Organ-specific in vitro models for prediction of hazard assessment of nanomaterials

Organ-specific multicellular in vitro models are used to mimic the lung-blood-brain axis, and to assess the nanomaterials (NMs) safety in humans. We employed a triculture lung model, a whole-blood model, an astrocytes-neurons coculture to examine health outcomes by three cerium dioxide (CeO₂) NMs and silver (Ag) nanowires. Endpoints included cytotoxicity, gene expression, genotoxicity, inflammatory markers at the air-liquid interface (ALI), complement activation, and secondary toxicity in astrocytes-neurons coculture. Post-exposure, CeO₂-3.5 nm high-dose decreased cell viability, no DNA damage was detected. At epithelial-macrophages interface, CeO₂-50 nm upregulated surfactant protein A (SPA), cell surface death receptor (FAS), and heme oxygenase-1 (HMOX1), whereas CeO₂-3.5 nm downregulated SPA. Ag-nanowires upregulated HMOX1, macrophage inflammatory protein-1β (MIP-1β), granulocyte colony-stimulator factor (G-CSF), chemokine C-X-C-motif ligand 1 (CXCL1). At endothelial side, CeO₂-50 nm and - 3.5 nm, and Ag-nanowires upregulated HMOX1. In whole-blood model, CeO₂-3.5 nm high-dose reduced terminal complement complex (TCC) proteins, while CeO₂-50 nm and Ag-nanowires increased them. Nanomaterials activated CD11b⁺ on granulocytes and monocytes. Ag-nanowires conditioned-medium (CM) on astrocytes-neurons coculture, decreased cell viability. CeO₂-50 nm CM upregulated IL1β, NFκB, and HMOX1. Overall, CeO₂-3.5 nm exhibits lung toxicity; CeO₂-50 nm CM triggers inflammatory response and Ag-nanowires CM may induce cytotoxicity in brain cells.