<p>TiO<sub>2</sub> Nanoparticles Caused DNA Damage in Lung and Extra-Pulmonary Organs Through ROS-Activated FOXO3a Signaling Pathway After Intratracheal Administration in Rats</p>
Bin Han, Zijie Pei, Lei Shi, Qian Wang, Chen Li, Boyuan Zhang, Xuan Su, Ning Zhang, Lixiao Zhou, Bo Zhao, Yujie Niu, Rong Zhang
Abstract
Introduction: Because of the increased production and application of manufactured Nano-TiO 2 in the past several years, it is important to investigate its potential hazards. TiO 2 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 TiO 2 nanoparticles. Methods: In the present study, SD rats were exposed to Nano-TiO 2 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-TiO 2 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-TiO 2 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-TiO 2 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-TiO 2 , DNA damage, PI3K/AKT/FOXO3a signaling pathway, DNA repair, GADD45α/ChK2/XRCC1 signaling pathway