节胎盘 11β-HSD2 的表达，导致胎盘和胎儿发育的差异。本研究为分析母体应激引起的胎-胎盘发育抑制及其性别差异提供了理论和实验依据。
