反复氡照射诱导小鼠和人类支气管上皮细胞发生 ATM 激酶介导的 DNA 损伤反应和保护性自噬。

IF 2.2 4区 医学 Q3 TOXICOLOGY Toxicology Research Pub Date : 2024-10-07 eCollection Date: 2024-10-01 DOI:10.1093/toxres/tfae165
Xiaoyu Chen, Shan Shan, Aiqing Wang, Cheng Tu, Jianmei Wan, Chengjiao Hong, Xiaohan Li, Xueying Wang, Jieyun Yin, Jian Tong, Hailin Tian, Lili Xin
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引用次数: 0

摘要

目的:氡(222 Rn)是一种天然放射性气体,与肺癌的发生密切相关。本研究调查了氡诱导的 DNA 链断裂(肺癌发生的一个关键事件)以及小鼠和人类支气管上皮细胞(BEAS-2B)中相应的 DNA 损伤反应(DDR):方法:测定氡照射后小鼠肺细胞和BEAS-2B细胞中DNA双链断裂(DSB)的生物标志物、DSB的DNA修复反应、共济失调-特朗吉赛突变(ATM)激酶、自噬、细胞凋亡信号通路以及细胞周期停滞和细胞凋亡率:结果:重复氡照射可诱导DSB,表现为γ-组蛋白2AX(H2AX)蛋白和H2AX基因的表达增加,且呈时间和剂量依赖性。此外,一系列依赖于ATM的修复级联[即非同源DNA末端连接(NHEJ)、细胞周期停滞和p38丝裂原活化蛋白激酶(p38MAPK)/Bax凋亡信号通路]以及自噬过程也被激活。通过3-甲基腺嘌呤预处理抑制自噬,可部分逆转氡暴露在BEAS-2B细胞中诱导的NHEJ相关基因的表达:研究结果表明,长期暴露于氡气可诱导DSB形式的DNA损伤和一系列依赖于ATM的DDR途径。激活ATM介导的自噬可对氡诱导的DSB起到保护和促进生存的作用。
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Repeated radon exposure induced ATM kinase-mediated DNA damage response and protective autophagy in mice and human bronchial epithelial cells.

Objective: Radon ( 222 Rn) is a naturally occurring radioactive gas that has been closely linked with the development of lung cancer. In this study, we investigated the radon-induced DNA strand breaks, a critical event in lung carcinogenesis, and the corresponding DNA damage response (DDR) in mice and human bronchial epithelial (BEAS-2B) cells.

Methods: Biomarkers of DNA double-strand breaks (DSBs), DNA repair response to DSBs, ataxia-telangiectasia mutated (ATM) kinase, autophagy, and a cell apoptosis signaling pathway as well as cell-cycle arrest and the rate of apoptosis were determined in mouse lung and BEAS-2B cells after radon exposure.

Results: Repeated radon exposure induced DSBs indicated by the increasing expressions of γ-Histone 2AX (H2AX) protein and H2AX gene in a time and dose-dependent manner. Additionally, a panel of ATM-dependent repair cascades [i.e. non-homologous DNA end joining (NHEJ), cell-cycle arrest and the p38 mitogen activated protein kinase (p38MAPK)/Bax apoptosis signaling pathway] as well as the autophagy process were activated. Inhibition of autophagy by 3-methyladenine pre-treatment partially reversed the expression of NHEJ-related genes induced by radon exposure in BEAS-2B cells.

Conclusions: The findings demonstrated that long-term exposure to radon gas induced DNA lesions in the form of DSBs and a series of ATM-dependent DDR pathways. Activation of the ATM-mediated autophagy may provide a protective and pro-survival effect on radon-induced DSBs.

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Toxicology Research
Toxicology Research TOXICOLOGY-
CiteScore
3.60
自引率
0.00%
发文量
82
期刊介绍: A multi-disciplinary journal covering the best research in both fundamental and applied aspects of toxicology
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