The crosstalk between M1 macrophage polarization and energy metabolism disorder contributes to polystyrene nanoplastics-triggered testicular inflammation

Ubiquitous microplastics have become a threat to animal and human health, due to their potential toxicity, persistent nature and consequent bioaccumulation. Supporting evidence elucidates that polystyrene nanoplastics (PS-NPs) can destroy blood-testis barrier integrity, thus causing testicular hypoplasia and impairment of spermatogenesis. Nevertheless, how PS-NPs modulate macrophage polarization-energy metabolism crosstalk has not been fully investigated in testicular tissue. Here, we observed that polystyrene PS-NPs exposure contributes to severe vacuolization in the seminiferous tubules, accompanied by apoptosis of testicular tissue and infiltration of M1 macrophages. Meanwhile, we found that PS-NPs could trigger the M1 polarization phenotype, which activated ROS-macrophage migration inhibitory factor (MIF)/NF-κB signaling that in turn induced apoptosis of GC2 cells in the GC2-macrophage cell coculture model. Simultaneously, we confirmed that PS-NPs exposure increased 3-phospho-D-glycerate, phosphoenolpyruvate and lactate concentrations, accompanied by decreased pyruvate and adenosine triphosphate (ATP) production, likely due to downregulated pyruvate kinase M2 (PKM2) dimer expression. In conclusion, the mechanism of PS-NPs-induced testicular inflammation can be mediated by promoting the infiltration of M1 macrophages, thereby resulting in an ROS burst and subsequent induction of energy metabolism disorders. The current study will provide new insights into PS-NPs-induced male reproductive toxicity and highlight the context-specific roles of testicular macrophages.