Short-term PS-NP exposure in early adulthood induces neuronal damage in middle-aged mice via microglia-mediated neuroinflammation

Nanoplastics (NPs) are ubiquitous environmental pollutants that have garnered considerable attention for their potential adverse health effects. In this study, male C57BL/6 J mice were orally treated with a mixture of 50-nm and 200-nm polystyrene (PS)-NPs for one week followed by measurements of their neurobehavioral performance and neuronal damage 10 months later. Notably, PS-NPs were detected in the brains of the mice by transmission electron microscopy (TEM) and a nanoscale hyperspectral microscope imaging system 10 months after the PS-NP exposure. The mice exposed to short-term PS-NPs exhibited cognitive dysfunction and anxiety-like symptoms, neuronal damage and synapse loss, and an increase in the number of M1-polarized microglia and A1-reactive astrocytes. Interestingly, the inhibition of microglial activation by minocycline significantly mitigated the PS-NP-induced synapse loss and neuron damage. In vitro studies showed that PS-NPs could be readily internalized by three types of neurovascular unit (NVU) cells, including microglia, astrocytes, and brain microvascular endothelial cells, via multiple pathways. RNA-seq analysis confirmed that microglia-mediated neuronal injury was associated with disturbances in synapse and cell death signaling pathways. Collectively, these findings suggest that short-term PS-NP exposure-induced neuroinflammation in early adulthood may not be resolved naturally but may deteriorate under the interaction of microglia and astrocytes, leading to synapse loss, neuron degeneration, and cognitive dysfunction in middle age. The results of the present study provide important insights into the potential neurological impacts of NPs and suggest that targeting microglia to suppress inflammation might be a potential intervention strategy for neurodegeneration induced by NPs.