title: Mode of action of human pharmaceuticals in fish: the effects of the 5-alpha-reductase inhibitor, dutasteride, on reproduction as a case study.
abstract: In recent years, a growing number of human pharmaceuticals have been detected in the aquatic environment, generally at low concentrations (sub-ng/L-low μg/L). In most cases, these compounds are characterised by highly specific modes of action, and the evolutionary conservation of drug targets in wildlife species suggests the possibility that pharmaceuticals present in the environment may cause toxicological effects by acting through the same targets as they do in humans. Our research addressed the question of whether or not dutasteride, a pharmaceutical used to treat benign prostatic hyperplasia, may cause adverse effects in a teleost fish, the fathead minnow (Pimephales promelas), by inhibiting the activity of both isoforms of 5α-reductase (5αR), the enzyme that converts testosterone into dihydrotestosterone (DHT). Mammalian pharmacological and toxicological information were used to guide the experimental design and the selection of relevant endpoints, according to the so-called "read-across approach", suggesting that dutasteride may affect male fertility and steroid hormone dynamics. Therefore, a 21-day reproduction study was conducted to determine the effects of dutasteride (10, 32 and 100 μg/L) on fish reproduction. Exposure to dutasteride significantly reduced fecundity of fish and affected several aspects of reproductive endocrine functions in both males and females. However, none of the observed adverse effects occurred at concentrations of exposure lower than 32 μg/L; this, together with the low volume of drug prescribed every year (10.34 kg in the UK in 2011), and the extremely low predicted environmental concentration (0.03 ng/L), suggest that, at present, the potential presence of dutasteride in the environment does not represent a threat to wild fish populations.
authors.affiliation: Brunel University, Institute for the Environment, Uxbridge, Middlesex, UK. Luigi.Margiotta-Casaluci@brunel.ac.uk
authors.forename: Luigi
authors.initials: L
authors.lastname: Margiotta-Casaluci
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hannah
authors.forename: John P
authors.initials: JP
authors.lastname: Sumpter
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000633:toxicity*; D000818:Animals; D001378:Azasteroids / Q000032:analysis / Q000633:toxicity*; D049628:Body Size / Q000187:drug effects; D003530:Cyprinidae / Q000502:physiology*; D000068538:Dutasteride; D005260:Female; D012739:Gonadal Steroid Hormones / Q000097:blood; D006066:Gonads / Q000187:drug effects; D008297:Male; D012098:Reproduction / Q000187:drug effects*; D012727:Sex Characteristics; D013094:Spermatozoa / Q000187:drug effects; D014819:Vitellogenins / Q000097:blood; D014867:Water / Q000737:chemistry; D014874:Water Pollutants, Chemical / Q000032:analysis / Q000633:toxicity*
chemical_list: D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D012739:Gonadal Steroid Hormones; D014819:Vitellogenins; D014874:Water Pollutants, Chemical; D014867:Water; D000068538:Dutasteride