Copper exposure induces oxidative injury, disturbs the antioxidant system and changes the Nrf2/ARE (CuZnSOD) signaling in the fish brain: Protective effects of myo-inositol
Copper exposure induces oxidative injury, disturbs the antioxidant system and changes the Nrf2/ARE (CuZnSOD) signaling in the fish brain: Protective effects of myo-inositol
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铜暴露会引起氧化损伤，扰乱抗氧化系统并改变鱼脑中的 Nrf2/ARE (CuZnSOD) 信号：肌醇的保护作用。
DOI：
10.1016/j.aquatox.2014.07.003
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发表时间：
2014-10-01
影响因子：
4.5
通讯作者：
Zhou, Xiao-Qiu
中科院分区：
文献类型：
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作者：
Jiang, Wei-Dan;Liu, Yang;Zhou, Xiao-Qiu
大脑是所有脊椎动物神经系统的中心，大脑的内稳态对鱼类的生存至关重要。铜（Cu）对大多数真核生物的正常细胞过程至关重要，但过量是有毒的。虽然铜被认为是一种强效的神经毒物，但关于其对鱼脑的威胁及其潜在机制的信息仍然很少。因此，本研究的目的是通过评估铜暴露后鱼脑氧化状态、抗氧化基因酶和mRNA水平以及Nrf2/ARE信号的变化，来评估铜中毒的影响及其潜在机制。肌醇（MI）对后续铜暴露的保护作用也进行了研究。结果表明，Cu对氧化应激的诱导表现为脑内ROS生成、脂质过氧化和蛋白质氧化的增加，并伴随着总超氧化物歧化酶（T-SOD）、CuZnSOD、谷胱甘肽- s转移酶（GST）、谷胱甘肽还原酶（GR）活性和谷胱甘肽（GSH）含量的消耗。铜暴露增加了过氧化氢酶（CAT）和谷胱甘肽过氧化物酶（GPx）活性。进一步的分子研究结果表明，Cu暴露可上调CuZnSOD、GPx1a和GR mRNA的表达水平，提示其具有抗应激的适应性机制。此外，Cu暴露增加了鱼脑Nrf2核积累，增加了其与ARE （CuZnSOD）结合的能力，这支持了CuZnSOD mRNA水平的升高。此外，Cu暴露导致Nrf2、Maf G1（而不是Maf G2基因）和PKCd基因的表达增加，这表明这些因子的重新合成是这些抗氧化基因长期诱导的必要条件。然而，铜暴露下的鱼脑Keap1a（而不是Keap1b）的调节可能被用来关闭信号级联，避免有害影响。有趣的是，MI预处理主要通过增加GSH含量和CuZnSOD和GST活性来防止鱼脑cu诱导的氧化损伤。综上所述，本研究表明，Cu虽然通过Nrf2/ARE信号刺激部分抗氧化酶基因表达的适应性增加，但由于ROS产生的增加，也会导致氧化和大部分抗氧化酶活性和GSH含量的消耗，而MI可以保护鱼脑免受Cu毒性。(C) 2014 Elsevier B.V.版权所有
The brain is the center of the nervous system in all vertebrates, and homeostasis of the brain is crucial for fish survival. Copper (Cu) is essential for normal cellular processes in most eukaryotic organisms but is toxic in excess. Although Cu is indicated as a potent neurotoxicant, information regarding its threat to fish brain and underlying mechanisms is still scarce. In accordance, the objective of this study was to assess the effects and the potential mechanism of Cu toxicity by evaluating brain oxidative status, the enzymatic and mRNA levels of antioxidant genes, as well as the Nrf2/ARE signaling in the brain of fish after Cu exposure. The protective effects of myo-inositol (MI) against subsequent Cu exposure were also investigated. The results indicate that induction of oxidative stress by Cu is shown by increases in brain ROS production, lipid peroxidation and protein oxidation, which are accompanied by depletions of antioxidants, including total superoxide dismutase (T-SOD), CuZnSOD, glutathione-S-transferase (GST) and glutathione reductase (GR) activities and glutathione (GSH) content. Cu exposure increased the catalase (CAT) and glutathione peroxidase (GPx) activities. Further molecular results showed that Cu exposure up-regulated CuZnSOD, GPx1a and GR mRNA levels, suggesting an adaptive mechanism against stress. Moreover, Cu exposure increased fish brain Nrf2 nuclear accumulation and increased its ability of binding to ARE (CuZnSOD), which supported the increased CuZnSOD mRNA levels. In addition, Cu exposure caused increases of the expression of the Nrf2, Maf G1 (rather than Maf G2 gene) and PKCd genes, suggesting that de nova synthesis of those factors is required for the protracted induction of such antioxidant genes. However, the modulation of Keap1a (rather than Keap1b) of fish brain under Cu exposure might be used to turn off of the signaling cascade and avoid harmful effects. Interestingly, pre-treatment of fish with MI prevented the fish brain from Cu-induced oxidative damages mainly by increasing the GSH content and CuZnSOD and GST activities. Summarily, this study indicates that although Cu stimulates adaptive increases in the expression of some antioxidant enzyme genes through Nrf2/ARE signaling, it also induces oxidation and the depletion of most of antioxidant enzyme activities and GSH content due to the increase of ROS production, and MI protects the fish brain against Cu toxicity. (C) 2014 Elsevier B.V. All rights reserved.