Lei Lei, Wu Xinmiao, Gu Hanwen, Ji Muhuo, Yang Jianjun
Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
Front Neurosci. 2020 Oct 21;14:573107. doi: 10.3389/fnins.2020.573107. eCollection 2020.
Prenatal stress (PS) can lead to neuroendocrine and emotional disorders later in adolescence. Sexual dimorphism in these neurodevelopmental outcomes have been observed; however, the underlying mechanisms are not fully understood. To address this issue, we investigated whether there are sex differences in epigenetic reprogramming in rats exposed to PS. Pregnant female rats were subjected to chronic restraint stress from gestational day (G)12 to G18. From postnatal day (P)38 to P45, subgroups of offspring including both males and females were subjected to behavioral testing and brain tissue specimens were analyzed by DNA pyrosequencing, western blotting, and Golgi staining to assess changes in methylation pattern of glucocorticoid receptor (GR) gene, expression of DNA methyltransferase (DNMT) and DNA demethylase, and dendrite morphology, respectively. The DNA methyltransferase inhibitor decitabine was administered to rats prior to PS to further evaluate the role of methylation in the sexually dimorphic effects of PS. The results showed that PS increased anxiety-like behavior in offspring, especially in females, while depression-like behavior was increased in male offspring compared to control littermates. The methylation pattern in the promoter region of the GR gene differed between males and females. Sex-specific changes in the expression of DNMTs (DNMT1 and DNMT3a) and DNA demethylase (Tet methylcytosine dioxygenase 2) were also observed. Interestingly, decitabine alleviated the behavioral disorder caused by PS and restored dendrite density and morphology in female but not male rats. These findings suggest that different change patterns of DNMT and demethylase in the two sexes after PS are responsible for the sexually dimorphism, which could have implications for the clinical management of stress-related disorders.
产前应激（PS）可导致青春期后期出现神经内分泌和情绪障碍。在这些神经发育结果中已观察到性别差异；然而，其潜在机制尚未完全了解。为解决这一问题，我们研究了暴露于PS的大鼠在表观遗传重编程方面是否存在性别差异。怀孕的雌性大鼠在妊娠第（G）12天至G18天接受慢性束缚应激。从出生后第（P）38天至P45天，对包括雄性和雌性在内的子代亚组进行行为测试，并通过DNA焦磷酸测序、蛋白质免疫印迹和高尔基染色分析脑组织标本，分别评估糖皮质激素受体（GR）基因的甲基化模式变化、DNA甲基转移酶（DNMT）和DNA去甲基化酶的表达以及树突形态。在PS处理前给大鼠施用DNA甲基转移酶抑制剂地西他滨，以进一步评估甲基化在PS性别差异效应中的作用。结果表明，PS增加了子代的焦虑样行为，尤其是雌性，而与对照同窝仔相比，雄性子代的抑郁样行为增加。GR基因启动子区域的甲基化模式在雄性和雌性之间存在差异。还观察到DNMTs（DNMT1和DNMT3a）和DNA去甲基化酶（Tet甲基胞嘧啶双加氧酶2）表达的性别特异性变化。有趣的是，地西他滨减轻了PS引起的行为障碍，并恢复了雌性而非雄性大鼠的树突密度和形态。这些发现表明，PS后两性中DNMT和去甲基化酶的不同变化模式是导致性别差异的原因，这可能对应激相关障碍的临床管理具有启示意义。
