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If placental ischemia (PI) primarily reduces fetal oxygen supply, the maternal hypoxia (MH) model also elicits a pronounced fetal glucocorticoid exposure. Here, we compared MH and PI in rats to distinguish their unique and overlapping effects on embryonic and newborn brain development. We analyzed glucocorticoid transport into the developing brain, glucocorticoid receptor (GR) expression, and GR-dependent transcription, along with key enzymes regulating glucocorticoid metabolism in maternal (MP) and fetal placentas (FP) and in the brain. Additionally, we examined hypoxia-inducible factor 1-alpha (HIF1\u03b1) and its downstream genes, as well as glycolysis and the pentose phosphate pathway, both associated with the transport of substrates essential for glucocorticoid synthesis and degradation. Both MH and PI induced HIF1-dependent metabolic alterations, enhancing glycolysis and transiently disrupting redox homeostasis. However, only MH caused a maternal glucocorticoid surge that altered early fetal brain glucocorticoid responsiveness. Over time, these differences may lead to distinct long-term outcomes in neuronal structure and function. This work clarifies the individual contributions of hypoxic and glucocorticoid stresses to fetal brain development, suggesting that combining the MH and PI models could provide valuable insights for future investigations into the mechanisms underlying developmental brain pathologies, including non-heritable psychoneurological and neurodegenerative disorders.<\/jats:p>","DOI":"10.3390\/ijms252413342","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T06:29:30Z","timestamp":1733984970000},"page":"13342","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Comparative Analysis of the Effects of Maternal Hypoxia and Placental Ischemia on HIF1-Dependent Metabolism and the Glucocorticoid System in the Embryonic and Newborn Rat Brain"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1860-5935","authenticated-orcid":false,"given":"Oleg","family":"Vetrovoy","sequence":"first","affiliation":[{"name":"Laboratory of Regulation of Brain Neuronal Functions, Pavlov Institute of Physiology, Russian Academy of Sciences, Makarova emb. 6, 199034 Saint-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0558-6811","authenticated-orcid":false,"given":"Sofiya","family":"Potapova","sequence":"additional","affiliation":[{"name":"Laboratory of Regulation of Brain Neuronal Functions, Pavlov Institute of Physiology, Russian Academy of Sciences, Makarova emb. 6, 199034 Saint-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6422-5338","authenticated-orcid":false,"given":"Viktor","family":"Stratilov","sequence":"additional","affiliation":[{"name":"Laboratory of Regulation of Brain Neuronal Functions, Pavlov Institute of Physiology, Russian Academy of Sciences, Makarova emb. 6, 199034 Saint-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Tyulkova","sequence":"additional","affiliation":[{"name":"Laboratory of Regulation of Brain Neuronal Functions, Pavlov Institute of Physiology, Russian Academy of Sciences, Makarova emb. 6, 199034 Saint-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1056\/NEJMra1011165","article-title":"Oxygen sensing, homeostasis, and disease","volume":"365","author":"Semenza","year":"2011","journal-title":"N. 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