A Western-style diet shapes the gut and liver responses to low-dose, fit-for-purpose polystyrene nanoplastics in mice

Abstract

Nanoplastics (NPLs) are an emerging global health concern, yet their toxicological impact remains uncertain, particularly among at-risk populations who are more susceptible to environmental stressors. While research on NPLs is expanding, most studies use commercial particles containing chemical additives, making it difficult to distinguish the effects of the polymer itself in its particulate form from those of confounding substances. In this study, we investigated the toxicity of fit-for-purpose, gold-labelled polystyrene NPLs (PS-NPLs; ~600 nm) in mice exposed via drinking water at literature-informed doses (0.1, 1, and 10 mg/kg/day) for 90 days, under either chow diet (CD) or Western diet (WD) conditions. Using ICP-MS, PS-NPLs were detected and quantified in intestinal contents. Moreover, low-dose exposure (0.1 or 1 mg/kg/day, depending on diet and endpoint considered) resulted in increased body weight gain, altered mucus quality (i.e. shift in mucin O-glycan profiles), and subtle impairment of gut barrier integrity in a diet-dependent manner. Low-dose exposure also altered the gut microbiota composition in both diet groups, with diet-specific profiles, and shifted caecal metabolomic signatures only in CD-fed mice. Metabolically, low-dose PS-NPL exposure exacerbated glucose intolerance in WD-fed mice and promoted hepatic lipid accumulation and a shift in droplet size, regardless of diet. Overall, these findings demonstrate that PS-NPLs, in their particulate form and in the absence of confounding additives, can induce non-monotonic, diet-modulated effects on the gut and liver. This highlights the importance of considering particle behaviour in complex biological environments and of including both healthy and at-risk populations in NPL toxicity assessments.