Integrative lipidomic and transcriptomic analysis unraveled polystyrene nanoplastics-induced liver injury via oral and inhalation exposure: All roads lead to Rome?

The ubiquitous environmental presence of nanoplastics (NPs) necessitates urgent investigation into their biological impacts. As the primary target organ for accumulated NPs, the liver faces substantial health risks, but the differential hepatotoxic effects of different exposure routes remain unknown. In this study, a four-week exposure experiment in mice using polystyrene nanoplastics (PS-NPs) through oral and inhalation routes were conducted. Multidimensional assessments revealed exposure route-specific pathological patterns: oral administration primarily caused histopathological damage, whereas inhalation exposure induced more severe hepatic synthetic impairment and systemic inflammatory responses. Transcriptomic profiling identified 739 and 1350 differentially expressed genes (DEGs) for oral and inhalation routes respectively, with merely 17% overlap (228 DEGs), demonstrating fundamentally distinct molecular responses. Pathway enrichment analysis further indicated substantial disruption of lipid metabolism processes. Lipidomic analysis revealed that PS-NPs caused wide hepatic lipid profile alterations, 693 and 882 lipids were significantly changed after oral and inhalation exposure, mainly focused on Glycerophospholipids (GPs) and Glycerolipids (GLs). Further integrated multi-omics approaches revealed route-dependent metabolic reprogramming: oral exposure decreased Diacylglycerols (DG) and Phosphatidic acids (PA) through enhanced lipid hydrolysis and suppressed PA biosynthesis, while inhalation exposure remarkably elevated these lipid species. Notably, inhaled PS-NPs significantly increased polyunsaturated fatty acid (PUFA) levels, showing strong correlation with lipid peroxidation markers. This study provides the first experimental evidence of exposure route-dependent hepatotoxicity mechanisms for PS-NPs, elucidating distinct molecular pathways in nanoplastic-induced liver injury and revealing route-specific lipid metabolic disturbances, thereby offering crucial insights for environmental risk assessment and targeted preventive strategies.