Single-cell RNA sequencing reveals cadmium-induced cell-type-specific mechanisms of developmental neurotoxicity in human cortical organoids.

Fetal brain development is crucial for lifelong neurological health, yet the impact of environmental heavy metal pollutants such as cadmium (Cd) remains incompletely understood. As a typical environmental heavy metal pollutant, Cd is widely encountered by various populations, including pregnant women, and disrupts zinc and copper ion homeostasis-processes essential for fetal brain development. However, cell-type-specific vulnerabilities underlying Cd-induced developmental neurotoxicity have been underexplored in human models. In this study, we employed cortical organoids with single-cell RNA sequencing (scRNA-seq) to evaluate the Cd-induced cell-type-specific developmental neurotoxicity and elucidate molecular mechanisms. scRNA-seq revealed that Cd exposure induced cell cycle arrest concurrent with zinc and copper ion dyshomeostasis in proliferating neural populations, inducing the loss of inhibitory neurons. Mechanistically, Cd activated ribosome biogenesis and mitochondrial energy metabolism across all cell types, while enhancing Cd2+ detoxification in astrocytes and inducing astrocyte dysfunction. Furthermore, Cd disrupted axon guidance as evidenced by decreased axonal growth length and enhanced aberrant intercellular communication via robust binding Glu and Asp of PSMD2, TUBA1B and CFL1. Finally, MEA assays revealed that Cd exposure impaired neural network activity in cortical organoids. Our study reveals previously unrecognized mechanisms by which environmentally relevant cadmium disrupts human corticogenesis at the single-cell level, providing compelling evidence for the developmental neurotoxicity of this ubiquitous pollutant and supporting efforts to reduce prenatal Cd exposure for lifelong neurological health.