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Polystyrene Nanoplastics Accumulate in Murine Cortex and Induce Transient Microglial Activation via Endolysosomal Retention
Summary
Polystyrene nanoplastics accumulated in mouse cerebral cortex after 60 days of exposure and triggered microglial activation and thousands of differentially expressed genes, including downregulation of synaptic signaling genes, in a particle-size-dependent manner. These findings provide mechanistic evidence that nanoplastics can cross the blood-brain barrier, activate neuroinflammation, and disrupt neural function, raising serious concerns about long-term neurological health impacts from chronic plastic exposure.
Abstract Environmental degradation and accumulation of plastics results in micro- and nanoplastics (MNPLs) that are small enough to cross biological barriers, including the blood–brain barrier. Microglia, resident immune cells of brain, are critical regulators of neuroimmune homeostasis and represent a cellular target of nanoplastic exposure. In this study, we assessed the neurotoxic effects of two sizes of polystyrene nanoplastics (PS-NPs; 100 nm and 500 nm) using integrated in vivo and in vitro exposure and washout paradigms. In vivo exposure in mice (60 days; 0.15 or 1.5 mg/day) showed the accumulation of both PS-NP sizes in the cerebral cortex without histopathological damage. However, cortical microglia showed pronounced morphological remodeling, observed as increased expression of Iba1 and GFAP. Transcriptomic profiling of cortical tissue revealed a strong size-dependent response. The 100 nm PS-NP group revealed 18 DEGs (|log 2 FC| ≥ 2, padj < 0.05), whereas the 500 nm PS-NPs showed more than 4,000 DEGs, including upregulation of immune- and microglia-associated genes (CCL5, CXCL10, LCN2, LYZ2) and downregulation of synaptic and neuronal signaling genes (GRIN2B, SYN1, STX1B, MAP1B, ITPR1/2). In vitro assessment, using BV2 microglia cells, showed internalization of PS-NPs via the endolysosomal pathway, with strong co-localization to Rab7- and LAMP2-positive compartments and prolonged intracellular retention following exposure washout. Also, microglial activation markers (Iba1, CD68) exhibited a transient, size- and concentration-dependent increase, correlated with intracellular particle burden rather than cumulative exposure. Overall, these findings demonstrate that PS-NPs accumulate in brain, driving size-dependent microglia activation and transcriptomic reprogramming, even after cessation of exposure to PS-NPs. Highlights PS-NPs (100 nm and 500 nm) reach mouse cerebral cortex following 60-day oral exposure. PS-NPs were internalized by microglia; accumulated in endolysosomal compartments. PS-NP exposure induced transient microglial activation without sustained cytotoxicity. Microglial activation was correlated with intracellular PS-NPs burden. Transcriptomics revealed disruption of neuroimmune and microglial regulatory pathways.