Mechanisms Underlying the Size-Dependent Neurotoxicity of Polystyrene Nanoplastics in Zebrafish

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Nanoplastics (NPs) are ubiquitous in the environment, posing significant threats to biological systems, including nervous systems, across various trophic levels. Nevertheless, the molecular mechanisms behind the size-dependent neurotoxicity of NPs remain unclear. Here, we investigated the neurotoxicity of 20 and 100 nm polystyrene NPs (PS-NPs) to zebrafish. Utilizing molecular dynamics simulations and complementary methods, we discovered that PS-NPs initiated neurotoxicity by promoting dimerization of the toll-like receptor 4/myeloid differentiation-2 (TLR4/MD-2) complex. This process involves the binding of PS-NPs to the hydrophobic pocket of MD-2, which induced the flipping of Phe-126 toward the dimer interface and the bending of the C-terminal domain of TLR-4, bringing the two domains into close proximity. Thereafter, the astrocytes and microglia were activated, initiating a cascade of events that include neuroinflammation, central nervous system cell apoptosis, inhibition of motor neuron development, and ultimately alteration of the swimming behavior of zebrafish. Further, 20 nm PS-NPs elicited more severe neurotoxicity than 100 nm PS-NPs, attributed to their higher accumulation in the brain as determined through 14 C-labeled PS-NPs and more effective interaction with the TLR4/MD-2 complex. Overall, our study uncovers the mechanisms underlying the size-dependent neurotoxicity of NPs, which merit attention during their risk assessment and regulation.

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