Integrated 3D human cerebral organoids and paediatric patient serum analysis reveals mechanisms and biomarkers of anaesthetic-induced neurotoxicity. Br J Anaesth 2026 Mar;136(3):915-932
Date
11/01/2025Pubmed ID
41173771Pubmed Central ID
PMC12718073DOI
10.1016/j.bja.2025.08.064Scopus ID
2-s2.0-105020434190 (requires institutional sign-in at Scopus site)Abstract
BACKGROUND: General anaesthetics are essential for paediatric surgery but have been associated with neuronal injury and long-term cognitive deficits, thereby raising concerns over neurodevelopmental safety. However, the molecular mechanisms underlying anaesthetic-induced developmental neurotoxicity remain poorly understood.
METHODS: Human cerebral organoids derived from induced pluripotent stem cells were exposed to propofol (1-6 h; single or repeated exposures). In parallel, serum samples were collected from paediatric patients (age: <4 yr; n=10 per group) undergoing short (<1 h) or prolonged (>3 h) anaesthetic procedures. Organoid pathology and mitochondrial function were assessed using chemical assays, electron microscopy, and immunoblotting. Genome-wide profiling of 18 855 coding RNAs (mRNAs) and 27 427 long noncoding RNAs (lncRNAs) was performed by microarray analysis.
RESULTS: Propofol exposure increased apoptosis (1.9 [0.3] vs 1.0 [0.1]; P=0.0173) and autophagy (0.78 [0.12] vs 0.45 [0.09]; P=0.028) in organoids, and dysregulated 553 mRNAs and 792 lncRNAs linked to synaptic function, mitochondrial activity, and inflammation. ATP production (P=0.045), and expression of CKMT1B (P=0.002) and synaptic markers PSD95 and c-Fos were reduced. Serum from children exposed to prolonged anaesthesia showed elevated neuronal injury markers and 33 overlapping dysregulated RNAs (21 mRNAs, 12 lncRNAs), including CKMT1B. Bioinformatics revealed enrichment of these dysregulated lncRNA-mRNA networks in pathways related to cell injury, neurodevelopment, and cognition.
CONCLUSIONS: This study establishes a human-relevant model of anaesthetic-induced developmental neurotoxicity by integrating human organoids with clinical serum profiling. Propofol exposure led to mitochondrial dysfunction and disruption of coding RNA and lncRNA networks involved in neuronal development and injury. Concordant gene signatures (e.g. CKMT1B) across models highlight their potential as translational biomarkers and therapeutic targets.
Author List
Pant T, Jiang C, Yan Y, Schultz B, Laws D, Logan S, Bedrat A, Juric M, Berens RJ, Taylor SP, Henry AM, Mohiuddin A, Bosnjak ZJ, Bai XAuthors
Richard J. Berens MD Professor in the Anesthesiology department at Medical College of WisconsinZeljko Bosnjak PhD, MS Emeritus Professor in the Medicine department at Medical College of Wisconsin
Tarun Pant Postdoctoral Researcher 4 in the Surgery department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Anesthetics, IntravenousApoptosis
Biomarkers
Brain
Child, Preschool
Female
Humans
Induced Pluripotent Stem Cells
Infant
Male
Mitochondria
Neurotoxicity Syndromes
Organoids
Propofol
