50 Chronic PET nanoplastics ingestion triggers genotoxic and immune responses disrupting gut and systemic homeostasis

Abstract Environmentally ubiquitous polyethylene terephthalate (PET) nanoplastics (NPs) can traverse biological barriers and engage immune pathways, yet their impact on gut and systemic homeostasis remains poorly understood. Here, we investigated the genotoxic, inflammatory, and mucosal responses in C57BL/6 mice following 7-d oral gavage to graded doses of bottle-derived PET NPs (50 to 150 nm; 0.6, 3, and 15 mg/kg bw). Primary (jejunum and distal colon) and secondary (liver and mesenteric lymph nodes) tissues were analysed for histological, transcriptional, immunophenotypic, and genotoxic responses over 28 d post-exposure. In the jejunum, PET exposure caused persistent dose-dependent DNA damage (1.5-fold at high dose) with activation of repair genes (ATM and Ogg1). This genotoxic stress coincided with early inflammatory responses (Nos2, IL-10) which resolved by day 28 with Arg1 upregulation, goblet-cell hyperplasia, and elevated Muc2 expression, indicating epithelial reinforcement across all doses. High-dose exposure caused mild hepatic inflammation with antioxidant responses until day 7, while low doses showed maximum antioxidant activity. At high doses, mesenteric lymph nodes exhibited immune suppression (CD4⁺ T-cell loss), while the distal colon developed a chronic inflammatory phenotype (Il-4, Tnf-α) by day 28. CD4⁺ T-cell reduction in lymph nodes and concurrent IL-4 upregulation in the distal colon may suggest Th2-type recruitment at high doses, a hypothesis that warrants further investigation. At low and medium doses, these molecular and tissue-level responses resolved early. Our findings reveal dose-dependent gut adaptation and systemic toxicity to environmentally realistic PET NPs, underscoring their relevance to human and occupational health risk assessment and for informing regulatory bodies.