Effects of simvastatin on the PXR signaling pathway and the liver histology in Mugilogobius abei

Abstract

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^-1 and 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 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^-1), 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.

Keywords: Gene expression; Histological change; Mugilogobius abei; PXR; Simvastatin; microRNA.