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Gestational diabetes mellitus amplifies sevoflurane-induced developmental neurotoxicity in offspring mice
Xiaoru Sun1, Xin Fang1, Yun Pan1
1Department of Anesthesiology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, People's Republic of China.
Insights
Maternal gestational diabetes mellitus (GDM) combined with sevoflurane anesthesia worsens offspring neurodevelopmental outcomes. This exacerbates cognitive impairment and neuroinflammation, highlighting risks for high-risk children.
Area of Science:
- Neuroscience
- Developmental Biology
- Toxicology
Background:
- Gestational diabetes mellitus (GDM) may heighten offspring vulnerability to neurodevelopmental challenges.
- Sevoflurane, a common pediatric anesthetic, poses potential neurotoxicity risks.
Purpose of the Study:
- To determine if maternal GDM exacerbates sevoflurane-induced developmental neurotoxicity in offspring.
- To investigate mechanisms including neuroinflammation, microglial activation, and mitochondrial dysfunction.
Main Methods:
- Established a mouse model of maternal GDM and exposed offspring to sevoflurane during brain development.
- Assessed cognitive function, neuronal apoptosis, dendritic spine morphology, microglial activation, and inflammatory profiles.
- Utilized multi-omics (transcriptomics, proteomics) and Western Blot for pathway and protein analysis.
Main Results:
- Combined GDM and sevoflurane exposure worsened cognitive impairment, increased neuronal apoptosis, and reduced hippocampal dendritic spine density.
- Observed robust microglial overactivation, disrupted cytokine homeostasis, and mitochondrial dynamic imbalance.
- Identified altered synaptic function, immune-inflammatory pathways, Mfn2, and CX3CR1 expression.
Conclusions:
- Maternal GDM aggravates sevoflurane-induced developmental neurotoxicity in offspring.
- Findings suggest links to altered mitochondrial homeostasis and microglial activation.
- Identified potential targets for preventing anesthesia-related neurotoxicity in at-risk children.
Objective:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
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