title: Testing the "read-across hypothesis" by investigating the effects of ibuprofen on fish.
abstract: Human pharmaceuticals present in the environment have the potential to cause adverse effects on non-target organisms. The "read-across hypothesis" stipulates that pharmaceuticals will exhibit similar biological effects across species (e.g. human and fish) if the molecular target has been conserved and the effective drug concentrations are reached (Cmax). We tested this hypothesis by evaluating if ibuprofen, a non-selective inhibitor of prostaglandins and the cyclooxygenase (COX) enzyme, can mimic its primary effect in humans, on fish, at comparable plasma concentrations. The endpoints, prostaglandin E metabolite (PGEM) levels and the mRNA expression of COX (ptgs) gene, were measured in the gills of control and exposed fathead minnows (Pimephales promelas), using enzyme-immunoassay and quantitative real-time PCR (qPCR). Fish were exposed, for 24-72 h, to measured water concentrations of 9 (n = 12), 370 (n = 40) and 470 μg ibuprofen/L (n = 12). Water and blood plasma concentrations were determined using LC-MS/MS. Results showed that PGEM levels in fish exposed to 370 and 470 μg ibuprofen/L were significantly decreased compared to control fish, when mean plasma ibuprofen concentrations were 1.8-5.6-fold below the Cmax. The plasma ibuprofen concentrations and PGEM levels varied greatly between individuals. In fish exposed to 9 μg ibuprofen/L, when the mean plasma ibuprofen concentration was 224-fold below Cmax, no change in PGEM levels was observed. These data provide evidence for the read-across hypothesis, but suggest establishing a direct dose-response between internal plasma and PGEM is difficult, and would require significantly larger numbers of fish to overcome the inter-individual variation.
authors: Biosciences, Institute of Environment, Health and Societies, Brunel University London, Uxbridge, Middlesex, UB8 3PH, United Kingdom.
authors: Alpa
authors: A
authors: Patel
authors: AstraZeneca, Brixham Environmental Laboratory, Freshwater Quarry, Brixham, Devon, TQ5 8BA, United Kingdom.
authors: Grace H
authors: GH
authors: Panter
authors: AstraZeneca, Brixham Environmental Laboratory, Freshwater Quarry, Brixham, Devon, TQ5 8BA, United Kingdom.
authors: Henry T
authors: HT
authors: Trollope
authors: AstraZeneca, Brixham Environmental Laboratory, Freshwater Quarry, Brixham, Devon, TQ5 8BA, United Kingdom.
authors: Yohanna C
authors: YC
authors: Glennon
authors: AstraZeneca, Brixham Environmental Laboratory, Freshwater Quarry, Brixham, Devon, TQ5 8BA, United Kingdom.
authors: Stewart F
authors: SF
authors: Owen
authors: Institute of Environment, Health and Societies, Brunel University London, Uxbridge, Middlesex, UB8 3PH, United Kingdom. Electronic address: John.Sumpter@Brunel.ac.uk.
authors: John P
authors: JP
authors: Sumpter
authors: Biosciences, Institute of Environment, Health and Societies, Brunel University London, Uxbridge, Middlesex, UB8 3PH, United Kingdom.
authors: Mariann
authors: M
authors: Rand-Weaver
mesh_terms: D000527:Alprostadil / Q000378:metabolism*; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003530:Cyprinidae / Q000502:physiology*; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood* / Q000737:chemistry / Q000235:genetics; D053719:Tandem Mass Spectrometry
chemical_list: D016861:Cyclooxygenase Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases; D000527:Alprostadil; D007052:Ibuprofen
keywords: Biological read-across; Blood plasma; Gene expression; Ibuprofen; Prostaglandin E metabolite