Brain organoids in environmental neurotoxicology: applications, mechanisms, and future perspectives

Overview

Human induced pluripotent stem cell-derived brain organoids represent an advancement in environmental neurotoxicology by providing human-relevant in vitro models that recapitulate key aspects of brain development including three-dimensional cytoarchitecture, cellular heterogeneity, and functional network activity. This review synthesizes current applications of brain organoids in toxicological assessment, examines mechanisms by which they elucidate adverse outcomes, and identifies critical directions for methodological refinement.

Methods and approach

The review systematically examines construction principles of hiPSC-derived brain organoids and their application to environmental neurotoxicology. Analysis encompasses the capacity of these models to identify adverse outcomes from chronic and low-dose environmental contaminant exposures, their integration within adverse outcome pathway frameworks, and technical advancement requirements including vascularization, automation, standardization, and artificial intelligence integration for data analysis.

Key Findings

Brain organoids demonstrate enhanced sensitivity in detecting subtle adverse outcomes from chronic, low-dose exposures to environmental contaminants compared to conventional approaches. Their three-dimensional architecture and multilineage cellular composition enable mechanistic deconstruction of complex toxicological pathways and precise tracing of adverse outcome pathways. Key advantages include reduced reliance on animal models, human-relevant biological context, and capacity to assess mixture exposures and species-specific vulnerabilities.

Implications

Brain organoids address critical limitations of traditional neurotoxicological models by bridging the species gap between animal and human biology, thereby improving hazard identification and risk characterization. Integration of organoid-derived data into adverse outcome pathway frameworks enhances mechanistic understanding of neurotoxicological processes, supporting transition toward more precise predictive toxicology paradigms.

Future advancement requires systematic enhancement of model complexity through vascularization and coupling with organ-on-a-chip technologies. Implementation of automation, standardization protocols, and artificial intelligence-driven data analysis infrastructure will improve throughput and reproducibility. Concurrent establishment of ethical oversight frameworks and international standardization guidelines is essential for translating these models into regulatory practice.