Polystyrene nanoplastics induce ovarian injury by PI3K-Akt pathway-driven macrophage extracellular trap formation

Nanoplastics (NPs), an emerging and increasingly prevalent environmental pollutant, pose a significant threat to organisms. Although recent research has begun to elucidate the mechanisms underlying ovarian toxicity induced by NPs, the involvement of cellular interactions, particularly those involving immune cells, in ovarian injury remains poorly understood. Here, we established a murine model exposed to polystyrene nanoplastics over an 8-week period to explore the role of macrophages in NPs-induced ovarian injury. Our in vivo results demonstrated that NPs accumulated in ovarian tissues, leading to ovarian endocrine disruption and follicular atresia, concomitant with macrophages infiltration and the formation of macrophage extracellular traps (METs). Complementary investigation using a co-culture system of macrophages and granulosa cells (GCs) indicated that NPs-induced METs triggered pyroptosis of GCs, and this biological crosstalk could be mitigated by DNase I. Further transcriptomic analysis revealed that NPs prompted macrophages to release METs through activating the PI3K-Akt signaling pathway. Notably, LY294002, a specific inhibitor of the PI3K-Akt pathway, significantly suppressed METs formation and consequently rescued GCs pyroptosis and ovarian injury induced by NPs. In summary, our findings uncover the mechanistic role of METs in exacerbating ovarian injury induced by NPs, and highlight the PI3K-Akt signaling pathway as a potential therapeutic target.