Recent evidence suggests that the prevalence of neurodevelopmental disorders is increasing in the last decades. Several studies have shown that this could be related to higher exposure to toxic chemicals that exert developmental neurotoxicity. However, the limitations in routine toxicity tests make it difficult to assess the dangers of all the existing chemicals. Nowadays, human iPSC are arising as a potential cost-effective alternative to build human platforms to perform toxicity assays. In this study, BrainSpheres, a human 3D platform based on multicellular brain spheroids derived from human iPSCs, is used to test rotenone's toxicity during neurodevelopment. The results showed that the toxicity of rotenone varies along the differentiation status, inducing higher oxidative stress levels at the early stages of the differentiation. Morphological analyses also showed that dopaminergic cells had higher sensitivity to rotenone's cytotoxicity than other cell types. Finally, the researchers show that exposure to rotenone induced changes in neurodevelopmental pathways that could potentially link to previously demonstrated effects of this toxic compound. Here, the BrainSpheres human platform is validated as a tool to study neurotoxicity and developmental defects, which is used to elucidate the neurotoxicity of rotenone and propose some key mechanisms associated to it.
Rotenone exerts developmental neurotoxicity in a human brain spheroid model
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