Department of Biotechnology, College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou, 310032, China.
Environ Toxicol. 2014 Dec;29(12):1399-408. doi: 10.1002/tox.21870. Epub 2013 May 27.
Polycyclic aromatic hydrocarbons (PAHs) are the most common contaminants in the environment. The primary focus on the toxicity of PAHs is their ability to activate the aryl hydrocarbon receptor (AhR)-mediated pathway and lead to carcinogenesis in different organisms. However, the influence of PAHs on the antioxidant system in mammalian systems has received only limited attention. In the present study, we observed that the intraperitoneal injection of 100 mg/kg 3-methylcholanthrene (3MC) into mice significantly increased reactive oxygen species (ROS) levels and malondialdehyde (MDA) contents and decreased glutathione (GSH) contents and the activity of total antioxidant capacity (T-AOC), indicating that serious oxidative stress had been induced in the liver of mice. Then, the oxidative stress signal activated the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway by enhancing the mRNA levels of Nrf2, p38, and Erk2. Moreover, the mRNA levels of Nrf2/ARE target genes, including glutathione peroxidase (Gpx), glutathione reductase (GR), glutathione synthetase (GS), NAD(P)H: quinone oxidoreductase 1 (Nqo1), superoxide dismutase 1 (Sod1), and Sod2, increased significantly after treatment with 3MC for 24 hours. The hepatic levels of NQO1 and the activities of GR and GS were also significantly enhanced at 24 hours after 3MC treatment. Because the expression of NQO1 is co-regulated by Nrf2/ARE and AhR/XRE in mammalian tissues, NQO1 may play an important role in protecting against the oxidative stress induced by 3MC. Taken together, our findings suggested that acute exposure to 3MC altered the cellular redox balance in hepatocytes to trigger Nrf2-regulated antioxidant responses, which may represent an adaptive cell defense mechanism against the oxidative stress induced by PAHs.
多环芳烃（PAHs）是环境中最常见的污染物。人们主要关注 PAHs 的毒性，是因为其能够激活芳烃受体（AhR）介导的途径，并导致不同生物体发生癌变。然而，PAHs 对哺乳动物系统抗氧化系统的影响仅受到有限关注。在本研究中，我们观察到，将 100mg/kg 的 3-甲基胆蒽（3MC）腹腔注射到小鼠体内，可显著增加活性氧（ROS）水平和丙二醛（MDA）含量，并降低谷胱甘肽（GSH）含量和总抗氧化能力（T-AOC）的活性，表明小鼠肝脏发生了严重的氧化应激。然后，氧化应激信号通过增强 Nrf2、p38 和 Erk2 的 mRNA 水平激活核因子红细胞 2 相关因子 2/抗氧化反应元件（Nrf2/ARE）通路。此外，Nrf2/ARE 靶基因，包括谷胱甘肽过氧化物酶（Gpx）、谷胱甘肽还原酶（GR）、谷胱甘肽合成酶（GS）、NAD(P)H：醌氧化还原酶 1（Nqo1）、超氧化物歧化酶 1（Sod1）和 Sod2 的 mRNA 水平在经 3MC 处理 24 小时后显著增加。在经 3MC 处理 24 小时后，肝组织中 NQO1 的水平和 GR 和 GS 的活性也显著增强。因为在哺乳动物组织中，NQO1 的表达受 Nrf2/ARE 和 AhR/XRE 共同调控，所以 NQO1 可能在保护 3MC 诱导的氧化应激方面发挥重要作用。综上所述，我们的研究结果表明，急性暴露于 3MC 改变了肝细胞的细胞内氧化还原平衡，引发了 Nrf2 调节的抗氧化反应，这可能代表了细胞针对 PAHs 诱导的氧化应激的一种适应性防御机制。
