Sex-specific effects of maternal gestational diabetes mellitus on offspring neurodevelopment: persistent hippocampal neurogenesis deficits in female but not male offspring

www.nature.com/emm ARTICLE OPEN Sex-specific effects of maternal gestational diabetes mellitus on offspring neurodevelopment: persistent hippocampal neurogenesis deficits in female but not male offspring ✉ Xiafei Wu1,2,8, Huisheng Ge3,8, Jie Fang1,2,8, Jie He1,2, Hongbing Xu1,2, Yangyu Zhao4, Philip N. Baker5, Xinyang Yu1,2 , 6,7 ✉ 1,2 ✉ Yubin Ding and Hongbo Qi 1234567890();,: © The Author(s) 2026 Gestational diabetes mellitus (GDM) represents a prevalent pregnancy complication with long-term health implications for offspring. While metabolic outcomes have been extensively studied, sex-specific effects on neurodevelopment remain poorly understood. Here we investigated the sex-dependent impact of maternal GDM on offspring brain development and behavior using a high-fat diet and low-dose streptozotocin induced mouse model. We found that adult female offspring exposed to maternal GDM exhibited depressive-like behaviors and sustained impairments in hippocampal neurogenesis across multiple developmental stages (embryonic, weaning and adult), characterized by reduced neural stem cell proliferation and altered differentiation. By contrast, male offspring displayed substantial metabolic dysfunction but no sustained neurogenic deficits beyond the embryonic period. Metabolomic analysis revealed persistent downregulation of myo-inositol in female offspring hippocampus, associated with disruptions in neurogenic signaling pathways. In vitro experiments with female-derived neural stem cells confirmed that hyperglycemic conditions directly impaired proliferation and differentiation, partly through oxidative stress mechanisms. These findings establish a sex-specific vulnerability to GDM-induced neurodevelopmental alterations and identify myo-inositol metabolism as a potential therapeutic target for preventing long-term neuropsychiatric consequences in female offspring. Experimental & Molecular Medicine; https://doi.org/10.1038/s12276-026-01741-z Graphical Abstract Maternal GDM induces sex-specific effects on offspring neurodevelopment, with females exhibiting persistent hippocampal neurogenesis deficits and depressive-like behaviors, while males show neurogenic resilience. The identification of myo-inositol depletion and oxidative stress as potential contributors to female-specific neurogenic impairments provides new insights into sex-specific vulnerability to maternal metabolic disturbances and suggests potential targets for intervention. HFD, High fat diet; STZ, Streptozotocin; GCL, Granule cell layer; SGZ, Subgranular zone; NSCs, Neural stem cells. Figure created with BioRender.com. 1 Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 2Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China. 3Department of Gynecology, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. 4Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. 5Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK. 6Department of Obstetrics and Gynecology, Women and Children’s Hospital of Chongqing Medical University, Chongqing, China. 7 Department of Pharmacology, Academician Workstation, Changsha Medical University, Changsha, China. 8These authors contributed equally: Xiafei Wu, Huisheng Ge, Jie Fang. ✉email: ; ; Received: 23 May 2025 Revised: 25 January 2026 Accepted: 20 March 2026 X. Wu et al. 2 INTRODUCTION Gestational diabetes mellitus (GDM), defined as glucose intolerance first diagnosed during pregnancy, affects approximately 15% of pregnant women worldwide1,2. GDM not only poses immediate risks to maternal health but also has long-term consequences for offspring, increasing their susceptibility to metabolic disorders such as obesity and type 2 diabetes (T2DM)3,4. Our previous work has similarly shown that maternal GDM predisposes offspring to a heightened risk of metabolic syndrome in adulthood5. Beyond metabolic dysfunction, there is growing evidence that GDM substantially impacts neurodevelopment and increases the risk of neuropsychiatric disorders in offspring6–8. Epidemiological studies suggest that children of mothers with GDM are at an elevated risk for conditions such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD)9,10. Notably, recent large cohort studies have revealed a dose-dependent relationship between maternal diabetes (T1DM > T2DM > GDM) and an increased vulnerability to depression and anxiety in offspring, highlighting hyperglycemia as a key modulator of neurobehavioral trajectories11. The Developmental Origins of Health and Disease hypothesis proposes that prenatal and early postnatal adversities elevate the risk of diseases across the lifespan12,13. As the neural networks responsible for regulating emotions and behavior are primarily programmed during prenatal development, exposure to suboptimal intrauterine conditions may increase the likelihood of mental health disorders later in life6,14. The hippocampus, a brain region central to emotional regulation and stress resilience, is particularly vulnerable to such developmental programming15. Neural stem cells (NSCs) in the hippocampal dentate gyrus (DG) subgranular zone (SGZ) continuously self-renew and differentiate throughout life, contributing to the formation of functional neural circuits critical for emotional regulation16,17. Disruptions in this process can impair neurogenesis, which has been implicated in the pathophysiology of neuropsychiatric disorders18–20. However, whether and how GDM, as a prenatal stressor, induces longterm depressive- and anxiety-like behaviors in offspring via hippocampal neurogenic impairment remains poorly understood. In this study, we established a GDM mouse model to investigate the effects of intrauterine hyperglycemia on depressive- and anxiety-like behaviors in adult offspring. We also longitudinally tracked hippocampal neurogenesis across developmental stages and explore the potential mechanisms underlying these behaviors, with a focus on neurometabolic changes and oxidative stress. MATERIALS AND METHODS Animals Eight-week-old female C57BL/6J mice (18–22 g) were purchased from Hunan SJA Laboratory Animal Co. The mice were housed in a controlled environment at 22–24 °C with 40–60% humidity and a 12-h light/dark cycle. Mice were allowed to acclimatize for 1 week before the experiment, with free access to food and water throughout the study. All animal experiments were conducted in accordance with the guidelines of the Laboratory Animal Welfare and Ethics Code. All experimental protocols in this study were approved by the Animal Ethical and Welfare Committee of the First Affiliated Hospital of Chongqing Medical University (approval no. IACUC-2022-K410). Female C57BL/6J mice were randomly assigned to either the GDM group or (...truncated)