Department of Physiology, Second Military Medical University, Shanghai, China.
Department of Clinical Genetics and Experimental Medicine, Fuzhou General Hospital, Xiamen University School of Medicine, Fuzhou, China.
FASEB J. 2018 Aug;32(8):4258-4269. doi: 10.1096/fj.201700948RR. Epub 2018 Mar 15.
Pregnant women at risk of preterm labor usually receive synthetic glucocorticoids (sGCs) to promote fetal lung development. Emerging evidence indicates that antenatal sGC increases the risk of affective disorders in offspring. Data from animal studies show that such disorders can be transmitted to the second generation. However, the molecular mechanisms underlying the intergenerational effects of prenatal sGC remain largely unknown. Here we show that prenatal dexamethasone (Dex) administration in late pregnancy induced depression-like behavior in first-generation (F1) offspring, which could be transmitted to second-generation (F2) offspring with maternal dependence. Moreover, corticotropin-releasing hormone (CRH) and CRH receptor type 1 (CRHR1) expression in the hippocampus was increased in F1 Dex offspring and F2 offspring from F1 Dex female rats. Administration of a CRHR1 antagonist to newborn F1 Dex offspring alleviated depression-like behavior in these rats at adult. Furthermore, we demonstrated that increased CRHR1 expression in F1 and F2 offspring was associated with hypomethylation of CpG islands in Crhr1 promoter. Our results revealed that prenatal sGC exposure could program Crh and Crhr1 gene expression in hippocampus across 2 generations, thereby leading to depression-like behavior. Our study indicates that prenatal sGC can cause epigenetic instability, which increases the risk of disease development in the offspring's later life.-Xu, Y.-J., Sheng, H., Wu, T.-W., Bao, Q.-Y., Zheng, Y., Zhang, Y.-M., Gong, Y.-X., Lu, J.-Q., You, Z.-D., Xia, Y., Ni, X. CRH/CRHR1 mediates prenatal synthetic glucocorticoid programming of depression-like behavior across 2 generations.
孕妇有早产风险通常会接受合成糖皮质激素（sGCs）以促进胎儿肺发育。新出现的证据表明，产前 sGC 会增加后代情感障碍的风险。动物研究数据表明，这种疾病可以传递给第二代。然而，产前 sGC 对子代表观遗传效应的分子机制在很大程度上仍不清楚。在这里，我们表明，妊娠晚期给予地塞米松（Dex）可导致第一代（F1）后代出现抑郁样行为，这种行为可通过母体依赖传递给第二代（F2）后代。此外，F1 Dex 后代和来自 F1 Dex 雌性大鼠的 F2 后代的海马中促肾上腺皮质激素释放激素（CRH）和 CRH 受体 1（CRHR1）表达增加。给新生的 F1 Dex 后代施用 CRHR1 拮抗剂可缓解这些大鼠成年时的抑郁样行为。此外，我们证明 F1 和 F2 后代中 CRHR1 表达的增加与 Crhr1 启动子中 CpG 岛的低甲基化有关。我们的研究结果表明，产前 sGC 暴露可跨 2 代编程海马中的 Crh 和 Crhr1 基因表达，从而导致抑郁样行为。我们的研究表明，产前 sGC 可引起表观遗传不稳定，从而增加后代后期疾病发展的风险。
