Distinctive respiratory toxicity induced by hypoxanthine metabolic disorder from polystyrene microplastics and nanoplastics at environmentally relevant doses: multi-omics insights and experimental validation

Microplastics (MPs) and nanoplastics (NPs) are pervasive environmental contaminants, raising concerns about their potential to cause inflammation, oxidative stress, and lung injury through respiratory toxicity. Due to their smaller size, larger surface area, and greater reactivity, NPs may pose a greater risk than MPs, yet size-dependent toxicity mechanisms remain unclear. This study investigates the distinct early molecular initiating events and toxicological effects of 1 μm polystyrene MPs (PS-MPs) and 20 nm polystyrene NPs (PS-NPs). Based on the internal exposure dose estimated from Py-GC/MS analysis, in vitro exposure concentrations were set at 0, 62.5, 125, 250, 500, and 1000 μg/mL. Multi-omics sequencing and integrative analysis identify specific proteomic and metabolomic alterations. Molecular dynamics simulations and co-immunoprecipitation assays elucidate binding interactions between PS-NPs-induced proteins and metabolic enzymes. In vitro and in vivo experiments reveal a greater accumulation of PS-NPs through endocytosis compared to PS-MPs; while pronounced histopathological damage with inflammatory response in mice lungs were only induced by PS-NPs, rather than PS-MPs. Compared to control group, PS-MPs partly caused proteomic or metabolomic perturbations, while PS-NPs induced significant differential expression of more extensive proteins and metabolites. PS-NPs exposure specifically upregulates insulin-like growth factor 2 receptor (IGF2R) expression and reduces Hypoxanthine levels when compared with PS-MPs. IGF2R directly interacts with Hypoxanthine-guanine phosphoribosyl transferase (HPRT), a key enzyme in Hypoxanthine metabolism, causing its disruption. This study provides important insights into the comparative toxic effects between PS-NPs with PS-MPs, especially the unique toxicological mechanisms of PS-NPs, thereby advancing the understanding of airborne plastic pollutant risks and supporting future regulatory assessments.