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

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.