TiO2 Nanoparticles Caused DNA Damage in Lung and Extra-Pulmonary Organs Through ROS-Activated FOXO3a Signaling Pathway After Intratracheal Administration in Rats

Abstract

Bin Han1 ,* Zijie Pei2 ,* Lei Shi,3 Qian Wang,4 Chen Li,1 Boyuan Zhang,1 Xuan Su,1 Ning Zhang,1 Lixiao Zhou,1 Bo Zhao,5 Yujie Niu,3,6 Rong Zhang1,6 1Department of Toxicology, Hebei Medical University, Shijiazhuang 050017, Hebei, People’s Republic of China; 2Department of Pathology, Medical School, China Three Gorge University, Yichang 443002, People’s Republic of China; 3Occupational Health and Environmental Health, Hebei Medical University, Shijiazhuang 050017, Hebei, People’s Republic of China; 4Experimental Center, Hebei Medical University, Shijiazhuang 050017, Hebei, People’s Republic of China; 5Department of Laboratory Diagnosis, Hebei Medical University, Shijiazhuang 050017, Hebei, People’s Republic of China; 6Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang 050017, Hebei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rong ZhangDepartment of Toxicology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, Hebei 050017, People’s Republic of ChinaFax [phone]Email [email protected]: 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

Keywords

• nano-tio2
• dna damage
• pi3k/akt/foxo3a signaling pathway
• dna repair，gadd45α/chk2/ xrcc1 signaling pathway