Atorvastatin up-regulate toxicologically relevant genes in rainbow trout gills.

There are large and increasing discharges of statins into the aquatic environment. Statins are cholesterol-lowering pharmaceuticals, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, an enzyme in the cholesterol synthesis pathway. Earlier studies have shown that statins will affect the expression of a range of genes in mammalian tissues and this group of pharmaceuticals has also been shown to affect membrane transporters. Changes in gene expression and ion transport in aquatic organisms may have dramatic consequences for the individual. The aim of the present study was to clarify whether waterborne exposure to a selected statin, atorvastatin, would affect gene expression in rainbow trout (Oncorhynchus mykiss) gill or liver or ion regulation in gills. Juvenile rainbow trout were exposed to two atorvastatin acid and atorvastatin lactone concentrations for 7 days (nominal concentrations 200 ng L(-1) and 10 µg L(-1)). The exposures caused up-regulated gene expression in gill, not liver, and only at the lowest concentration. Genes involved in membrane transport (pgp, mrp1), oxidative stress response (sod, mt), apoptosis (bax) and biotransformation (sult2b) were differentially expressed whereas the expression of genes involved in cholesterol biosynthesis (hmgr, fdps) or peroxisomal proliferation (ppar) were not affected. There were no significant changes in gill Na(+)/K(+) ATPase activity following exposure to atorvastatin. The pattern of differentially expressed genes in rainbow trout gills differ from responses previously observed in mammalian tissues following statin exposure.

Species-dependent sensitivity to contaminants: an approach using primary hepatocyte cultures with three marine fish species.

There is limited knowledge about the sensitivity of different fish species to environmental pollutants. Such information is pivotal in risk assessment and to understand why some species appear to be more tolerant to contaminants than others. The aim of the current study was to evaluate whether primary hepatocyte cultures of three marine fish species could be established in the field and whether their sensitivity to selected contaminants would differ. Primary hepatocyte cultures of three marine fish species (plaice, long rough dab, Atlantic cod) were established and exposed for 24 h to copper (20-2500 mg L⁻¹) and statins (1-200 mg L⁻¹). Endpoints were esterase activity, metabolic activity and reduced glutathione (GSH) content, all using fluorescent probes. Flatfish hepatocytes were more susceptible to copper and statin exposure than hepatocytes from cod. This study has shown that species-dependent differences in contaminant sensitivity can be investigated using primary hepatocyte cultures.

Cytotoxicity of atorvastatin and simvastatin on primary rainbow trout (Oncorhynchus mykiss) hepatocytes.

Statins are cholesterol-lowering pharmaceuticals and commonly prescribed drugs in European countries. Their discharge into the aquatic environment has increased in the last few years and they are present at detectable levels in most sewage effluents. The aim of the present study was to quantify the cytotoxic effects of acid and lactone forms of two statins, atorvastatin and simvastatin, as well as selected metabolites (ortho- and para-hydroxy atorvastatin acid, ortho-hydroxy atorvastatin lactone, simvastatin hydroxyl carboxylic acid, and 3''hydroxy simvastatin lactone) to hepatocytes from rainbow trout (Oncorhynchus mykiss). Hepatocytes were exposed for 24, 48, and 72 h to different concentrations of each test substance (0.4-400 microM). Cytotoxicity was measured as metabolic inhibition and loss of membrane integrity with the fluorescent probes alamar blue (AB) and 5-carboxyfluorescein diacetate, acetoxymethyl ester (CFDA-AM), respectively. Atorvastatin, simvastatin, and ortho-hydroxy atorvastatin lactone had dose-dependent cytotoxic effects on hepatocytes. Simvastatin was more toxic than atorvastatin and the lactone form more toxic than the acid form. Exposure time affected atorvastatin and ortho-hydroxy atorvastatin lactone but not simvastatin toxicity.