Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China.
Mol Neurobiol. 2013 Dec;48(3):544-55. doi: 10.1007/s12035-013-8444-4. Epub 2013 Mar 26.
Stress during gestation increases vulnerability to disease and changes behavior in offspring. We previously reported that hypoxia and restraint during pregnancy sensitized the hypothalamic-pituitary-adrenal (HPA) axis and induced anxiety-like behavior in the adult offspring. Here, we report that gestational intermittent hypoxia (GIH) elicited a sex-dependent anxiety-like behavior in male P90 offspring and activation of corticotropin-releasing hormone (CRH) and CRH type-1 receptor (CRHR1) mRNA in the hypothalamic paraventricular nucleus (PVN) and in male E19 hypothalamus. These linked to demethylation at several specific sites of CpG island of Crhr1 promoter in P90 PVN and E19 embryo hypothalamus in GIH groups. Crhr1 DNA demethylation is more crucial in CpG island 1 than island 2 for activation of CRHR1 mRNA. DNMT3b is required for the Crhr1 DNA methylation than DNMT1 and DNMT3a in increased CRHR1 mRNA. We first address a novel hypothesis that GIH-induced male-sex-dependent demethylation at CpG sites of Crhr1 DNA in promoter triggers elevation of CRHR1 mRNA in PVN and anxiety-like behavior in adult offspring.
孕期压力会增加后代易患疾病和行为改变的脆弱性。我们之前曾报道过，孕期缺氧和束缚会使下丘脑-垂体-肾上腺（HPA）轴敏感，并在成年后代中引起类似焦虑的行为。在这里，我们报告妊娠期间歇性缺氧（GIH）会在雄性 P90 后代中引起类似焦虑的行为，并激活下丘脑室旁核（PVN）中的促肾上腺皮质激素释放激素（CRH）和 CRH 型 1 受体（CRHR1）mRNA，以及雄性 E19 下丘脑中的 CRH 和 CRHR1 mRNA。这与 GIH 组中 P90 PVN 和 E19 胚胎下丘脑的 Crhr1 启动子的几个特定 CpG 岛的去甲基化有关。在 Crhr1 启动子的 CpG 岛 1 中，Crhr1 DNA 去甲基化对于 CRHR1 mRNA 的激活比岛 2 更为重要。DNMT3b 比 DNMT1 和 DNMT3a 更需要 Crhr1 DNA 甲基化，以增加 CRHR1 mRNA。我们首次提出了一个新的假设，即 GIH 诱导的雄性特异性 Crhr1 DNA 启动子中 CpG 位点的去甲基化会引发 PVN 中 CRHR1 mRNA 的升高，并导致成年后代出现类似焦虑的行为。
