title: Bioavailability and Kidney Responses to Diclofenac in the Fathead Minnow (Pimephales promelas).
abstract: Diclofenac is one of the most widely prescribed nonsteroidal anti-inflammatory drugs worldwide. It is frequently detected in surface waters; however, whether this pharmaceutical poses a risk to aquatic organisms is debated. Here we quantified the uptake of diclofenac by the fathead minnow (Pimephales promelas) following aqueous exposure (0.2-25.0 μg L-1) for 21 days, and evaluated the tissue and biomolecular responses in the kidney. Diclofenac accumulated in a concentration- and time-dependent manner in the plasma of exposed fish. The highest plasma concentration observed (for fish exposed to 25 μg L-1diclofenac) was within the therapeutic range for humans. There was a strong positive correlation between exposure concentration and the number of developing nephrons observed in the posterior kidney. Diclofenac was not found to modulate the expression of genes in the kidney associated with its primary mode of action in mammals (prostaglandin-endoperoxide synthases) but modulated genes associated with kidney repair and regeneration. There were no significant adverse effects following 21 days exposure to concentrations typical of surface waters. The combination of diclofenac's uptake potential, effects on kidney nephrons and relatively small safety margin for some surface waters may warrant a longer term chronic health effects analysis for diclofenac in fish.
authors.affiliation: Biosciences, College of Life and Environmental Sciences, University of Exeter , Exeter, EX4 4QD, U.K.
authors.forename: Lisa K
authors.identifier: 0000-0003-2986-8746
authors.initials: LK
authors.lastname: Bickley
authors.affiliation: Biosciences, College of Life and Environmental Sciences, University of Exeter , Exeter, EX4 4QD, U.K.|Centre for Environment, Fisheries, and Aquaculture Science (Cefas), Barrack Road, The Nothe, Weymouth, Dorset DT4 8UB, U.K.
authors.forename: Ronny
authors.initials: R
authors.lastname: van Aerle
authors.affiliation: Biosciences, College of Life and Environmental Sciences, University of Exeter , Exeter, EX4 4QD, U.K.
authors.forename: A Ross
authors.initials: AR
authors.lastname: Brown
authors.affiliation: AstraZeneca Drug Safety and Metabolism, Alderley Park, Macclesfield, Cheshire SK10 4TF, U.K.|PathCelerate Ltd. The BioHub at Alderley Park, Alderley Edge, Cheshire SK10 4TG, U.K.
authors.forename: Adam
authors.initials: A
authors.lastname: Hargreaves
authors.affiliation: Bioscript, St Peter's Institute , Macclesfield, Cheshire SK11 7HS, U.K.
authors.forename: Russell
authors.initials: R
authors.lastname: Huby
authors.affiliation: AstraZeneca Global Environment, Alderley Park, Macclesfield, Cheshire SK10 4TF, U.K.
authors.forename: Victoria
authors.initials: V
authors.lastname: Cammack
authors.affiliation: AstraZeneca Drug Safety and Metabolism, Alderley Park, Macclesfield, Cheshire SK10 4TF, U.K.|Institute of Psychiatry, Psychology and Neuroscience, King's College London , De Crespigny Park, Box 63, SE5 8AF, London, U.K.
authors.forename: Richard
authors.initials: R
authors.lastname: Jackson
authors.affiliation: Biosciences, College of Life and Environmental Sciences, University of Exeter , Exeter, EX4 4QD, U.K.
authors.forename: Eduarda M
authors.initials: EM
authors.lastname: Santos
authors.affiliation: Biosciences, College of Life and Environmental Sciences, University of Exeter , Exeter, EX4 4QD, U.K.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Tyler
mesh_terms: D000818:Animals; D001682:Biological Availability; D003530:Cyprinidae / Q000378:metabolism; D004008:Diclofenac / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000378:metabolism
chemical_list: D014874:Water Pollutants, Chemical; D004008:Diclofenac