Toxic effects of T i O 2 nanoparticles in primary cultured rat sertoli cells are mediated via a dysregulated C a 2+ / PKC /p38 MAPK / NF ‐κ B cascade

Although numerous studies have demonstrated that titanium dioxide nanoparticles (TiO 2 NPs) can be accumulated in various animal organs and can cause toxicity, there is currently only limited data regarding reproductive toxicity especially on the toxic mechanisms of TiO 2 NPs in Sertoli cells. In order to investigate the mechanism of reproductive toxicity, primary cultured rat Sertoli cells were exposed to 5, 15, or 30 μg/mL TiO 2 NPs for 24 h, and TiO 2 NPs internalization, expression of PKC (p‐PKC) and p38 MAPK (p‐p38 MAPK) as well as calcium homeostasis were examined. Our findings demonstrated that TiO 2 NPs crossed the membrane into the cytoplasm or nucleus, and significantly suppressed cell viability of primary cultured rat Sertoli cells in a concentration‐dependent manner. Furthermore, immunological dysfunction caused by TiO 2 NPs was involved in the increased expression of NF‐κB, TNF‐α, and IL‐1β, and decreased IκB expression. TiO 2 NPs significantly decreased Ca 2+ ‐ATPase and Ca 2+ /Mg 2+ ‐ATPase activity and enhanced intracellular Ca 2+ levels, and up‐regulated the expression of p‐PKC and p‐p38 MAPK in a dose‐dependent manner in primary cultured rat Sertoli cells. Taken together, these findings indicate that TiO 2 NPs may induce immunological dysfunction of primary cultured rat Sertoli cells by stimulating the Ca 2+ /PKC/p38 MAPK cascade, which triggers NF‐κB activation and ultimately induces the expression of inflammatory cytokines in primary cultured rat Sertoli cells. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1374–1382, 2017.