Intrauterine RAS programming alteration-mediated susceptibility and heritability of temporal lobe epilepsy in male offspring rats induced by prenatal dexamethasone exposure
Intrauterine RAS programming alteration-mediated susceptibility and heritability of temporal lobe epilepsy in male offspring rats induced by prenatal dexamethasone exposure
复制标题
产前地塞米松暴露所致雄性子代大鼠颞叶癫痫的宫内 RAS 编程改变介导的易感性和遗传性
DOI：
10.1007/s00204-020-02796-1
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发表时间：
2020-06-03
影响因子：
6.1
通讯作者：
Xu, Dan
中科院分区：
文献类型：
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作者：
Hu, Shuwei;Yi, Yiwen;Xu, Dan
部分性颞叶癫痫（TLE）具有宫内发育起源。本研究旨在阐明产前地塞米松暴露（PDE）诱发子代大鼠颞叶癫痫的遗传效应和编程机制。从妊娠第9天至第20天，对妊娠Wistar大鼠皮下注射地塞米松（0.2 mg/kg/天）。对F1和F2代雄性后代给予匹罗卡品锂（LiPC）进行癫痫或行为测试的脑电图和视频监测。结果显示PDE + LiPC组表现出TLE易感性，其在整个F2代中持续。海马糖皮质激素受体（GR）、CCAAT增强子结合蛋白α（C/EBPα）、子宫内肾素-血管紧张素系统（RAS）经典通路相关基因表达、血管紧张素转换酶（ACE）启动子H3 K27 ac水平、高迁移率族蛋白1（HMGB 1）和Toll样受体4（TLR 4）表达增加，谷氨酸脱氢酶（GLUD）1/2表达降低，伴随PDE胎儿和成年大鼠以及PDE + LiPC组的F1和F2后代中谷氨酸水平升高。用地塞米松处理H19-7胎海马细胞系也观察到这些一致的变化，并被GR抑制剂（RU 486）和ACE抑制剂（依那普利拉）逆转。我们的研究结果证实PDE诱导ACE启动子中H3 K27 ac富集，并通过在子宫内激活GR-C/EBPα-p300增强RAS经典通路，从而引起HMGB 1通路的改变和谷氨酸兴奋性损伤。海马ACE异常组蛋白修饰介导的宫内程序化可持续至成年期甚至F2代，从而导致雄性子代大鼠TLE的遗传性。
Partial temporal lobe epilepsy (TLE) has an intrauterine developmental origin. This study was aimed at elucidating the heritable effects and programming mechanism of TLE in offspring rats induced by prenatal dexamethasone exposure (PDE). Pregnant Wistar rats were injected subcutaneously with dexamethasone (0.2 mg/kg day) from gestational day 9 to 20. The F1 and F2 generations of male offspring were administered lithium pilocarpine (LiPC) for electroencephalography and video monitoring in epilepsy or behavioral tests. Results showed that the PDE + LiPC group exhibited TLE susceptibility, which continued throughout F2 generation. Expression of hippocampal glucocorticoid receptor (GR), CCAAT enhancer-binding protein α (C/EBPα), intrauterine renin–angiotensin system (RAS) classical pathway related genes, the H3K27ac level in angiotensin-converting enzyme (ACE) promoter, as well as high mobility group box 1 (HMGB1) and toll-like receptor 4 (TLR4) were increased, but glutamate dehydrogenase (GLUD) 1/2 expression were decreased, accompanied by increased glutamate levels in PDE fetal and adult rats, as well as in F1 and F2 offspring of the PDE + LiPC group. These consistent changes were also observed by treating the H19-7 fetal hippocampal cell line with dexamethasone and were reversed by GR inhibitor (RU486) and ACE inhibitor (enalaprilat). Our results confirmed that PDE-induced H3K27ac enrichment in the ACE promoter and enhanced the RAS classic pathway via activating GR-C/EBPα-p300 in utero, which caused changes of the HMGB1 pathway and glutamate excitatory damage. Intrauterine programming mediated by abnormal histone modification of hippocampal ACE could continue to adulthood and even F2 generation, which induced the heritability of TLE in male offspring rats.