Journal Article

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

He, Jie, Ding, Yubin, Ge, Huisheng, Fang, Jie, Wu, Xiafei, Xu, Hongbing, Zhao, Yangyu, Baker, Philip N., Yu, Xinyang, Qi, Hongbo

2026

Overview

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. 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. Sex-specific effects of GDM on offspring neurogenesis Gestational diabetes mellitus (GDM), a condition of glucose intolerance first identified during pregnancy, affects about 15% of pregnant women globally, posing risks to both maternal and offspring health. This study explores how GDM impacts neurodevelopment, particularly focusing on depressive- and anxiety-like behaviors in offspring. Using a GDM mouse model, researchers tracked hippocampal neurogenesis and examined neurometabolic changes and oxidative stress. The results showed that GDM selectively induces depressive-like behaviors in female offspring, linked to impaired neurogenesis and reduced synaptic plasticity in the hippocampus. Notably, female offspring exhibited decreased dendritic complexity and reduced levels of neurotransmitters such as serotonin and dopamine. These findings highlight the sex-specific impact of GDM on neurodevelopment, with potential implications for understanding the developmental origins of neuropsychiatric disorders. Future research could explore therapeutic interventions targeting metabolic-neural pathways to mitigate these effects. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Korean Society for Biochemistry and Molecular Biology,Nature Publishing Group,생화학분자생물학회
• Subject: 101/58 / 13/100 / 14/19 / 631/136/368/2430 / 64/60 / 692/163/2743/137 / Animals / Anxiety / Artificial intelligence / Behavior / Biomedical and Life Sciences / Biomedicine / Cell Differentiation / Cell Proliferation / Developmental Origins of Health and Disease / Developmental stages / Diabetes mellitus / Diabetes, Gestational - metabolism / Diabetes, Gestational - physiopathology / Diet / Diet, High-Fat - adverse effects / Disease Models, Animal / Embryos / Female / Females / Gestational diabetes / Glucose / Glucose tolerance / Hippocampus / Hippocampus - metabolism / Hippocampus - pathology / Hyperglycemia / Insulin / Laboratory animals / Male / Maternal behavior / Medical Biochemistry / Mental disorders / Metabolism / Mice / Molecular Medicine / Neural stem cells / Neural Stem Cells - metabolism / Neurodevelopment / Neurogenesis / Nutrient deficiency / Nutrition research / Offspring / Oxidative stress / Pregnancy / Pregnancy complications / Prenatal development / Prenatal Exposure Delayed Effects - metabolism / Sex / Sex Characteristics / Sex differences / Software / Stem Cells / Sucrose / Synaptic plasticity / Therapeutic applications / Therapeutic targets / Weaning / 생화학