Jiang Tao, Hu Shuwei, Dai Shiyun, Yi Yiwen, Wang Tingting, Li Xufeng, Luo Mingcui, Li Ke, Chen Liaobin, Wang Hui, Xu Dan
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, 430071, China.
Demonstration Center for Experimental Basic Medicine Education, Wuhan University, Wuhan, 430071, China.
Cell Biol Toxicol. 2022 Feb;38(1):69-86. doi: 10.1007/s10565-021-09590-4. Epub 2021 Feb 22.
Depression is a neuropsychiatric disorder and has intrauterine developmental origins. This study aimed to confirm the depression susceptibility in offspring rats induced by prenatal dexamethasone exposure (PDE) and to further explore the intrauterine programming mechanism. Wistar rats were injected with dexamethasone (0.2 mg/kg·d) subcutaneously during the gestational days 9-20 and part of the offspring was given chronic stress at postnatal weeks 10-12. Behavioral results showed that the adult PDE female offspring was susceptible to depression, accompanied by increased hippocampal miR-134-5p expression and decreased sex-determining region Y-box 2 (SOX2) expression, as well as disorders of neural progenitor cells proliferation and hippocampal neurogenesis. The PDE female fetal rats presented consistent changes with the adult offspring, accompanied by the upregulation of glucocorticoid receptor (GR) expression and decreased sirtuin 1 (SIRT1) expression. We further found that the H3K9ac level of the miR-134-5p promoter was significantly increased in the PDE fetal hippocampus, as well as in adult offspring before and after chronic stress. In vitro, the changes of GR/SIRT1/miR-134-5p/SOX2 signal by dexamethasone were consistent with in vivo experiments, which could be reversed by GR receptor antagonist, SIRT1 agonist, and miR-134-5p inhibitor. This study confirmed that PDE led to an increased expression level as well as H3K9ac level of miR-134-5p by activating the GR/SIRT1 pathway in the fetal hippocampus and then inhibited the SOX2 expression. The programming effect mediated by the abnormal epigenetic modification could last from intrauterine to adulthood, which constitutes the intrauterine programming mechanism leading to hippocampal neurogenesis disorders and depression susceptibility in female offspring. Intrauterine programming mechanism for the increased depressive susceptibility in adult female offspring by prenatal dexamethasone exposure (PDE). GR, glucocorticoid receptor; SIRT1, sirtuin 1; SOX2, sex-determining region Y-box 2; NPCs, neuroprogenitor cells; H3K9ac, histone 3 lysine 9 acetylation; GRE, glucocorticoid response element.
抑郁症是一种神经精神疾病，具有宫内发育起源。本研究旨在证实产前地塞米松暴露（PDE）诱导的子代大鼠的抑郁易感性，并进一步探索宫内编程机制。在妊娠第9至20天，对Wistar大鼠皮下注射地塞米松（0.2mg/kg·d），部分子代在出生后第10至12周给予慢性应激。行为学结果显示，成年PDE雌性子代易患抑郁症，伴有海马miR-134-5p表达增加、性别决定区Y盒2（SOX2）表达降低，以及神经祖细胞增殖和海马神经发生紊乱。PDE雌性胎鼠与成年子代呈现一致变化，伴有糖皮质激素受体（GR）表达上调和沉默调节蛋白1（SIRT1）表达降低。我们进一步发现，PDE胎鼠海马中miR-134-5p启动子的H3K9ac水平显著升高，成年子代在慢性应激前后也是如此。在体外，地塞米松引起的GR/SIRT1/miR-134-5p/SOX2信号变化与体内实验一致，可被GR受体拮抗剂、SIRT1激动剂和miR-134-5p抑制剂逆转。本研究证实，PDE通过激活胎鼠海马中的GR/SIRT1通路，导致miR-134-5p的表达水平以及H3K9ac水平升高，进而抑制SOX2表达。由异常表观遗传修饰介导的编程效应可从宫内持续到成年期，这构成了导致雌性子代海马神经发生紊乱和抑郁易感性的宫内编程机制。产前地塞米松暴露（PDE）导致成年雌性子代抑郁易感性增加的宫内编程机制。GR，糖皮质激素受体；SIRT1，沉默调节蛋白1；SOX2，性别决定区Y盒2；NPCs，神经祖细胞；H3K9ac，组蛋白3赖氨酸9乙酰化；GRE，糖皮质激素反应元件。
