TLR4/NF-κB signaling in polystyrene nanoparticle-induced endometrial injury: evidence from transcriptomic profiling and pharmacological inhibition

Polystyrene nanoparticles (PS-NPs) have raised concerns regarding female reproductive toxicity, yet their endometrial effects and underlying mechanisms remain poorly understood. Primary human endometrial stromal cells (hESCs) and a mouse exposure model were used to characterize PS-NP-associated injury and changes in receptivity-related markers. Exploratory transcriptomic profiling in hESCs was followed by targeted evaluation of TLR4/NF-κB signaling and pharmacological intervention with TAK-242. PS-NP exposure increased reactive oxygen species accumulation, induced mitochondrial membrane depolarization and apoptosis, and reduced HOXA10, FOXO1, and ITGB3 expression in hESCs. Mouse uterine tissue showed concordant apoptosis-related changes and reductions in these proteins, while implantation sites were reduced at the higher PS-NP doses. Transcriptomic profiling highlighted innate immune and inflammatory responses, including Toll-like receptor and NF-κB signaling. Targeted analyses showed increased TLR4 and PTGS2 expression and elevated p-IκBα/IκBα and p-p65/p65 ratios in both models. TAK-242 attenuated NF-κB activation and apoptosis and mitigated reductions in HOXA10, FOXO1, and ITGB3 in hESCs. These findings support a contributory role for TLR4/NF-κB signaling in PS-NP-induced endometrial stromal cell injury and disruption of a receptivity-associated molecular profile.