Effects of atorvastatin on the Sirtuin/PXR signaling pathway in Mugilogobius chulae.

Atorvastatin (ATV) is a hypolipidemic drug widely detected in the aquatic environment. Nevertheless, limited information is provided about the toxic effects of ATV on estuary or coastal species and the underlying mechanisms. In the present study, the responses of genes expression in pregnane X receptor (PXR) signaling pathway and enzymatic activities in the liver of the estuarine benthic fish (Mugilogobius chulae) were investigated under acute and sub-chronic ATV exposure. Results showed that PXR was significantly inhibited in the highest exposure concentration of ATV for a shorter time (24 h, 500 µg L-1) but induced in a lower concentration (72 h, 5 µg L-1). The downstream genes in PXR signaling pathway such as CYP3A, SULT, UGT, and GST showed similar trends to PXR. P-gp and MRP1 were repressed in most treatments. GCLC associated with GSH synthesis was mostly induced under ATV exposure for a long time (168 h), suggesting that reactive oxygen species (ROS) were generated under ATV exposure. Similarly, GST and SOD enzymatic activities significantly increased in most exposure treatments. Under ATV exposure, SIRT1 and SIRT2 displayed induction to some extent in most treatments, suggesting that SIRTs may affect PXR expression by regulating the acetylation levels of PXR. The investigation demonstrated that ATV exposure affected the expression of the Sirtuin/PXR signaling pathway, thus further interfered adaption of M. chulae to the environment.

Atorvastatin causes oxidative stress and alteration of lipid metabolism in estuarine goby Mugilogobius abei.

The potential effects of the environmental residues of Atorvastatin (ATV) as a widely used antilipemic agent on aquatic organisms deserve more investigations because of its high detection frequency in environment. The responses of Nrf2/Keap1 signaling pathway (including the transcriptional expression of Nrf2, Keap1, GCLC, GPx, GST, SOD, CAT, Trx2, TrxR, HMG-CoAR and PGC-1α) in Mugilogobius abei were investigated under acute and sub-chronic exposure of ATV in the simulated laboratory conditions. The changes of related enzymatic activity (GST, GPx, SOD, CAT and TrxR) and the content of GSH and MDA combining with the observation of histology sections of liver in M. abei were also addressed. The results show Nrf2 and its downstream antioxidant genes were induced to different degrees under ATV exposure. The activities of antioxidant enzymes were inhibited at 24 h and 72 h but induced/recovered at 168 h. Correspondingly, negatively correlated to GSH, MDA increased first but reduced then. Notably, with the increase of exposure concentration/time, the volume of lipid cells in liver decreased, suggesting more lipid decomposition. Therefore, lipid metabolism was suppressed (down-regulation of PGC-1α) and cholesterol biosynthesis was induced (up-regulation of HMG-COAR) at 168 h. In short, ATV brings oxidative stress to M. abei in the initial phase. However, with the increase of exposure time, ATV activates Nrf2/Keap1 signaling pathway and improves the antioxidant capacity of M. abei to reverse this adverse effect. ATV also affects lipid metabolism of M. abei by reducing cholesterol content and accelerating lipid decomposition.

Effects of triclosan on the RedoximiRs/Sirtuin/Nrf2/ARE signaling pathway in mosquitofish (Gambusia affinis).

Triclosan (TCS) has been widely used in daily life for its broad-spectrum antibacterial property and subsequently detected frequently in aquatic waterborne. Environmental relevant concentrations of TCS in water (ng-µg/L) may pose potential unexpected impact on non-target aquatic organisms. In the present work, we investigated the transcriptional responses of Nrf2 as well as its downstream genes, sirtuins and redox-sensitive microRNAs (RedoximiRs) in livers of the small freshwater fish mosquitofish (Gambusia affinis) which were exposed to environmental relevant concentrations of TCS (0.05 µg/L, 0.5 µg/L and 5 µg/L for 24 h and 168 h). Results showed there were similar up-regulations in Nrf2 and its target genes (e. g. NQO1, CAT and SOD) at transcriptional, enzymatic and protein levels, reflecting oxidative stress of TCS to mosquitofish. Meanwhile, up-regulations of Sirt1, Sirt2 and down-regulations of miR-34b, miR-200b-5p and miR-21 could modulate antioxidant system via the Nrf2/ARE signaling pathway by the post-transcriptional regulations. Some oxidative stress-related biomarkers displayed in concentration-dependent manners (e. g. NQO1 mRNA, CAT mRNA) and/or time-dependent manners (e. g. GSH contents). This study indicated that the RedoximiRs/Sirtuin/Nrf2/ARE signaling pathway played a crucial role in mosquitofish exposed to TCS, and there might be potentially profound effects for TCS on the aquatic ecological safety.

Simvastatin affects Nrf2/MAPK signaling pathway and hepatic histological structure change in Gambusia affinis.

Simvastatin (SV) is a typical lipid-lowering agent detected widely in waters, so its latent toxic effects to fish are deserved of concern. The purposes of this study aim at revealing the responses of antioxidant system in mosquitofish (Gambusia affinis) under SV exposure. Transcriptional expressions of oxidative stress-related key transcriptional factor Nrf2 and its downstream genes in mosquitofish were determined under SV exposure for different time. Partly related enzymatic activities, Nrf2 and MAPK protein expressions were also addressed in the same conditions, and histological changes in liver tissues were investigated too. Results showed that Nrf2 mRNA increased with the rising SV concentrations at 3 d and 7 d, displaying typical dose-dependent relationship, and Nrf2 protein by WB showed consistency with transcriptional changes to some degree. Comparatively, responses of gene expressions were more sensitive than enzymatic changes. The histological changes in the mosquitofish liver exposed to SV for 7 d indicated the potential adverse effects of statins. This work demonstrated that SV in aquatic environment could affect the transcriptional expression of antioxidant system, partly related enzymatic activity, and hepatic structure in the mosquitofish, revealing its potential risk on non-target organisms and environmental safety.