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 (TgSCARm) expression reduced testis size but had no effect on male fertility. Here, we reveal that higher TgSCAR expression (TgSCARH) causes male infertility. Higher SCAR activity, shown by upregulated AR-dependent transcripts ( Rhox5, Spinw1), resulted in smaller adult TgSCARH testes (50% of normal) despite normal or elevated circulating and intratesticular testosterone levels. Unlike fertile TgSCARm males, testes of adult TgSCARH 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 TgSCARH 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 TgSCARH Sertoli cells were increased levels of apoptotic germ cells in TgSCARH relative to TgSCARm testes. In addition, TgSCARH 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.

Notch signaling regulates nuclear androgen receptor AR and membrane androgen receptor ZIP9 in mouse Sertoli cells

“…In gain‐of‐function mouse model with Sertoli cell‐specific transgenic AR, Hazra et al . () demonstrated altered Leydig cell function, markedly reduced Sertoli cell numbers, increased germ cell apoptosis, and, consequently, reduced sperm output, and disrupted fertility. These findings suggest that conditions linked to significantly upregulated AR in Sertoli cells may lead to spermatogenic impairment.…”

“…It was previously reported that elevated expression of the AR in Sertoli cell of adult male adversely affected testis physiology. In gain-of-function mouse model with Sertoli cell-specific transgenic AR, Hazra et al (2016) demonstrated altered Leydig cell function, markedly reduced Sertoli cell Figure 8 Effects of Notch pathway inhibition on testosterone-regulated claudin-5 and claudin-11 mRNA and protein expression. (A) Cells were treated with a vehicle (control, C), 10 nM testosterone (T), 50 lM DAPT, or 50 lM DAPT + 10 nM T for 24 h. (B) Cells were treated with transfection reagent (TR) alone (control, C), TR + non-targeting siRNA (negative control, NT), 50 nM RBP-J siRNA, TR + 50 nM RBP-J siRNA.…”

Does Propecia Cause More Harms than Good: Assessing Reproductive and Non-Reproductive Effects of Finasteride on Male Health

“…34 These findings point to possible mechanisms related to local androgen supersensitivity following inhibition of DHT by finasteride. In transgenic mice, upregulated androgen receptor expression specific to sertoli cells induced infertility, 35 suggesting that normal DHT levels after finasteride treatment with increased androgen receptor may underlie impaired spermatogenesis.…”

What Does Androgen Receptor Signaling Pathway in Sertoli Cells During Normal Spermatogenesis Tell Us?

“…When the AR transgene was injected into a prenatal mouse model, precocious maturation of SCs occurred and limited the window for SC proliferation. The production of fewer SCs can lead to lower-than-normal sperm output ( 74 ).…”