title: Evaluation of the 5α-reductase inhibitor finasteride on reproduction and gonadal development in medaka, Oryzias latipes.
abstract: 5-α reductase (5αR) inhibitors have an anti-androgenic effect in mammals because they inhibit the conversion of testosterone to the potent androgen, dihydrotestosterone. Finasteride is a type-2 5αR inhibitor that is used as a human pharmaceutical for the treatment of prostate cancer, benign prostate hyperplasia and male pattern baldness. This study evaluated the impacts of finasteride (50, 500 and 5000μg/L) on the development and reproduction of medaka (Oryzias latipes) exposed continuously over multiple generations (F0, F1 and F2). The exposure was initiated with reproductively mature fish (F0 generation) and continued until the hatching of the F2 generation. There were no significant effects on survival, fecundity or fertility in the F0 (50, 500, 5000μg/L) and F1 (50, 500μg/L) generations. The F1 generation exposed to 5000μg/L exhibited significant mortality. Histopathology of the gonads demonstrated that medaka and pre-clinical species respond similarly to finasteride exposure. Intersex condition and maldeveloped gonads were observed in F0 generation males exposed to 5000μg/L and F1 generation males exposed to 500μg/L. F1 generation males exposed to 500μg/L displayed reduced gonadosomatic index with an increased incidence of testicular degeneration. Males in both generations exhibited an increased incidence of Leydig cell hyperplasia at concentrations ⩾500μg/L. F0 generation females exposed to 5000μg/L exhibited increased gonadosomatic index. An increased prevalence of accelerated post-ovulatory follicle involution was observed in females at concentrations ⩾500μg/L in both generations. The gonadal changes induced by finasteride support the idea that 5-α reductase inhibition impacts androgen signaling in fish. Results from this study are discussed in the context of differential expression of the androgen receptor between species of fish.
authors.affiliation: University of Massachusetts Dartmouth, 238 Old Westport Road, North Dartmouth, MA 02747, USA; Smithers Viscient, 790 Main Street, Wareham, MA 02571, USA. Electronic address: mlee1@umassd.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lee
authors.affiliation: Smithers Viscient, 790 Main Street, Wareham, MA 02571, USA.
authors.forename: Jana R
authors.initials: JR
authors.lastname: Loux-Turner
authors.affiliation: University of Massachusetts Dartmouth, 238 Old Westport Road, North Dartmouth, MA 02747, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Oliveira
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology*; D000728:Androgens / Q000378:metabolism; D000818:Animals; D013196:Dihydrotestosterone / Q000378:metabolism; D012734:Disorders of Sex Development; D005260:Female; D005298:Fertility / Q000187:drug effects; D018120:Finasteride / Q000494:pharmacology*; D006066:Gonads / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D008297:Male; D009990:Oryzias / Q000502:physiology*; D006080:Ovarian Follicle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D036801:Parturition; D011944:Receptors, Androgen / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D013739:Testosterone / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D000728:Androgens; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone; D018120:Finasteride
keywords: Androgen receptor; Intersex; Multi-generation; Post-ovulatory follicle involution; Rao–Scott Cochran–Armitage by slices; Teleost