Introduction: Prenatal hypoxia is a risk factor for the development of numerous neurological disorders. It is known that the maternal stress response to hypoxia determines the epigenetic impairment of the perinatal expression of glucocorticoid receptors (GR) in the hippocampus of the progeny, but so far no detailed study of how this affects the functional state of the glucocorticoid system during further ontogenesis has been performed. Objective: The goal of the present study was to examine the long-term effects of the prenatal hypoxia on the functioning of the glucocorticoid system throughout life. Methods: Prenatal severe hypobaric hypoxia (PSH) was induced in the critical period of embryonic hippocampal formation on days 14–16 of gestation in a hypobaric chamber (180 Torr, 5% oxygen, 3 h). The activity of central (hippocampus) and peripheral (liver) components of the glucocorticoid system was assessed in 1-day-old (newborn), 2-week-old (juvenile), 3-month-old (adult), and 18-month-old (aged) male rats. Results: The PSH resulted in continuously elevated baseline corticosterone blood levels in the adult and aged rats. The chronic elevation of the corticosterone levels was accompanied by a progressive deficit of the GR expression in the liver, increased hepatic glycogen content, dysregulated glucose-6-phosphatase activity, and eventually hypoglycemia. Elevated corticosterone appears to result from the impairment of the mechanisms of glucocorticoid negative feedback since a substantial decrease in both the total number of GR and their nuclear localization was observed already in the hippocampus of newborn rat pups and persisted throughout life. Corresponding stable hippocampal downregulation of GR-dependent genes was observed as well. Suppression of the maternal glucocorticoid stress response to hypoxia by metyrapone injection to pregnant rats prior to each hypoxic challenge considerably reduced corticosterone over-response to hypoxia and prevented reduced hippocampal GR. Conclusions: Our findings demonstrate that in progeny a deficit of hippocampal GR resulting from maternal glucocorticoid response to hypoxia remains stable throughout life and is accompanied by severe disturbances of baseline glucocorticoid levels and its peripheral reception. Negative consequences of PSH can be prevented by injection with an inhibitor of corticosterone synthesis (metyrapone) to pregnant females undergoing hypoxia.
Dev Neurosci

中文翻译：

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产前严重缺氧对大鼠糖皮质激素系统中枢和外周成分的长期影响

简介：产前缺氧是许多神经系统疾病发展的危险因素。众所周知，母体对缺氧的应激反应决定了后代海马中糖皮质激素受体 (GR) 围产期表达的表观遗传损伤，但到目前为止还没有详细研究这如何影响糖皮质激素系统的功能状态。已经进行了个体发生。目的：本研究的目的是检查产前缺氧对终生糖皮质激素系统功能的长期影响。方法：在胚胎海马形成的关键时期，在低压室（180 Torr，5% 氧气，3 小时）中，在妊娠第 14-16 天诱导产前严重低压缺氧 (PSH)。糖皮质激素系统的中枢（海马）和外周（肝脏）成分的活性在 1 天大（新生儿）、2 周大（幼年）、3 个月大（成人）和 18 岁大的婴儿中进行评估。月龄（老年）雄性大鼠。结果：PSH 导致成年和老年大鼠的基线血皮质酮水平持续升高。皮质酮水平的慢性升高伴随着肝脏中 GR 表达的进行性缺陷、肝糖原含量增加、葡萄糖 6-磷酸酶活性失调，并最终导致低血糖。升高的皮质酮似乎是糖皮质激素负反馈机制受损的结果，因为在新生大鼠幼崽的海马体中已经观察到 GR 总数及其核定位的显着减少，并持续终生。还观察到 GR 依赖性基因的相应稳定海马下调。结论：我们的研究结果表明，由于母体糖皮质激素对缺氧的反应导致后代海马 GR 缺陷在整个生命中保持稳定，并且伴随着基线糖皮质激素水平及其外周接收的严重紊乱。通过向经历缺氧的怀孕女性注射皮质酮合成抑制剂（美替拉酮），可以预防 PSH 的负面后果。
开发神经科学