INTRODUCTION Many socially significant diseases are associated with prenatal developmental disorders. Previously, we showed the pathological role of hypoxia-inducible factor HIF1 in post-hypoxic reoxygenation. This study aimed to investigate the effect of prenatal severe hypoxia (PSH) on HIF1α protein expression as well as on HIF1-dependent activity of the pentose phosphate pathway (PPP) and anaerobic glycolysis in the hippocampus (HPC) of offspring that reached adulthood. METHODS PSH was induced during the critical period of fetal hippocampal formation on gestation days 14-16 in a hypobaric chamber (180 Torr, 5% oxygen, 3 hours). Subsequent studies were conducted on both the HPC of adult control and PSH rats under normal conditions, as well as in response to severe hypobaric hypoxia (SH) or psycho-emotional stress ("learned helplessness" model, LH). We evaluated HIF1α protein levels using both immunohistochemistry and western blotting techniques. The amount of glucose-6-phosphate dehydrogenase (G6PD) was also determined by western blotting. Colorimetric enzymatic assays were employed to analyze enzymatic activity of lactate dehydrogenase (LDH), the concentration of lactate, NADPH, reduced glutathione (GSHred), and malonic dialdehyde (MDA). RESULTS We showed that PSH caused a stable increase in the content of HIF1α protein in the HPC, which was accompanied by an increase in the efficiency of anaerobic glycolysis. This was confirmed by increased LDH activity and lactate concentration. At the same time, the amounts of G6PD, NADPH, and reduced glutathione decreased in the HPC of PSH rats, whereas the concentration of MDA, an oxidative stress marker, exceeded the control values. In a series of experiments using the LH or SH stress, it was shown that in the HPC of control rats, there was an increase in the amount of HIF1α in response to stress, which was also accompanied by more efficient anaerobic glycolysis and decreased of PPP-dependent NADPH production, similar to the intact PSH rats. In PSH rats, emotional stress resulted in higher HIF1α levels without affecting glycolysis or PPP. CONCLUSION Therefore, the increased content and activity of the transcription factor HIF1α in the HPC of adult rats exposed to prenatal hypoxia leads to an imbalance between glycolysis and PPP, which is accompanied by oxidative stress.

中文翻译：

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在产前严重缺氧的成年大鼠海马中，氧化应激伴随着 HIF1 依赖性葡萄糖代谢损伤。

引言 许多具有社会意义的疾病都与产前发育障碍有关。此前，我们展示了缺氧诱导因子 HIF1 在缺氧后复氧中的病理作用。本研究旨在探讨产前严重缺氧 (PSH) 对 HIF1α 蛋白表达以及对成年后代海马中 HIF1 依赖性戊糖磷酸途径 (PPP) 活性和无氧糖酵解 (HPC) 的影响。方法 在妊娠第 14-16 天胎儿海马形成的关键时期，在低压室（180 Torr，5% 氧气，3 小时）中诱导 PSH。随后的研究在正常条件下以及对严重低压缺氧（SH）或心理情绪应激（“习得性无助”模型，LH）下的成年对照和 PSH 大鼠的 HPC 进行。我们使用免疫组织化学和蛋白质印迹技术评估了 HIF1α 蛋白水平。葡萄糖-6-磷酸脱氢酶（G6PD）的量也通过蛋白质印迹法测定。采用比色酶法分析乳酸脱氢酶 (LDH) 的酶活性、乳酸浓度、NADPH、还原型谷胱甘肽 (GSHred) 和丙二醛 (MDA)。结果我们发现，PSH 导致 HPC 中 HIF1α 蛋白含量稳定增加，同时无氧糖酵解效率增加。LDH 活性和乳酸浓度的增加证实了这一点。与此同时，PSH大鼠HPC中G6PD、NADPH和还原型谷胱甘肽的含量下降，而氧化应激标志物MDA的浓度超过对照值。在一系列使用 LH 或 SH 应激的实验中，结果表明，在对照大鼠的 HPC 中，响应应激反应的 HIF1α 量增加，同时伴随着更有效的无氧糖酵解和 PPP 下降依赖于 NADPH 的产生，类似于完整的 PSH 大鼠。在 PSH 大鼠中，情绪压力导致 HIF1α 水平升高，但不影响糖酵解或 PPP。结论 产前缺氧成年大鼠HPC中转录因子HIF1α含量和活性增加导致糖酵解和PPP之间的失衡，并伴有氧化应激。