title: Waterborne beclomethasone dipropionate affects the physiology of fish while its metabolite beclomethasone is not taken up.
abstract: Asthma is commonly treated with inhalable glucocorticosteroids, including beclomethasone dipropionate (BDP). This is a synthetic prodrug which is metabolized to the more active monopropionate (BMP) and free beclomethasone in humans. To evaluate potential effects of residual drugs on fish, we conducted a 14 day flow-through exposure experiment with BDP and beclomethasone using rainbow trout, and analyzed effects on plasma glucose, hepatic glutathione and catalase activity together with water and body concentrations of the BDP, BMP and beclomethasone. We also analyzed hepatic gene expression in BDP-exposed fish by microarray and quantitative PCR. Beclomethasone (up to 0.65 μg/L) was not taken up in the fish while BDP (0.65 and 0.07 μg/L) resulted in accumulation of both beclomethasone, BMP and BDP in plasma, reaching levels up to those found in humans during therapy. Accordingly, exposure to 0.65 μg/L of BDP significantly increased blood glucose as well as oxidized glutathione levels and catalase activity in the liver. Exposure to beclomethasone or the low concentration of BDP had no effect on these endpoints. Both exposure concentrations of BDP resulted in significantly higher transcript abundance of phosphoenolpyruvate carboxykinase involved in gluconeogenesis, and of genes involved in immune responses. As only the rapidly metabolized prodrug was potent in fish, the environmental risks associated with the use of BDP are probably small. However, the observed physiological effects in fish of BDP at plasma concentrations known to affect human physiology provides valuable input to the development of read-across approaches in the identification of pharmaceuticals of environmental concern.
authors.affiliation: Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Box 430, SE-405 30 Göteborg, Sweden. Electronic address: bethanie.carney@bioenv.gu.se.
authors.forename: Bethanie M
authors.initials: BM
authors.lastname: Carney Almroth
authors.affiliation: Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Box 440, SE-405 30 Göteborg, Sweden. Electronic address: lina.gunnarsson@fysiologi.gu.se.
authors.forename: Lina M
authors.initials: LM
authors.lastname: Gunnarsson
authors.affiliation: Genomics Core Facility at the Sahlgrenska Academy, University of Gothenburg, Box 413, SE-405 30 Göteborg, Sweden. Electronic address: filip.stern@gu.se.
authors.forename: Filip
authors.initials: F
authors.lastname: Cuklev
authors.affiliation: Department of Chemistry, Umeå University, Linaeus väg 10, SE-907 36 Umeå, Sweden. Electronic address: jerker.fick@umu.se.
authors.forename: Jerker
authors.initials: J
authors.lastname: Fick
authors.affiliation: Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, SE-412 96 Göteborg, Sweden. Electronic address: erik.kristiansson@chalmers.se.
authors.forename: Erik
authors.initials: E
authors.lastname: Kristiansson
authors.affiliation: Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Box 440, SE-405 30 Göteborg, Sweden. Electronic address: joakim.larsson@fysiologi.gu.se.
authors.forename: D G Joakim
authors.initials: DG
authors.lastname: Larsson
mesh_terms: D000818:Animals; D001507:Beclomethasone / Q000633:toxicity*; D002374:Catalase / Q000378:metabolism; D005399:Fishes / Q000502:physiology*; D005938:Glucocorticoids / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D005938:Glucocorticoids; D014874:Water Pollutants, Chemical; D002374:Catalase; D005978:Glutathione; D001507:Beclomethasone
keywords: Asthma medicine; Beclomethasone dipropionate; Environmental risk assessment; Gene expression; Glucocorticoid; Rainbow trout