title: Temporal evaluation of effects of a model 3β-hydroxysteroid dehydrogenase inhibitor on endocrine function in the fathead minnow.
abstract: Inhibition of enzymes involved in the synthesis of sex steroids can substantially impact developmental and reproductive processes controlled by the hypothalmic-pituitary-gonadal (HPG) axis. A key steroidogenic enzyme that has received little attention from a toxicological perspective is 3β-hydroxysteroid dehydrogenase (3β-HSD). In these studies, we exposed reproductively-active fathead minnows (Pimephales promelas) to the model 3β-HSD inhibitor trilostane at two test concentrations (300 and 1,500 µg/L) over a 16-d period that included both 8-d exposure and 8-d recovery phases. Plasma concentrations of 17β-estradiol (E2) in females were depressed within hours of exposure to the drug and remained decreased at the highest trilostane concentration throughout the 8-d exposure. Reductions in E2 were accompanied by decreases in plasma concentrations of the estrogen-responsive protein vitellogenin (VTG). During the recovery phase of the test, plasma E2 and VTG concentrations returned to levels comparable to those of controls, in the case of E2 within 1 d. Up-regulation of ovarian expression of gene products for follicle-stimulating hormone receptor (fshr) and aromatase (cyp19a1a) suggested active compensation in trilostane-exposed animals. Effects of trilostane on HPG-related endpoints in exposed males were less pronounced, although, as in females, up-regulation of gonadal fshr was seen. Data from these time-course studies provide insights as to direct impacts, compensatory responses, and recovery from effects associated with perturbation of a comparatively poorly characterized enzyme/pathway critical to sex steroid synthesis. This information is important to the design and interpretation of approaches for assessing the occurrence and effects of HPG-active chemicals in both the laboratory and the field.
authors.affiliation: US Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Lab, Duluth, Minnesota, USA. ankley.gerald@epa.gov
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Ankley
authors.forename: Jenna E
authors.initials: JE
authors.lastname: Cavallin
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Durhan
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: Dalma
authors.initials: D
authors.lastname: Martinovic-Weigelt
authors.forename: Leah C
authors.initials: LC
authors.lastname: Wehmas
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Villeneuve
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D003530:Cyprinidae; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000633:toxicity; D052244:Endocrine Disruptors / Q000633:toxicity; D004703:Endocrine System / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity*; D004958:Estradiol / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006066:Gonads / Q000378:metabolism; D008297:Male; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D011962:Receptors, FSH / Q000235:genetics / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D014819:Vitellogenins / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D052244:Endocrine Disruptors; D004791:Enzyme Inhibitors; D011962:Receptors, FSH; D014819:Vitellogenins; D014874:Water Pollutants, Chemical; D013196:Dihydrotestosterone; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D001141:Aromatase; C009954:trilostane