P-352 HEXAVALENT CHROMIUM CAUSED DNA DAMAGE RESPONSE AND APOPTOSIS VIA THE PI3K/AKT/FOXO1 PATHWAY TRIGGERED BY OXIDATIVE STRESS IN LUNG OF RAT

Abstract

Introduction Hexavalent chromium [Cr (VI)] is an occupational carcinogen, but the molecular mechanism of Cr (VI) causing lung injury and even lung cancer is still unclear. Methods 36 SD male rats received inhalable intratracheal instillation of Cr (VI) (0.05, 0.25 mg Cr/kg) or same volume(3 ml/kg) of normal saline weekly for 28 days (total 5 times).Half of the rats in each group were sacrificed after 28d exposure, and the rest stopped exposure and self-repair for two weeks.the research was approved by the Experimental Animal Ethics Committee of Zhengzhou University (Grant Number: ZZUIRB 2021-117). Results Cr (VI) exposure caused the increase of blood Cr, urinary Cr, MDA, 8-OHDG, and the decrease of GSH and MDA,while two-week repair only reduced urinary Cr.Exposure to Cr (VI) upregulated FOXO1 and downregulated P-AKT and P-FOXO1 for two weeks.PI3K in the 0.25 mg Cr/kg group was inhibited after two-week repair. Cr (VI) exposure mainly promoted GADD45a and CHK2 in exposure group, mainly promoted BIM, BAX/BCL-2 and suppressed BCL-2 and BCL-XL in repair group. Discussion Cr (VI) exposure caused blood Cr accumulation, lung oxidative stress and DNA damage, also obvious after two-week repair, suggested that two-week repair couldn’t eliminate these effects. Cr (VI) exposure stimulated DNA damage response and apoptosis, and the PI3K/AKT/FOXO1 pathway was also activated, suggested there was a connection between them, PPI analysis also confirmed this hypothesis. Conclusion Cr (VI) may induce DNA damage response and apoptosis in lung by activating the PI3K/AKT/FOXO1 pathway, two-week repair may alleviate oxidative stress and DNA damage induced by Cr (VI) exposure but couldn’t eliminate its effects.