title: Environmental chemicals active as human antiandrogens do not activate a stickleback androgen receptor but enhance a feminising effect of oestrogen in roach.
abstract: Sexual disruption is reported in wild fish populations living in freshwaters receiving discharges of wastewater treatment works (WwTW) effluents and is associated primarily with the feminisation of males by exposure to oestrogenic chemicals. Antiandrogens could also contribute to the feminisation of male fish, but there are far less data supporting this hypothesis and almost nothing is known for the effects of oestrogens in combination with antiandrogens in fish. We conducted a series of in vivo exposures in two fish species to investigate the potency on reproductive-relevant endpoints of the antiandrogenic antimicrobials triclosan (TCS), chlorophene (CP) and dichlorophene (DCP) and the resin, abietic acid (AbA), all found widely in WwTW effluents. We also undertook exposures with a mixture of antiandrogens and a mixture of antiandrogens in combination with the oestrogen 17α-ethinyloestradiol (EE2). In stickleback (Gasterosteus aculeatus), DCP showed a tendency to reduce spiggin induction in females androgenised by dihydrotestosterone (DHT), but these findings were not conclusive. In roach (Rutilus rutilus), exposures to DCP (178 days), or a mixture of TCS, CP and AbA (185 days), or to the model antiandrogen flutamide (FL, 178 days) had no effect on gonadal sex ratio or on the development of the reproductive ducts. Exposure to EE2 (1.5ng/L, 185 days) induced feminisation of the ducts in 17% of the males and in the mixture of antiandrogens (TCS, CP, AbA) in combination with EE2, almost all (96%) of the males had a feminised reproductive ducts. In stickleback androgen receptor (ARα and ARβ) transactivation assays, the model antiandrogens, FL and procymidone inhibited 11-ketotestosterone (11-KT) induced receptor activation, but none of the human antiandrogens, TCS, CP, DCP and AbA had an effect. These data indicate that antimicrobial antiandrogens in combination can contribute to the feminisation process in exposed males, but they do not appear to act through the androgen receptor in fish.
authors.affiliation: University of Exeter, Biosciences, College of Life & Environmental Sciences, Exeter EX4 4QD, United Kingdom. Electronic address: A.Lange@exeter.ac.uk.
authors.forename: Anke
authors.initials: A
authors.lastname: Lange
authors.affiliation: University of Exeter, Biosciences, College of Life & Environmental Sciences, Exeter EX4 4QD, United Kingdom; Cefas Weymouth Laboratory, Barrack Road, The Nothe, Weymouth, Dorset DT4 8UB, United Kingdom.
authors.forename: Marion
authors.initials: M
authors.lastname: Sebire
authors.affiliation: University of Sussex, School of Life Sciences, Brighton BN1 9QJ, United Kingdom.
authors.forename: Pawel
authors.initials: P
authors.lastname: Rostkowski
authors.affiliation: Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, and Department of Basic Biology, School of Life Science, SOKENDAI (Graduate University for Advanced Studies), 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mizutani
authors.affiliation: Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, and Department of Basic Biology, School of Life Science, SOKENDAI (Graduate University for Advanced Studies), 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Miyagawa
authors.affiliation: Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, and Department of Basic Biology, School of Life Science, SOKENDAI (Graduate University for Advanced Studies), 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan.
authors.forename: Taisen
authors.initials: T
authors.lastname: Iguchi
authors.affiliation: University of Sussex, School of Life Sciences, Brighton BN1 9QJ, United Kingdom.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Hill
authors.affiliation: University of Exeter, Biosciences, College of Life & Environmental Sciences, Exeter EX4 4QD, United Kingdom. Electronic address: C.R.Tyler@exeter.ac.uk.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Tyler
mesh_terms: D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D003530:Cyprinidae / Q000502:physiology*; D004347:Drug Interactions; D004967:Estrogens / Q000633:toxicity*; D005260:Female; D006066:Gonads / Q000187:drug effects*; D006801:Humans; D008297:Male; D011944:Receptors, Androgen / Q000378:metabolism; D023701:Smegmamorpha / Q000502:physiology*; D014874:Water Pollutants, Chemical / Q000633:toxicity
chemical_list: D000726:Androgen Antagonists; D004967:Estrogens; D011944:Receptors, Androgen; D014874:Water Pollutants, Chemical
keywords: Antiandrogen; Endocrine disruption; Feminisation; Fish; Mixture; Oestrogen