Human blood-derived neural progenitor cells as a platform for developmental neurotoxicity of micro- and nanoplastics.

Micro- and nanoplastics (MNPs) are increasingly detected in human tissues, including the placenta and brain, raising concerns about their potential impact on early neurodevelopment. However, mechanistic insight is limited by the lack of human-relevant, scalable test systems for developmental neurotoxicity (DNT). Here, we establish and apply a peripheral blood-derived human neural progenitor cell (NPC) platform as a reproducible in vitro model to evaluate MNP-induced DNT under low-dose conditions reflecting currently available estimates of human exposure. Using this system, we systematically investigated the effects of 2 µm, 100 nm, and 20 nm polystyrene particles and polyester microfibers over a 21-day neuronal differentiation paradigm. The model enables simultaneous assessment of key DNT endpoints, including neuronal differentiation, neurite outgrowth, cell cycle progression, and oxidative stress. MNP exposure impaired neuronal maturation in a size- and shape-dependent manner, reducing neurite outgrowth and βIII-tubulin (TUJ1) expression. Nanoscale particles were efficiently internalized and localized to endo-lysosomal compartments, whereas micron-sized particles remained primarily surface-associated. Mechanistically, MNP exposure induced mitochondrial oxidative stress, decreased superoxide dismutase 2 expression, and disrupted cell cycle exit, resulting in sustained progenitor proliferation. Importantly, pharmacological scavenging of reactive oxygen species with N-acetyl-L-cysteine rescued differentiation deficits and normalized cell cycle dynamics, demonstrating a causal role for redox imbalance. Together, these findings validate peripheral blood-derived human NPCs as a sensitive and scalable platform for DNT assessment and provide mechanistic evidence that MNPs impair early human neurodevelopment through size-dependent uptake and oxidative stress pathways.