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Updated: Aug 4, 2026
Generation of iPSC-derived Human Brain Organoids to Model Early Neurodevelopmental Disorders
Published on: April 14, 2017
Developmental stage-dependent neurotoxicity of sevoflurane: evidence from brain organoids
Niqi Chen1, Yanting Zhang1, Yeru Chen1,2
1Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Insights
Sevoflurane anesthesia in children may affect brain development by disrupting progenitor zones and differentiation. Human brain organoids reveal dose-dependent neurotoxic mechanisms, aiding risk assessment for anesthetic planning.
Area of Science:
- Neuroscience
- Developmental Biology
- Anesthesiology
Background:
- Sevoflurane is a common pediatric anesthetic, but concerns exist regarding its impact on developing brains.
- Experimental data suggest sevoflurane affects mitochondrial function, oxidative stress, and immune responses.
Purpose of the Study:
- To review the developmental stage-dependent effects of sevoflurane on the brain.
- To highlight the utility of human brain organoids in dissecting sevoflurane's neurotoxic mechanisms.
- To propose a framework for understanding and stratifying sevoflurane neurotoxicity risk.
Main Methods:
- Review of experimental data on sevoflurane's effects on neural development.
- Analysis of studies using human brain organoids (cortical and midbrain-like) to model sevoflurane exposure.
- Synthesis of molecular, cellular, and electrophysiological findings from organoid models.
Main Results:
- Sevoflurane exposure in brain organoids alters progenitor zones, disrupts cell migration and division, and accelerates differentiation.
- Organoids exhibit molecular and electrophysiological signatures of mitochondrial stress, iron dysregulation, and inflammation.
- Exposure intensity and duration correlate with the severity of observed neurodevelopmental changes.
Conclusions:
- Human brain organoids provide valuable in vitro models for studying sevoflurane's neurodevelopmental toxicity.
- Findings from organoids parallel clinical observations of subtle neurocognitive deficits associated with prolonged or repeated anesthetic exposure.
- Future organoid models with increased maturity and complexity, integrated with clinical data, can refine anesthetic risk assessment.
Abstract:
Sevoflurane is widely used in pediatric anesthesia because it allows rapid induction and recovery, yet its use during vulnerable periods of brain development has raised concerns about long-term neurocognitive effects. Experimental data indicate that sevoflurane engages multiple interacting pathways, including mitochondrial dysfunction, oxidative and iron-dependent injury, and immune-mediated synaptic and inflammatory responses, whose net impact depends on dose, timing, and exposure duration. Human brain organoids have meanwhile emerged as human-based three-dimensional models that reproduce key aspects of cortical and midbrain development and permit clinically relevant exposure paradigms to be tested in vitro. In both cortical-like and midbrain-like organoids, sevoflurane narrows and disorganizes progenitor zones, disrupts interkinetic nuclear migration, reduces apical mitoses, and accelerates neuronal or dopaminergic differentiation, with more pronounced changes after more intense exposure. These architectural alterations are accompanied by molecular and electrophysiological signatures of mitochondrial stress, iron dysregulation, and inflammatory activation, forming multidimensional "injury fingerprints" that parallel clinical observations that single, brief anesthetics rarely cause overt global decline, whereas repeated or prolonged anesthetics are associated with subtler, domain-specific deficits. This review synthesizes current evidence on the developmental stage-dependent effects of sevoflurane and highlights how brain organoids are being used to dissect underlying cellular and molecular mechanisms. It also discusses key limitations of current organoid systems and considers how more mature, vascularized, and microglia-containing models, integrated with perioperative cohorts and targeted interventions, may eventually inform exposure-aware anesthetic planning without delaying necessary surgery. Overall, this review advances a developmental stage-aware, organoid-centered conceptual framework that integrates animal and human-based evidence to better understand and stratify the risk of sevoflurane-induced neurotoxicity.
