title: Characterization of responses to the antiandrogen flutamide in a short-term reproduction assay with the fathead minnow.
abstract: A short-term reproduction assay with the fathead minnow (Pimephales promelas) has been developed to detect chemicals with the potential to disrupt reproductive endocrine function controlled by estrogen- and androgen-mediated pathways. The objective of this study was to use the assay to characterize responses of fathead minnow reproductive endocrinology and physiology to the mammalian antiandrogen, flutamide. Male and female fish were exposed to nominal (target) concentrations of 50 and 500 microg flutamide/l for 21-days, following which plasma steroid and vitellogenin concentrations were determined and gonadal morphology assessed. Fecundity of the fish was significantly reduced by exposure to a measured test concentration of 651 microg flutamide/l. In addition, embryo hatch was significantly reduced at this concentration. Qualitative histological assessment of ovaries from females exposed to flutamide indicated a decrease in mature oocytes and an increase in atretic follicles. Testes of males exposed to flutamide exhibited spermatocyte degeneration and necrosis. Concentration-dependent increases in plasma testosterone and vitellogenin concentrations were observed in the females. Flutamide also altered reproductive endocrinology of male fathead minnows. Males exposed to 651 microg flutamide/l exhibited elevated concentrations of beta-estradiol and vitellogenin. In summary, the results of this study with the fathead minnow demonstrate that flutamide affects reproductive endocrine function in fish and that the type of hormonal pattern and histopathology effects observed are consistent with an antiandrogenic mode-of-action. Consequently, our findings suggest that the 21-day reproduction assay utilizing fathead minnows is a sensitive short-term screening method for the detection of endocrine-disrupting chemicals, including antiandrogens.
authors.affiliation: U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Boulevard, Duluth, MN 55804 USA. jensen.kathleen@epa.gov
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Jensen
authors.forename: Michael D
authors.initials: MD
authors.lastname: Kahl
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Makynen
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Korte
authors.forename: Richard L
authors.initials: RL
authors.lastname: Leino
authors.forename: Brian C
authors.initials: BC
authors.lastname: Butterworth
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Ankley
mesh_terms: D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D003530:Cyprinidae / Q000097:blood / Q000502:physiology*; D004958:Estradiol / Q000097:blood; D005260:Female; D005485:Flutamide / Q000633:toxicity*; D006651:Histocytochemistry / Q000662:veterinary; D008297:Male; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D011863:Radioimmunoassay; D012098:Reproduction / Q000187:drug effects*; D013737:Testis / Q000187:drug effects / Q000473:pathology; D013739:Testosterone / Q000031:analogs & derivatives* / Q000097:blood; D018675:Toxicity Tests / Q000379:methods; D014819:Vitellogenins / Q000097:blood; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D000726:Androgen Antagonists; D014819:Vitellogenins; D014874:Water Pollutants, Chemical; D013739:Testosterone; D004958:Estradiol; D005485:Flutamide; C003600:11-ketotestosterone