Introduction: Because of the increased production and application of manufactured Nano-TiO₂ in the past several years, it is important to investigate its potential hazards. TiO₂ is classified by IARC as a possible human carcinogen; however, the potential mechanism of carcinogenesis has not been studied clearly. The present study aimed to investigate the mechanism of DNA damage in rat lung and extra-pulmonary organs caused by TiO₂nanoparticles.
Methods: In the present study, SD rats were exposed to Nano-TiO₂ by intratracheal injection at a dose of 0, 0.2, or 1 g/kg body weight. The titanium levels in tissues were detected by ICP-MS. Western blot was used to detect the protein expression levels. The DNA damage and oxidative stress were detected by comet assay and ROS, MDA, SOD, and GSH-Px levels, respectively.
Results: The titanium levels of the 1 g/kg group on day-3 and day-7 were significantly increased in liver and kidney as well as significantly decreased in lung compared to day-1. ROS and MDA levels were statistically increased, whereas SOD and GSH-Px levels were statistically decreased in tissues of rats in dose-dependent manners after Nano-TiO₂ treatment. PI3K, p-AKT/AKT, and p-FOXO3a/FOXO3a in lung, liver, and kidney activated in dose-dependent manners. The levels of DNA damage in liver, kidney, and lung in each Nano-TiO₂ treatment group were significantly increased and could not recover within 7 days. GADD45α, ChK2, and XRCC1 in liver, kidney, and lung of rats exposed to Nano-TiO₂ statistically increased, which triggered DNA repair.
Conclusion: This work demonstrated that Ti could deposit in lung and enter extra-pulmonary organs of rats and cause oxidative stress, then trigger DNA damage through activating the PI3K-AKT-FOXO3a pathway and then promoting GADD45α, ChK2, and XRCC1 to process the DNA repair.

Keywords: Nano-TiO₂, DNA damage, PI3K/AKT/FOXO3a signaling pathway, DNA repair, GADD45α/ChK2/XRCC1 signaling pathway


中文翻译：

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在大鼠气管内给药后，二氧化钛纳米颗粒通过 ROS 激活的 FOXO3a 信号通路导致肺和肺外器官的 DNA 损伤。

简介：由于过去几年人造纳米TiO ₂的生产和应用不断增加，因此调查其潜在危害非常重要。TiO ₂被 IARC 列为可能的人类致癌物；然而，致癌作用的潜在机制尚未得到明确研究。_{本研究旨在探讨纳米TiO 2}对大鼠肺和肺外器官DNA损伤的机制。
方法：在本研究中，SD大鼠暴露于 Nano-TiO ₂气管内注射，剂量为 0、0.2 或 1 g/kg 体重。通过ICP-MS检测组织中的钛水平。Western印迹用于检测蛋白质表达水平。采用彗星法检测DNA损伤和氧化应激，分别检测ROS、MDA、SOD和GSH-Px水平。
结果：与第1天相比，1 g/kg组第3天和第7天的钛水平在肝脏和肾脏中显着升高，在肺中显着降低。Nano-TiO 后大鼠组织中ROS 和MDA水平显着升高，而SOD和GSH-Px水平显着降低，呈剂量依赖性₂治疗。肺、肝和肾中的PI3K、p-AKT / AKT和p-FOXO3a / FOXO3a以剂量依赖性方式激活。_{每个 Nano-TiO 2}治疗组的肝、肾和肺中 DNA 损伤水平显着增加，并且在 7 天内无法恢复。_{暴露于 Nano-TiO 2}的大鼠肝脏、肾脏和肺中的GADD45α、ChK2和XRCC1显着增加，从而触发了 DNA 修复。结论：
本研究表明，Ti可以在大鼠肺内沉积并进入肺外器官，引起氧化应激，然后通过激活PI3K-AKT-FOXO3a通路，进而促进GADD45α、ChK2和XRCC1进行DNA修复，从而引发DNA损伤。

关键词: Nano-TiO ₂ , DNA损伤, PI3K/AKT/FOXO3a信号通路, DNA修复, GADD45α/ChK2/XRCC1信号通路