Silica nanoparticles disrupt blood-testis barrier integrity in Sertoli cells by inducing inflammation-mediated p38 MAPK pathway.

Concerns have grown regarding the potential reproductive toxicity of silica nanoparticles (SiNPs), yet the mechanisms by which they compromise Sertoli cell barrier function remain incompletely understood. This study investigated the effects of SiNPs on mouse Sertoli cells (TM4) treated with escalating concentrations (0, 1, 10, 100 μg/mL) for 24 h, with or without the anti-inflammatory agent pirfenidone (PFD), the p38 MAPK inhibitor SB203580, or the clathrin-mediated endocytosis (CME) inhibitor Pitstop2. The results showed that SiNPs accumulated in the lysosomes of TM4 cells, leading to reduced cell viability and increased morphological abnormalities. In addition, SiNPs exposure decreased the expression of tight junction proteins, resulting in increased BTB permeability. Further investigation revealed that SiNPs triggered inflammatory responses and activated p38 MAPK signaling, which accelerated CME of membrane proteins while impairing their recycling back to the cell surface. Co-treatment with PFD, SB203580, or Pitstop2 reversed these SiNP-induced alterations. Collectively, these findings indicate that SiNPs compromise Sertoli cell monolayer integrity by inducing inflammation-mediated p38 MAPK activation, which in turn dysregulates clathrin-dependent endocytic recycling.