Department of Ecology/Hydrobiology Research Institute, Jinan University, Guangzhou 510632, China.
Department of Ecology/Hydrobiology Research Institute, Jinan University, Guangzhou 510632, China; Key Laboratory of Eutrophication and Red Tide Prevention of Guangdong Higher Education Institutes, Jinan University, Guangzhou 510632, China.
Sci Total Environ. 2019 Feb 15;651(Pt 1):399-409. doi: 10.1016/j.scitotenv.2018.09.133. Epub 2018 Sep 11.
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, 5 μg L, 50 μg L and 500 μg L) 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 in Mugilogobius abei were investigated. Result showed that the expressions of P-gp, CYP 1A, CYP 3A, GST and PXR were induced to some extend under simvastatin exposure for 72 h. A positive correlation was observed between PXR and CYP1A, CYP3A and P-gp. While for microRNA, a negative relationship was found between miR-34a and CYP3A, CYP1A. The expression of miR-148a was significantly induced under the exposure of SV (50 μg L), which was positive related to the transcriptional expression of PXR. For enzyme activity, erythromycin N-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 of M. abei, especially the size of adipocyte significantly decreased. The present study indicated that environmentally relevant concentration SV may affect the PXR signaling pathway in M. abei and pose potential ecological risks to non-target organisms like fish.
辛伐他汀是全世界最常用的降胆固醇处方药之一。近年来，随着这些药物的消费增加以及随后排放到水生环境中，它们在大多数污水废水中都能被检测到。不幸的是，关于它们对水生生物的潜在影响的信息有限，特别是对鱼类解毒相关代谢的影响。在本研究中，中国南方的一种当地底栖鱼类（Mugilogobius abei）被用作测试物种，并暴露于辛伐他汀（0.5μg/L、5μg/L、50μg/L 和 500μg/L）中 72 小时。研究了核转录因子孕烷 X 受体（PXR）及其下游靶基因包括多药耐药蛋白或渗透糖蛋白（P-gp）、细胞色素 1A（CYP1A）、细胞色素 P450 3A（CYP3A）、谷胱甘肽-S-转移酶（GST）的转录表达以及相关 microRNA（如 miR-27、miR-34 和 miR-148）的表达。结果表明，在辛伐他汀暴露 72 小时内，P-gp、CYP1A、CYP3A、GST 和 PXR 的表达在一定程度上被诱导。PXR 与 CYP1A、CYP3A 和 P-gp 之间存在正相关关系。而对于 microRNA，miR-34a 与 CYP3A 和 CYP1A 之间存在负相关关系。miR-148a 的表达在 SV（50μg/L）暴露下显著增加，这与 PXR 的转录表达呈正相关。对于酶活性，红霉素 N-去甲基酶（ERND）在 24 小时时显著增加，而过氧化氢酶（CAT）和超氧化物歧化酶（SOD）的活性表现出不同的趋势。CAT 在 24 小时暴露时略有抑制，但 SOD 在高浓度时显著诱导。72 小时暴露后，谷胱甘肽-S-转移酶（GST）活性显著抑制。还原小分子谷胱甘肽（GSH）含量明显减少，而丙二醛（MDA）含量在高浓度 SV 暴露时显著增加。GSH 和 MDA 呈负相关。此外，辛伐他汀导致 M. abei 肝组织发生组织学变化，特别是脂肪细胞的大小显著减小。本研究表明，环境相关浓度的辛伐他汀可能会影响 M. abei 中的 PXR 信号通路，并对鱼类等非目标生物构成潜在的生态风险。
