Climate‐Modulated Particle Toxicity: Acute Exposure to an Environmentally Informed Microplastic Mixture Induces Sex‐Dependent Systemic Reorganization in Swiss Mice

Microplastic (MP) pollution is widely recognized as an emerging environmental threat. Yet, most studies still rely on controlled experimental conditions that poorly reflect environmental complexity, potentially underestimating risks under realistic scenarios, particularly during short-term exposures. Here, we tested whether acute oral exposure to an environmentally relevant mixture of MPs (PE, PS, PP, and PVC) induces physiological changes in Swiss mice under contrasting climate regimes. Males and females were exposed for 7 days to two MP doses (8 and 80 mg/kg/day) under a realistic thermal regime with gradual, predictable fluctuations and a pessimistic regime characterized by abrupt, unpredictable temperature shifts. MPs accumulated in the liver primarily as a function of exposure group and sex, with scenario-related differences detected in specific sex/exposure contrasts, alongside alterations in oxidative stress and biotransformation biomarkers, including ROS, MDA, SOD, CAT, and GST. Behavioral alterations, including changes in locomotion and anxiety-like responses, also varied according to the interaction between dose and thermal regime. Multivariate analyses (Permutational Multivariate Analysis of Variance, Principal Coordinates Analysis, multivariate trajectories, and Distance to Control) showed clear separation among groups and greater deviation from controls, particularly in males under the pessimistic regime. Partial Least Squares Discriminant Analysis identified key biomarkers linked to redox balance, energy metabolism, and neurochemical regulation. At the same time, network analysis suggested correlation-based changes in physiological integration under more stressful conditions. Together, our results show that acute MP exposure can induce measurable systemic physiological shifts under dynamic environmental conditions. The findings indicate that MP toxicity is strongly context-dependent and may be underestimated by conventional approaches, underscoring the need for more integrative and ecologically realistic ecotoxicological frameworks.