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.

颞叶部分性癫痫（TLE）具有宫内发育起源。这项研究旨在阐明TLE对产前地塞米松暴露（PDE）诱导的后代大鼠的遗传效应和编程机制。从妊娠第9天到第20天，对怀孕的Wistar大鼠进行皮下注射地塞米松（0.2 mg / kg /天）。对F1和F2代雄性后代给予皮毛果芸香酸锂（LiPC）进行脑电图检查和癫痫或行为学测试的视频。结果表明，PDE + LiPC组表现出TLE敏感性，在整个F2代中持续存在。海马糖皮质激素受体（GR），CCAAT增强剂结合蛋白α（C /EBPα），子宫内肾素-血管紧张素系统（RAS）经典途径相关基因的表达，血管紧张素转换酶（ACE）启动子中的H3K27ac水平升高，高迁移率族1号框（HMGB1）和toll样受体4（TLR4）升高，但谷氨酸脱氢酶（GLUD）1/2表达降低，并伴有通过增加PDE胎儿和成年大鼠以及PDE + LiPC组的F1和F2后代中的谷氨酸水平。通过用地塞米松处理H19-7胎儿海马细胞系，也观察到了这些一致的变化，并被GR抑制剂（RU486）和ACE抑制剂（依那普利拉）逆转。我们的结果证实，PDE诱导ACE启动子中H3K27ac富集，并通过激活子宫内GR-C /EBPα-p300增强了RAS经典途径，从而引起HMGB1途径的改变和谷氨酸兴奋性损伤。