Gestational diabetes mellitus amplifies sevoflurane-induced developmental neurotoxicity in offspring mice

Gestational diabetes mellitus (GDM) may increase offspring susceptibility to neurodevelopmental stressors. Sevoflurane is widely used in pediatric anesthesia but carries potential neurotoxicity risks. This study investigated whether maternal GDM exacerbates sevoflurane-induced developmental neurotoxicity in offspring, and explored the underlying mechanisms related to neuroinflammation, microglial activation and mitochondrial dysfunction.

A mouse model of maternal GDM was established, and offspring received sevoflurane exposure during brain development. Cognitive function was assessed by behavioral tests. Neuronal apoptosis and dendritic spine morphology were detected by TUNEL and Golgi-Cox staining. Microglial activation and inflammatory profiles were analyzed using immunofluorescence and multiplex liquid-chip assays. Transcriptomic and proteomic analyses were integrated to identify dysregulated molecular pathways, and key proteins were verified by Western Blot.

Compared with control and single-treatment groups, combined GDM and sevoflurane exposure significantly worsened long-term cognitive impairment, promoted neuronal apoptosis, and reduced dendritic spine density in the hippocampus. The dual-hit induced robust microglial overactivation and disrupted inflammatory cytokine homeostasis. Multi-omics analyses revealed significant enrichment of pathways governing synaptic vesicle cycling, glutamatergic synaptic function, and immune-inflammatory responses. Mechanistically, the dual-hit caused severe mitochondrial dynamic imbalance characterized by downregulation of the fusion protein Mfn2, together with abnormal expression of the microglial receptor CX3CR1.

Maternal GDM exposure is associated with aggravated sevoflurane-induced developmental neurotoxicity in offspring. Our correlative findings suggest potential underlying links involving altered mitochondrial homeostasis and excessive microglial activation. This study provides potential targets for preventing anesthesia-related neurotoxicity in high-risk children.