Using Nrf2/antioxidant response element-dependent signaling to assess the toxicity potential of fly ash particles
Using Nrf2/antioxidant response element-dependent signaling to assess the toxicity potential of fly ash particles
复制标题
使用 Nrf2/抗氧化反应元件依赖性信号传导评估飞灰颗粒的潜在毒性
DOI：
10.1016/j.ecoenv.2018.11.093
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发表时间：
2019
影响因子：
6.8
通讯作者：
Wang Xiu Jun
中科院分区：
文献类型：
--
作者：
Wang Hongyan;Chen Yiping;Zhang Jingwen;Tang Xiuwen;Wang Xiu Jun
流行病学研究表明，环境颗粒物污染与人类健康不良影响之间存在关联。由转录因子 NF-E2 p45 相关因子 2 (Nrf2) 介导的抗氧化响应元件 (ARE) 细胞保护系统是针对颗粒物引发的氧化应激的主要防御。在这项研究中，使用基于细胞的 ARE 报告基因检测，检查了从中国四个城市的城市固体废物焚烧炉收集的飞灰的细小部分激活 Nrf2/ARE 信号的能力。我们发现，在非致死剂量下，所有飞灰样品都能以剂量和氧化还原依赖性方式激活 ARE 报告基因，这与其细胞毒性和诱导 DNA 损伤的能力相关。动力学研究表明，飞灰颗粒引起了 ARE 报告基因活性的长时间激活。暴露于颗粒后，ARE-荧光素酶活性在2小时内显着增加，在24小时达到峰值，并在72小时保持高水平。这与 Nrf2 激活剂叔丁基氢醌和萝卜硫素触发的 ARE 报告基因的瞬时激活形成对比，而 ARE 荧光素酶活性在 72 小时从 24 小时的峰值降至基础水平。这些结果证明了使用基于细胞的 ARE 报告基因检测来评估飞灰氧化潜力的稳健性。我们的新发现表明，飞灰颗粒诱导的 Nrf2/ARE 信号通路持续激活会扰乱细胞氧化还原稳态，进而导致毒性。
Epidemiological studies have demonstrated an association between ambient particulate pollution and adverse health effects in humans. The antioxidant-responsive element (ARE) cytoprotective system mediated by the transcription factor NF-E2 p45-related factor 2 (Nrf2) serves as a primary defense against the oxidative stress triggered by particulate matter. In this study, using a cell-based ARE-reporter assay, the fine fractions of the fly ash collected from the municipal solid waste incinerators at four cities in China were examined for their ability to activate Nrf2/ARE signaling. We found that, at a non-lethal dose, all the fly ash samples were able to activate the ARE-reporter gene in a dose- and redox-dependent manner, and this was correlated with their cytotoxicity and their ability to induce DNA damage. Study of the kinetics revealed that fly ash particles elicited a prolonged activation of the ARE-reporter activity. Upon exposure to the particles, the ARE-luciferase activity significantly increased in 2 h, reached a peak at 24 h, and remained high level at 72 h. This was in contrast to the transient activation of the ARE-reporter gene triggered by the Nrf2 activatorstert-butylhydroquinone and sulforaphane, while ARE-luciferase activity dropped to the basal level at 72 h from the peak at 24 h. These results demonstrate the robustness of using cell-based ARE-reporter assays to evaluate the oxidative potential of fly ash. Our novel findings suggest that the sustained activation of the Nrf2/ARE signaling pathway induced by fly ash particles perturbs cellular redox homeostasis, which in turn contributes to toxicity.