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In this study, we established a model of PH by exposing C57 mice to hypoxia (10.5% oxygen) environment from gestational day (GD) 12.5\u201317.5. We found that PH resulted in cognitive impairment and reduced hippocampal neurogenesis in male offspring compared to control offspring. Mechanistically, PH is a form of prenatal stress that promotes placental transfer of maternal glucocorticoids (GC), which induces hyperactivity of the fetal hypothalamic\u2013pituitary\u2013adrenal (HPA) axis, leading to downregulation of the hippocampal glucocorticoid receptor (GR) in the offspring. In addition, PH promotes increased nuclear translocation of the GR and histone deacetylase 3 (HDAC3) complex, which represses the expression of immediate\u2010early gene Npas4. By acting as a GR receptor antagonist, Mifepristone (MIF) mitigates ameliorated neurogenesis and cognitive impairment in the hippocampus of PH male offspring through the GR\/HDAC3\u2010Npas4 pathway. Thus, our study reveals that the GR\/HDAC3\u2010Npas4 signaling pathway is implicated in reduced hippocampal neurogenesis and cognitive impairment in PH male offspring. This research provides support for the pathogenesis of fetal cognitive impairment caused by PH.<\/jats:p>","DOI":"10.1096\/fj.202502736r","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T14:46:26Z","timestamp":1773672386000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>GR<\/scp>\n                    \/\n                    <scp>HDAC3<\/scp>\n                    Regulates Npas4 Signaling Pathway and Mediates Cognitive Impairment in Prenatal Hypoxia Male Offspring"],"prefix":"10.1096","volume":"40","author":[{"given":"Zejun","family":"Zhao","sequence":"first","affiliation":[{"name":"Institute for Fetology The First Affiliated Hospital of Soochow University  Suzhou City Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueyang","family":"Song","sequence":"additional","affiliation":[{"name":"Institute for Fetology The First Affiliated Hospital of Soochow University  Suzhou City Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5740-6540","authenticated-orcid":false,"given":"Xi","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute for Fetology The First Affiliated Hospital of Soochow University  Suzhou City Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinqin","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute for Fetology The First Affiliated Hospital of Soochow University  Suzhou City Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6159-5242","authenticated-orcid":false,"given":"Bin","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute for Fetology The First Affiliated Hospital of Soochow University  Suzhou City Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute for Fetology The First Affiliated Hospital of Soochow University  Suzhou City Jiangsu China"},{"name":"McKusick\u2010Zhang Center for Genetic Medicine, State Key Laboratory for Complex Severe and Rare Diseases Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.301.6761.1111"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanhl.2024.100660"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2024.172411"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu16162751"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2024.111367"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2021.105147"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/1028415X.2021.1943996"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2023.05.013"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-023-02191-z"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12987-023-00416-5"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-020-0437-z"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23052885"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdr2.1135"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1155\/2010\/401323"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-020-0372-6"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2017.11.577"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13293-023-00557-0"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105461"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202003-0601OC"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2019.06.011"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2014.181"},{"key":"e_1_2_12_23_1","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1001\/jama.2021.17456","article-title":"WHO: Need for Global Dementia Care Planning Is Urgent","volume":"326","author":"Kuehn B. 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