title: Elevated expression of the Sertoli cell androgen receptor disrupts male fertility.
abstract: Recently, we created a unique gain-of-function mouse model with Sertoli cell-specific transgenic androgen receptor expression (TgSCAR) showing that SCAR activity controls the synchronized postnatal development of somatic Sertoli and Leydig cells and meiotic-postmeiotic germ cells. Moderate TgSCAR (TgSCAR(m)) expression reduced testis size but had no effect on male fertility. Here, we reveal that higher TgSCAR expression (TgSCAR(H)) causes male infertility. Higher SCAR activity, shown by upregulated AR-dependent transcripts (Rhox5, Spinw1), resulted in smaller adult TgSCAR(H) testes (50% of normal) despite normal or elevated circulating and intratesticular testosterone levels. Unlike fertile TgSCAR(m) males, testes of adult TgSCAR(H) males exhibited focal regions of interstitial hypertrophy featuring immature adult Leydig cells and higher intratesticular dihydrotestosterone and 5α-androstane 3α,17β-diol levels that are normally associated with pubertal development. Mature TgSCAR(H) testes also exhibited markedly reduced Sertoli cell numbers (70%), although meiotic and postmeiotic germ cell/Sertoli cell ratios were twofold higher than normal, suggesting that elevated TgSCAR activity supports excessive spermatogenic development. Concurrent with the higher germ cell load of TgSCAR(H) Sertoli cells were increased levels of apoptotic germ cells in TgSCAR(H) relative to TgSCAR(m) testes. In addition, TgSCAR(H) testes displayed unique morphological degeneration that featured accumulated cellular and spermatozoa clusters in dilated channels of rete testes, consistent with reduced epididymal sperm numbers. Our findings reveal for the first time that excessive Sertoli cell AR activity in mature testes can reach a level that disturbs Sertoli/germ cell homeostasis, impacts focal Leydig cell function, reduces sperm output, and disrupts male fertility.
authors.affiliation: ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, New South Wales, Australia.
authors.forename: Rasmani
authors.initials: R
authors.lastname: Hazra
authors.affiliation: ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, New South Wales, Australia.
authors.forename: Dannielle
authors.initials: D
authors.lastname: Upton
authors.affiliation: ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, New South Wales, Australia.
authors.forename: Reena
authors.initials: R
authors.lastname: Desai
authors.affiliation: ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, New South Wales, Australia.
authors.forename: Omar
authors.initials: O
authors.lastname: Noori
authors.affiliation: ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, New South Wales, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Jimenez
authors.affiliation: ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, New South Wales, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Handelsman
authors.affiliation: ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, New South Wales, Australia charles@anzac.edu.au.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Allan
mesh_terms: D015113:Androstane-3,17-diol / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000378:metabolism; D004822:Epididymis; D005298:Fertility / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D008540:Meiosis; D008822:Mice, Transgenic; D010880:Piperidines / Q000378:metabolism*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000235:genetics; D011506:Proteins / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics*; D012152:Rete Testis / Q000473:pathology; D012708:Sertoli Cells / Q000378:metabolism*; D013091:Spermatogenesis; D013094:Spermatozoa; D013737:Testis; D014157:Transcription Factors / Q000235:genetics
chemical_list: D001549:Benzamides; D018398:Homeodomain Proteins; C543004:N-phenyl-N-(1-(piperidine-1-carbonyl)cyclohexyl)benzamide; D010880:Piperidines; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011944:Receptors, Androgen; C498048:Rhox5 protein, mouse; D014157:Transcription Factors; C477828:eppin protein, mouse; D013196:Dihydrotestosterone; D015113:Androstane-3,17-diol
keywords: Sertoli cell; androgen; spermatogenesis; testis; transgenic mouse