In vivo Inhalation Toxicity of Polystyrene Nanoplastic Particles: PSLT-Like Responses of Apical Endpoints and Transcriptomic Changes

Overall, the concordance between exposure concentration, retained lung burden, apical responses, and transcriptomic changes supports a PSLT-like, overload-associated interpretation of the findings. The study did not provide evidence for a PS-specific mode of inhalation toxicity under the conditions tested and demonstrates that integrating transcriptomics with apical endpoints can refine the mechanistic interpretation of particle-induced lung responses. Background Inhalation is a relevant route of exposure to micro- and nanoplastics (MNPs), yet it remains unclear whether inhaled polymer particles represent a distinct inhalation hazard or conform to established principles of poorly soluble low-toxicity particles (PSLTs). This study tested whether low-reactivity polystyrene (PS) particles elicit responses consistent with the PSLT paradigm, in which adverse pulmonary effects are expected primarily under conditions of excessive retained lung burden and impaired clearance. Methods Male Wistar rats were exposed nose-only to respirable agglomerates of PS particles at 5 and 50 mg/m ³ for 28 days, 6 hours/day and 5 days/week, followed by post-exposure periods of approximately five and 13 weeks. Apical endpoints, including bronchoalveolar lavage fluid parameters and histopathology, were evaluated together with transcriptomic analyses of lung and liver tissues. Results At 50 mg/m ³ , pulmonary effects including neutrophilic infiltration, type II pneumocyte and bronchiolo-alveolar hyperplasia, increased lung weight, and persistent particle-associated lung changes were observed, consistent with overload-associated responses. In contrast, no adverse apical effects occurred at 5 mg/m ³ , although transcriptomic alterations involving complement, coagulation, and lipid metabolism pathways were detected. These molecular changes occurred in the absence of adverse apical findings and are therefore interpreted as early exposure-related responses below the threshold for overt toxicity. In the liver, transcriptomic changes were limited, providing no evidence for relevant systemic toxicity. Conclusions