Exposure to polyethylene terephthalate nanoplastics elicits renal injury with limited compensation and associated intestinal alterations: A time-resolved multi-omics study

Polyethylene terephthalate nanoplastics (PET-NPs) are emerging contaminants of toxicological concern. However, the temporal progression of PET-NPs-induced renal injury during repeated oral exposure remains poorly understood. Male C57BL/6 J mice received PET-NPs at 50 mg/kg/day by oral gavage for 14, 28, or 56 days to characterize time-dependent nephrotoxicity and intestinal alterations. Fluorescence imaging detected gastrointestinal signals at all time points and a time-dependent increase in renal fluorescence following administration of Nile red-labeled PET-NPs. PET-NPs exposure was associated with impaired intestinal barrier integrity and altered gut microbial composition. Renal assessments revealed functional impairment, tubular injury, inflammatory activation, oxidative stress, and lipid peroxidation. Integrated renal transcriptomic and metabolomic analyses identified alterations in inflammatory signaling, redox homeostasis, oxidative phosphorylation, and lipid metabolism. Mean TUNEL positivity was numerically highest at 28 days and remained elevated relative to controls at 56 days. At 56 days, tubular injury, renal dysfunction, and inflammation persisted alongside increased Ki-67 positivity. Although the renal Nrf2/HO-1/GPX4 antioxidant axis was activated, glutathione depletion, lipid peroxidation, and renal injury indicated insufficient antioxidant compensation. Repeated oral PET-NPs exposure elicited time-dependent nephrotoxicity characterized by inflammatory-redox-lipid metabolic remodeling and constrained antioxidant compensation. These findings provide a time-resolved multi-omics framework for assessing PET-NPs-associated renal hazards following repeated oral exposure.