Prenatal dexamethasone exposure disrupts offspring hippocampal neurogenesis and triggers depression-like behaviors via epigenetic regulation

Prenatal glucocorticoid therapy is commonly used to manage preterm fetal delivery risks; however, such exposure elevates the risk of adult psychiatric disorders, though the underlying mechanisms remain elusive. The present study utilized a mouse model exposed to dexamethasone (DEX, a synthetic glucocorticoid) during late pregnancy (GD14.5-GD20.5). Here, we found that prenatal DEX exposure decreased hippocampal expression of Tet1, Yy1, and Ezh2, increased Pten expression, reduced neurogenesis, and induced depression-like behaviors.

Mechanistically, prenatal DEX exposure suppressed Tet1 levels in offspring, inhibiting Tet1 enrichment and 5hmC levels in the Yy1 and Ezh2 promoter regions, thereby downregulating their expression. Subsequently, reduced Yy1 and Ezh2 levels disinhibited Pten expression, leading to Pten upregulation that inhibits the PI3K-Akt-mTOR pathway. This cascade ultimately impaired neurogenesis and promoted depression-like behaviors.

Notably, administering the Pten inhibitor bpV(pic) or supplementing Tet1 expression to DEX-exposed offspring restored neurogenesis and behavioral phenotypes. In summary, this study demonstrates that prenatal DEX exposure mediates the upregulation of hippocampal Pten expression through epigenetic mechanisms, leading to suppressed neurogenesis and the emergence of depression-like phenotypes. These results elucidate novel signaling mechanisms and contribute to the theoretical framework for understanding how prenatal DEX exposure influences offspring psychiatric health.

This work was supported by grants from the National Natural Science Foundation of China (82101793 and 81974244), the National Key R&D Program of China (2022YFC2703700 and 2019YFA0802600), Suzhou Basic Research Pilot Program (SSD2024069) and Suzhou Gusu Health Talents Project (GSWS2022010). We appreciate the support of Suzhou city Gusu Talent Program (2021057), Suzhou Municipal Key Laboratory of Maternal and developmental origins of chronic diseases, and Suzhou Municipal Key Discipline of Obstetrics and Gynecology (SZXK202504). These authors contributed equally: Zejun Zhao, Jie zhang, XiuWu Tang.

Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu, 215006, China Zejun Zhao, Xi Yu, Bin Wei, Yueyang Song, Qinqin Gao, Miao Sun & Bin Wang Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China Department of Neurology, The People’s Hospital of Suzhou New District, Suzhou, Jiangsu, 215129, China McKusick-Zhang 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, 100005, China Correspondence to Qinqin Gao, Miao Sun or Bin Wang. The authors declare no competing interests. This experimental protocol was approved by the Research Ethics Committee of the Soochow University (Approval No. 202411A0159).

All procedures conformed to the “Guidelines on the Humane Treatment of Laboratory Animals” and the “Guidelines for Ethical Review of Laboratory Animal Welfare” (GB/T 35892-2018). Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material.