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  2. 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

  • Arch Toxicol. 2020 Sep;94(9):3201-3215. doi: 10.1007/s00204-020-02796-1.
Shuwei Hu 1 Yiwen Yi 1 Tao Jiang 1 Zhexiao Jiao 1 Shiyun Dai 1 Xiaohan Gong 1 Ke Li 2 Hui Wang 1 3 Dan Xu 4 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China.
  • 2 Demonstration Center for Experimental Basic Medicine Education, Wuhan University, Wuhan, 430071, China.
  • 3 Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China.
  • 4 Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China. xuyidan70188@whu.edu.cn.
  • 5 Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China. xuyidan70188@whu.edu.cn.
Abstract

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.

Keywords

Angiotensin-converting enzyme; Dexamethasone; Histone acetylation; Intrauterine programming; Temporal lobe epilepsy.

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