Soman-induced neurotoxicity in human iPSC-derived cerebral organoids: A whole-transcriptome analysis of ceRNA regulatory networks

Traditional animal models present challenges in fully elucidating chemical-induced neurotoxicity and its underlying mechanisms in humans due to physiological and genetic differences between species. To transcend inherent species limitations, cerebral organoids were differentiated from human induced pluripotent stem cells as a human-relevant model to delineate the neurotoxic profile of soman, classified among the most potent organophosphorus nerve agents. Organoid cell diversity and architecture were assessed via immunofluorescence and single-cell RNA sequencing. A 24-hour soman exposure elicited significant nerve damage in cerebral organoids, characterized by TUNEL assay-confirmed apoptosis and Fluoro-Jade C-stained neuronal degeneration. Whole transcriptome sequencing revealed 1012 differentially expressed mRNAs, 78 differentially expressed miRNAs and 203 differentially expressed long non-coding RNAs between the soman-exposed and control groups. Bioinformatics research suggested that the differentially expressed mRNAs were linked to axon guidance, long-term potentiation, and calcium signaling pathways. Furthermore, we constructed a competive endogenous RNA network including lncRNAs, miRNAs, and mRNAs, identifying two hub lncRNAs, two hub miRNAs, and 16 key mRNAs. This regulatory network implicates soman neurotoxicity in neuroinflammation and synaptic plasticity alterations, while validating glutamate receptor dysregulation and calcium homeostasis disruption as critical pathological mediators. Concurrently, it identifies the associated lncRNAs and miRNAs as potential biomarkers and therapeutic targets for soman-induced neuronal injury. Our findings elucidate the neurotoxic effects of soman in cerebral organoids at tissue, cellular, gene expression, and regulatory network levels. This work advances our knowledge of the underlying biological processes of soman exposure by offering new insights into prospective biomarkers and treatment targets.