Polystyrene nanoplastics exposure induces reproductive toxicity in male mice associated with the gut-liver/testis axis.

Environmental nanoplastics are increasingly prevalent in global environments and represent an emerging systemic health risk, yet the mechanistic links between nanoplastic exposure and multi-organ dysfunction in mammals remain incompletely characterized. We integrated phenotypic assessments, gut shotgun metagenomics, and dual-organ transcriptomics to investigate the toxic effects of 28-day oral exposure to polystyrene nanoplastics (PS-NPs) in male CD-1 mice. PS-NPs induced a non-monotonic dose-dependent response, characterized by significant body weight loss at high doses, severe impairment of sperm motility, and progressive epididymal histopathological lesions. Gut metagenomics revealed significant microbiota dysbiosis, including an elevated Firmicutes/Bacteroidota ratio and marked depletion of beneficial commensal bacteria such as Ligilactobacillus murinus. Hepatic transcriptomics identified dysregulation of metabolic, detoxification, and circadian rhythm pathways, while testicular transcriptomics identified sustained transcriptional downregulation of genes annotated to steroid hormone biosynthesis and alterations in FoxO and apoptosis-related signaling. Spearman correlation network analysis identified associations between specific microbial shifts and organ-specific transcriptional alterations, providing a hypothesis-generating framework for the proposed gut-liver/testis axis. Together, these findings indicate that, under the present experimental conditions, oral PS-NPs exposure was associated with gut microbial dysbiosis, hepatic transcriptional perturbations, reduced sperm motility, and epididymal histopathological alterations, while the mechanistic relationships among these changes require further experimental validation.