Effects of simvastatin on the PXR signaling pathway and the liver histology in Mugilogobius abei.
Effects of simvastatin on the PXR signaling pathway and the liver histology in Mugilogobius abei.
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DOI：
10.1016/j.scitotenv.2018.09.133
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发表时间：
2019-02
期刊：
影响因子：
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通讯作者：
Chao Wang;Peijia Ku;X. Nie;Shuang Bao;Zhaohui Wang;Kaibin Li
中科院分区：
文献类型：
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作者：
Chao Wang;Peijia Ku;X. Nie;Shuang Bao;Zhaohui Wang;Kaibin Li
辛伐他汀是世界上最常用的降胆固醇药物之一。近年来，随着这些药物的消费量增加以及随后排放到水生环境中，它们在大多数污水流出物中的含量都是可检测的。遗憾的是，关于其对水生生物的潜在影响，特别是对鱼类解毒相关代谢的影响，所提供的信息有限。本研究以我国南方特有的一种底栖鱼类（Mugilogobius abei）为试验种，将其暴露于SV（0.5 μg L−1、5 μg L−1、50 μg L− 1和500 μg L−1）72 h。研究了阿氏无尾蝮蛇（Mugilogobius abei）细胞核转录因子PXR及其下游靶基因P-gp、细胞色素1A（CYP 1A）、细胞色素P450 3A（CYP 3A）、谷胱甘肽-S-转移酶（GST）的转录表达及相关microRNA（miR-27、miR-34和miR-148）的表达。结果显示，辛伐他汀作用72 h后，P-gp、P1 A、P13 A、GST和PXR的表达均受到不同程度的诱导。PX与CYP 1A、CYP 3A、P-gp呈正相关。而microRNA中miR-34 a与CYP 3A、CYP 1A呈负相关。SV（50 μg L−1）可显著诱导miR-148 a的表达，并与PXR的转录表达呈正相关。在酶活性方面，红霉素N-脱甲基酶（ERND）在24 h时显著升高，过氧化氢酶（CAT）和超氧化物歧化酶（SOD）活性变化趋势不同。CAT在24 h时受到轻度抑制，而SOD在高浓度时受到显著诱导。谷胱甘肽-S-转移酶（GST）活性显着抑制后，72小时的曝光。高浓度SV染毒后，还原型小分子谷胱甘肽（GSH）含量明显降低，丙二醛（MDA）含量明显升高。GSH与MDA在一定程度上呈典型的负相关。此外，辛伐他汀还可引起M. abei，尤其是脂肪细胞的大小明显减少。本研究表明，环境相关浓度的SV可能会影响M的PXR信号通路。阿贝兰对鱼类等非目标生物构成潜在的生态风险。
Simvastatin is one of the most commonly cholesterol-lowering prescribed drugs all over the world. With the increase of consumption of these pharmaceuticals and subsequent their discharge into the aquatic environment in recent years, they are present at detectable levels in most sewage effluents. Unfortunately, limited information is provided about their potential impacts on aquatic organisms, especially on the detoxification-related metabolism in fish. In the present study, one local native benthic fish (Mugilogobius abei) in southern China was employed as test species and exposed to SV (0.5 μg L−1, 5 μg L−1, 50 μg L−1and 500 μg L−1) for 72 h. The transcriptional expression of nucleus transcriptional factor pregnane X receptor (PXR) and its downstream targeted genes including multixenobiotics resistance protein or permeability glycoprotein (P-gp), cytochrome 1A (CYP1A), cytochrome P450 3A (CYP3A), glutathione-S-transferase (GST) and the expression of associated microRNA such as miR-27, miR-34 and miR-148 inMugilogobius abeiwere investigated. Result showed that the expressions ofP-gp,CYP 1A,CYP 3A,GSTandPXRwere induced to some extend under simvastatin exposure for 72 h. A positive correlation was observed betweenPXRandCYP1A,CYP3AandP-gp. While for microRNA, a negative relationship was found betweenmiR-34aandCYP3A,CYP1A. The expression ofmiR-148awas significantly induced under the exposure of SV (50 μg L−1), which was positive related to the transcriptional expression ofPXR. For enzyme activity, erythromycinN-demethylase (ERND) significantly increased at 24 h and the activity of catalase (CAT) and superoxide dismutase (SOD) exhibited different trends. CAT was slightly inhibited at 24 h exposure but SOD was significantly induced in high concentration. Glutathione-S-transferase (GST) activity was significant inhibited after 72 h exposure. The reductive small molecule glutathione (GSH) content showed obvious decrease, while the quantity of malondialdehyde (MDA) increased significantly in high concentrations of SV exposure. GSH and MDA showed a typical negative correlation to some degree. Moreover, simvastatin caused histological changes in the liver tissues ofM. abei, especially the size of adipocyte significantly decreased. The present study indicated that environmentally relevant concentration SV may affect the PXR signaling pathway inM. abeiand pose potential ecological risks to non-target organisms like fish.