Hepatotoxic mechanisms of functionalized nanopolystyrene: decoding the role of ionic surface groups

BACKGROUND: With annual global plastic production exceeding 400 million tons, nanoscale polystyrene particles (nPS) have become a major health concern due to their bioaccumulation capacity and ability to cross biological barriers. Surface-charged nPS variants (cationic, anionic, and neutral) show distinct biodistribution patterns, yet the mechanisms underlying their systemic damage remain incompletely understood. This study aimed to investigate the systemic injury mechanisms of nPS with different surface charges. METHODS: Mice were exposed to fluorescently labeled cationic (amino-modified), anionic (carboxyl-modified), and neutral nPS via drinking water (25 mg/mL) for 3 weeks. Tissue distribution was analyzed using fluorescence microscopy; pathological changes were assessed via hematoxylin-eosin (HE) staining; metabolic perturbations were detected by metabolomic profiling. Mechanistic investigations were performed using metabolomics, flow cytometry, and molecular assays in AML12 hepatocytes and vascular endothelial cells. RESULTS: Fluorescence microscopy showed neutral nPS accumulated in the vascular endothelium of the stomach, intestine, and lung via passive diffusion, while cationic/anionic nPS penetrated hepatic sinusoids through charge-mediated interactions. HE staining revealed severe liver injury, with no significant abnormalities in other tissues. Metabolomic profiling indicated disrupted hepatic amino acid and lipid metabolism, depleted antioxidants (e.g., vitamin E and glutathione), and induced oxidative stress (evidenced by elevated hydroxy fatty acids). In hepatocytes, nPS-induced endoplasmic reticulum (ER) stress triggered excessive reactive oxygen species (ROS) production, inhibiting SLC7A11-mediated cystine uptake and glutathione synthesis, leading to disulfide stress (β-actin disulfide mispairing) and ferroptosis (GPX4 inactivation and iron accumulation). In contrast, neutral nPS induced endothelial cell senescence via phagolysosome dysfunction, causing lysosomal membrane permeabilization and β-galactosidase release. CONCLUSIONS: This study identifies a "charge-specific injury" paradigm: charged nPS induce hepatocyte ferroptosis via an ER stress-disulfide stress cascade, while neutral nPS trigger endothelial senescence through phagocytic dysfunction. These findings provide critical insights for the biosafety assessment of nanoplastics and identify potential targets for preventing plastic pollution-related liver diseases.