Silver Brian B, Fannin Rick, Gerrish Kevin, Tokar Erik J
Mechanistic Toxicology Branch, DNTP, NIEHS, Research Triangle Park, NC, United States.
Molecular Genomics Core, DIR, NIEHS, Research Triangle Park, NC, United States.
Curr Res Toxicol. 2025 Mar 8;8:100229. doi: 10.1016/j.crtox.2025.100229. eCollection 2025.
Environmental toxicants can contribute to the development of several neurodegenerative diseases. However, the mechanisms behind this pathology are still incompletely understood. Prompt diagnosis of impending neurodegeneration is crucial for early interventions to prevent cognitive decline. Towards this end, accurate biomarkers for early neurodegenerative processes and exposure risk are needed. Extracellular vesicles (EVs) are lipid particles released by cells which contain many bioactive molecules including miRNAs. EVs may serve both as a route of propagating neurotoxic phenotypes and as a source of biomarkers for neurological disease. However, the exact mechanisms though which EVs could spread the deleterious effects of toxicants and the full spectrum of their usage as biomarkers remain unclear. Organoid models have several advantages, including potential for use in high-throughput toxicant testing and applications in personalized medicine and disease models. However, few studies have examined EV release in brain organoids to determine if the EVs could contain useful biomarkers. We employed several technologies to characterize EVs released by human cerebral organoids and their associated miRNAs. We identified that cerebral organoids consistently release EV-associated miRNA in quantities sufficient for robust analysis with NanoString. Further, pathway analyses revealed that terms related to neurodegenerative disease and nervous system signaling are associated with the recovered miRNAs. Together, these data suggest that cerebral organoids have utility as a tool for the discovery of EV-associated miRNAs involved in neurodegenerative disease and neurotoxicity.
环境毒物可促使多种神经退行性疾病的发生。然而，这种病理背后的机制仍未完全明确。对即将发生的神经退行性变进行及时诊断对于预防认知能力下降的早期干预至关重要。为此，需要用于早期神经退行性过程和暴露风险的准确生物标志物。细胞外囊泡（EVs）是细胞释放的脂质颗粒，其中包含许多生物活性分子，包括微小RNA（miRNAs）。EVs既可以作为传播神经毒性表型的途径，也可以作为神经疾病生物标志物的来源。然而，EVs传播毒物有害作用的确切机制以及它们作为生物标志物的全部用途仍不清楚。类器官模型具有多个优点，包括可用于高通量毒物测试以及在个性化医学和疾病模型中的应用潜力。然而，很少有研究检测脑类器官中EVs的释放情况，以确定这些EVs是否可能包含有用的生物标志物。我们采用了多种技术来表征人脑类器官释放的EVs及其相关的miRNAs。我们发现脑类器官持续释放与EV相关的miRNAs，其数量足以用NanoString进行可靠分析。此外，通路分析显示，与神经退行性疾病和神经系统信号传导相关的术语与回收的miRNAs有关。总之，这些数据表明脑类器官可作为一种工具，用于发现参与神经退行性疾病和神经毒性的与EV相关的miRNAs。
