Toxic effects of TiO₂ nanoparticles in primary cultured rat sertoli cells are mediated via a dysregulated Ca²⁺ /PKC/p38 MAPK/NF-κB cascade.

Abstract

Although numerous studies have demonstrated that titanium dioxide nanoparticles (TiO₂ 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 TiO₂ 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 TiO₂ NPs for 24 h, and TiO₂ NPs internalization, expression of PKC (p-PKC) and p38 MAPK (p-p38 MAPK) as well as calcium homeostasis were examined. Our findings demonstrated that TiO₂ 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 TiO₂ NPs was involved in the increased expression of NF-κB, TNF-α, and IL-1β, and decreased IκB expression. TiO₂ NPs significantly decreased Ca²⁺ -ATPase and Ca²⁺ /Mg²⁺ -ATPase activity and enhanced intracellular Ca²⁺ 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 TiO₂ NPs may induce immunological dysfunction of primary cultured rat Sertoli cells by stimulating the Ca²⁺ /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.