Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
Toxicol Lett. 2019 Mar 1;302:7-17. doi: 10.1016/j.toxlet.2018.12.001. Epub 2018 Dec 6.
Glucocorticoids play a major factor in fetal maturation and fate decision after birth. We have previously demonstrated that prenatal caffeine exposure (PCE) resulted in adrenal dysplasia. However, its molecular mechanism has not been clarified. In the present study, a rat model of intrauterine growth retardation (IUGR) was established by PCE, and offspring were sacrificed. Moreover, NCI-H295 A cells were used to confirm glucocorticoid-related molecular mechanism. Results showed that PCE fetal weight decreased, and the IUGR rate increased, while serum corticosterone levels increased but insulin-like growth factor 1 (IGF1) levels decreased. Fetal adrenals exhibited an activated glucocorticoid-activation system, and the downregulated expression of IGF1 signal pathway and steroidal synthetases. For adult rats, there was no significant change in the glucocorticoid-activation system in the PCE group, the IGF1 signal pathway showed increased trend, and the expression levels of adrenal steroidal synthetases were close to normal. The data in vitro showed that the cortisol of 1200 nM can inhibit the expression of adrenocortical cell steroidal synthetases and IGF1 signal pathway when compared with the control. Meanwhile, the glucocorticoid-activation system was activated while GR inhibitor mifepristone can reverse the effect of cortisol. Furthermore, cortisol can also promote GR into the nucleus after its activation. Based on these findings, we speculated that high concentrations of glucocorticoid in utero led to GR in the nucleus through its activation and then inhibited the IGF1 signaling pathway by activating the glucocorticoid-activation system, which could further downregulate steroid synthesis.
糖皮质激素在胎儿成熟和出生后命运决策中起主要作用。我们之前的研究表明，产前咖啡因暴露（PCE）会导致肾上腺发育不良。然而，其分子机制尚未阐明。在本研究中，通过 PCE 建立了宫内生长迟缓（IUGR）大鼠模型，并对后代进行了处死。此外，还使用 NCI-H295A 细胞来验证糖皮质激素相关的分子机制。结果表明，PCE 胎儿体重下降，IUGR 发生率增加，而血清皮质酮水平升高但胰岛素样生长因子 1（IGF1）水平下降。胎肾上腺表现出激活的糖皮质激素激活系统，IGF1 信号通路的下调表达和甾体合成酶。对于成年大鼠，PCE 组的糖皮质激素激活系统没有明显变化，IGF1 信号通路呈增加趋势，肾上腺甾体合成酶的表达水平接近正常。体外数据显示，与对照组相比，1200nM 的皮质醇可抑制肾上腺皮质细胞甾体合成酶和 IGF1 信号通路的表达。同时，激活的糖皮质激素激活系统被激活，而 GR 抑制剂米非司酮可以逆转皮质醇的作用。此外，皮质醇激活后还可以促进 GR 进入细胞核。基于这些发现，我们推测宫内高浓度的糖皮质激素通过其激活作用使 GR 进入细胞核，然后通过激活糖皮质激素激活系统抑制 IGF1 信号通路，从而进一步下调类固醇合成。
