Effects of the lipid regulating drug clofibric acid on PPARα-regulated gene transcript levels in common carp (Cyprinus carpio) at pharmacological and environmental exposure levels.
In mammals, the peroxisome proliferator-activated receptor α (PPARα) plays a key role in regulating various genes involved in lipid metabolism, bile acid synthesis and cholesterol homeostasis, and is activated by a diverse group of compounds collectively termed peroxisome proliferators (PPs). Specific PPs have been detected in the aquatic environment; however little is known on their pharmacological activity in fish. We investigated the bioavailability and persistence of the human PPARα ligand clofibric acid (CFA) in carp, together with various relevant endpoints, at a concentration similar to therapeutic levels in humans (20mg/L) and for an environmentally relevant concentration (4μg/L). Exposure to pharmacologically-relevant concentrations of CFA resulted in increased transcript levels of a number of known PPARα target genes together with increased acyl-coA oxidase (Acox1) activity, supporting stimulation of lipid metabolism pathways in carp which are known to be similarly activated in mammals. Although Cu,Zn-superoxide dismutase (Sod1) activity was not affected, mRNA levels of several biotransformation genes were also increased, paralleling previous reports in mammals and indicating a potential role in hepatic detoxification for PPARα in carp. Importantly, transcription of some of these genes (and Acox1 activity) were affected at exposure concentrations comparable with those reported in effluent discharges. Collectively, these data suggest that CFA is pharmacologically active in carp and has the potential to invoke PPARα-related responses in fish exposed in the environment, particularly considering that CFA may represent just one of a number of PPAR-active compounds present to which wild fish may be exposed.
University of Exeter, Biosciences, College of Life & Environmental Sciences, Exeter EX4 4QD, UK. Electronic address: J.F.Corcoran@exeter.ac.uk.
Jenna
J
Corcoran
AstraZeneca Global Environment, Brixham Laboratory, Freshwater Quarry, Brixham TQ5 8BA, UK. Electronic address: M.Winter@exeter.ac.uk.
Matthew J
MJ
Winter
University of Exeter, Biosciences, College of Life & Environmental Sciences, Exeter EX4 4QD, UK. Electronic address: A.Lange@exeter.ac.uk.
Anke
A
Lange
AstraZeneca Global Environment, Brixham Laboratory, Freshwater Quarry, Brixham TQ5 8BA, UK. Electronic address: Rob.Cumming@astrazeneca.com.
Rob
R
Cumming
AstraZeneca Global Environment, Brixham Laboratory, Freshwater Quarry, Brixham TQ5 8BA, UK. Electronic address: Stewart.Owen@astrazeneca.com.
Stewart F
SF
Owen
University of Exeter, Biosciences, College of Life & Environmental Sciences, Exeter EX4 4QD, UK. Electronic address: C.R.Tyler@exeter.ac.uk.
Charles R
CR
Tyler
D042962:Acyl-CoA Oxidase / Q000378:metabolism; D000818:Animals; D002347:Carps / Q000235:genetics / Q000502:physiology*; D002995:Clofibric Acid / Q000378:metabolism / Q000633:toxicity*; D004781:Environmental Exposure; D050356:Lipid Metabolism / Q000187:drug effects; D057847:Lipid Regulating Agents; D008099:Liver / Q000187:drug effects; D047493:PPAR alpha / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000378:metabolism / Q000633:toxicity
D057847:Lipid Regulating Agents; D047493:PPAR alpha; D012333:RNA, Messenger; D014874:Water Pollutants, Chemical; D002995:Clofibric Acid; D042962:Acyl-CoA Oxidase
Acyl-coA oxidase (Acox1); Bile acid synthesis; Clofibric acid; Drug metabolism; Fibrate; Lipid metabolism; Peroxisomal β-oxidation; Peroxisome proliferator activated receptor α (PPARα); Teleost fish