Transgenic Sertoli cell AR expression causes dose-dependent disruption of spermatogenesis and male fertility in mice (#132)
Androgen actions are essential for spermatogenesis. Androgen-deficiency or loss of functional androgen receptor (AR) causes spermatogenic arrest and infertility. Yet, androgen-dependent male germ cells do not express AR, demonstrating the functional importance of testicular AR-expressing somatic cells, like Sertoli cells. Recently, we created a unique transgenic (Tg) mouse model to determine the temporal role of Sertoli cell (SC) AR expression in spermatogenic development. The Tg SC-specific rat Abp promoter directed human AR (TgSCAR) expression, providing strong premature postnatal AR immunolocalized to SC nuclei, and induced precocious spermatogenic development. In TgSCAR adults, immunodetection of SCAR was confined to stage III-X seminiferous tubules, resembling the stage-specific SCAR expression pattern in WT testes. However, stronger staining of SC nuclei in stage III-V and VIII-X tubules from TgSAR versus WT testes suggested higher SCAR levels in TgSCAR testes. Comparison of independent TgSCAR lines with distinct levels of TgAR mRNA expression (qPCR) showed that TgSCAR dose-dependently reduced adult testis size (to 60% of normal), whereas androgen-dependent mature seminal vesicle weights and serum testosterone levels (LC-MSMS) remained normal. Detailed stereological analysis revealed that total adult SC numbers were reduced, despite normal circulating FSH levels (immunoassay). Comparison of total testicular germ cell populations demonstrated normal spermatogonia:Sertoli ratios and elevated spermatocyte:SC ratios in TgSCAR mice, indicating predominant SCAR-mediated control of meiotic development. In contrast, postmeiotic spermatid:SC ratios declined below normal. Despite smaller testes and reduced postmeiotic development, hemizygous TgSCAR males remained fertile. However, preliminary analysis of homozygous TgSCAR males has revealed infertile males exhibiting testes 35-40% of normal size, which had tubules with variable spermatogenic development, some devoid of germ cells displaying vacuolisation and SC nests. Therefore, our unique TgSCAR gain-of-function model shows, for the first time, a vital role for carefully regulated onset and expression levels of SC-specific AR for optimal spermatogenic development and male fertility.