Pxr- and Nrf2-mediated induction of ABC transporters by heavy metal ions in zebrafish embryos
Pxr- and Nrf2-mediated induction of ABC transporters by heavy metal ions in zebrafish embryos
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Pxr 和 Nrf2 介导斑马鱼胚胎中重金属离子对 ABC 转运蛋白的诱导。
DOI：
10.1016/j.envpol.2019.113329
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发表时间：
2019-12-01
影响因子：
8.9
通讯作者：
Yin, Jian
中科院分区：
文献类型：
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作者：
Hu, Jia;Tian, Jingjing;Yin, Jian
转录因子Pxr和Nrf 2是哺乳动物细胞三磷酸腺苷结合盒（Adenosine triphosphate-binding cassette，ABC）转运蛋白的重要调节因子。然而，这种调制是否在斑马鱼胚胎中是保守的仍然在很大程度上未知。本论文利用CRISPR/Cas9系统构建了pxr和nrf 2缺陷模型，以评价Pxr和Nrf 2在ABC转运蛋白调控和重金属离子Cd 2+和Ag+解毒中的个体功能。结果表明，Cd ~（2+）和Ag ~+均能与野生型（WT）胚胎中的ABC转运蛋白发生广泛的相互作用：Cd ~（2+）和Ag ~+的蓄积和毒性受到ABC转运蛋白活性的影响，并能显著诱导ABC转运蛋白mRNA的表达。这些诱导作用减少了突变的pxr和nrf 2，但在基础表达的ABC转运蛋白的海拔补偿其inducibility的损失。这可以解释在两种突变模型中剩余的转运蛋白功能，以及在pxr缺陷胚胎中金属离子的毒性不变。然而，nrf 2的突变破坏了谷胱甘肽（GSH）的产生，导致镉/银+在斑马鱼胚胎中的毒性增强。此外，在pxr缺陷模型中发现其他转录因子如芳烃受体（ahr）1b，过氧化物酶体增殖物激活受体（ppar）-β和nrf 2的表达升高，而在金属离子处理后，仅在nrf 2缺陷胚胎中发现ahr 1b，ppar-β和pxr的诱导增强，表明转录因子缺失时的不同补偿现象。毕竟，pxr缺陷和nrf 2缺陷的斑马鱼胚胎是研究Pxr和Nrf 2在水生生物早期生命阶段功能的有用工具。但是，在解释结果时应考虑补偿机制，并需要深入研究。(C)2019爱思唯尔有限公司版权所有。
Transcription factors including pregnane X receptor (Pxr) and nuclear factor-erythroid 2-related factor-2 (Nrf2) are important modulators of Adenosine triphosphate-binding cassette (ABC) transporters in mammalian cells. However, whether such modulation is conserved in zebrafish embryos remains largely unknown. In this manuscript, pxr- and nrf2-deficient models were constructed with CRISPR/Cas9 system, to evaluate the individual function of Pxr and Nrf2 in the regulation of ABC transporters and detoxification of heavy metal ions like Cd2+ and Ag+. As a result, both Cd2+ and Ag+ conferred extensive interactions with ABC transporters in wild type (WT) embryos: their accumulation and toxicity were affected by the activity of ABC transporters, and they significantly induced the mRNA expressions of ABC transporters. These induction effects were reduced by the mutation of pxr and nrf2, but elevations in the basal expression of ABC transporters compensated for the loss of their inducibility. This could be an explanation for remaining transporter function in both mutant models as well as the unaltered toxicity of metal ions in pxr-deficient embryos. However, mutation of nrf2 disrupted the production of glutathione (GSH), resulting in the enhanced toxicity of Cd2+/Ag+ in zebrafish embryos. In addition, elevated expressions of other transcription factors like aryl hydrocarbon receptor (ahr) 1b, peroxisome proliferator-activated receptor (ppar)-beta, and nrf2 were found in pxr-deficient models without any treatment, while enhanced induction of ahr1b, ppar-beta and pxr could only be seen in nrf2-deficient embryos after the treatment of metal ions, indicating different compensation phenomena for the absence of transcription factors. After all, pxr-deficient and nrf2-deficient zebrafish embryos are useful tools in the functional investigation of Pxr and Nrf2 in the early life stages of aquatic organisms. However, the compensatory mechanisms should be taken into consideration when interpreting the results and need in-depth investigations. (C) 2019 Elsevier Ltd. All rights reserved.