Ye Lingqun, Hong Fashui, Ze Xiao, Li Lingjuan, Zhou Yaoming, Ze Yuguan
Department of Biochemistry and Molecular Biology, School of Basic Medical and Biological Sciences, Soochow University, Suzhou, 215123, China.
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture and Environmental Protection, Huaiyin Normal University, Huaian, 223300, China.
J Biomed Mater Res A. 2017 May;105(5):1374-1382. doi: 10.1002/jbm.a.36021. Epub 2017 Feb 24.
Although numerous studies have demonstrated that titanium dioxide nanoparticles (TiO 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 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 NPs for 24 h, and TiO 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 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 NPs was involved in the increased expression of NF-κB, TNF-α, and IL-1β, and decreased IκB expression. TiO NPs significantly decreased Ca -ATPase and Ca /Mg -ATPase activity and enhanced intracellular Ca 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 NPs may induce immunological dysfunction of primary cultured rat Sertoli cells by stimulating the Ca /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.
尽管众多研究表明二氧化钛纳米颗粒（TiO NPs）可在多种动物器官中蓄积并能导致毒性，但目前关于生殖毒性的数据有限，尤其是TiO NPs对支持细胞毒性机制的研究。为了探究生殖毒性机制，将原代培养的大鼠支持细胞暴露于5、15或30μg/mL的TiO NPs中24小时，检测TiO NPs的内化、蛋白激酶C（p-PKC）和p38丝裂原活化蛋白激酶（p-p38 MAPK）的表达以及钙稳态。我们的研究结果表明，TiO NPs穿过细胞膜进入细胞质或细胞核，并以浓度依赖的方式显著抑制原代培养的大鼠支持细胞的活力。此外，TiO NPs引起的免疫功能障碍与核因子κB（NF-κB）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）表达增加以及IκB表达降低有关。TiO NPs显著降低钙-ATP酶和钙/镁-ATP酶活性，提高细胞内钙水平，并在原代培养的大鼠支持细胞中以剂量依赖的方式上调p-PKC和p-p38 MAPK的表达。综上所述，这些研究结果表明，TiO NPs可能通过刺激钙/PKC/p38 MAPK级联反应诱导原代培养的大鼠支持细胞免疫功能障碍，该级联反应触发NF-κB活化并最终诱导原代培养的大鼠支持细胞中炎性细胞因子的表达。© 2017威利期刊公司。《生物医学材料研究杂志》A部分：105A：1374 - 1382，2017年。
