Overexpression of Androgen-Binding Protein/Sex Hormone-Binding Globulin in Male Transgenic Mice: Tissue Distribution and Phenotypic Disorders1

Abstract

The rat androgen-binding protein/sex hormone-binding globulin (ABP/SHBG) gene in transgenic mice was previously shown to be specifically expressed in the testes. This study verifies a Sertoli cell location of ABP and translation of testicular ABP mRNA in the transgenic mice by dihydrotestosterone (DHT)-binding assays and immunohistochemistry. DHT-binding activities in the testis and epididymis of the hemizygous transgenic mice were elevated 20-fold as compared to activity in the wild-type tissues. DHT-binding activities were also elevated in blood plasma at least 25- to 50-fold in the transgenic mice; binding was undetectable in the plasma from control mice. Immunohistochemical analysis revealed that the transgenic testicular ABP was primarily in the cytoplasm of Sertoli cells and lumen of the seminiferous tubules. In some tubules, intense staining also was associated with spermatids. After transport to the epididymis, there were large amounts of immunoreactive ABP internalized in the epithelium of the initial segment and proximal caput. The increased levels of plasma and testicular ABP had no effect on levels of testosterone; there was a 30-fold range of plasma and testicular testosterone levels in the wild-type and transgenic mice. Increased ABP levels in the transgenic mice were associated with structural and functional abnormalities in the testis. Abnormal spermatogenesis resulted in extensive structural changes in the transgenic testis; the degree of the defect varied from near normality to the loss of most germ cells. In the affected mice, seminiferous tubules had smaller diameters and decreased numbers of germ cells, particularly in the spermatid stages of differentiation. Pyknotic nuclei and multinucleated cells were associated with the spermatids in the defective tubules, but not in the wild-type tubules. Consequently, mice with the spermatogenic disorder had reduced epididymal sperm numbers. The variable spermatogenic disorder was associated with variable male fertility. The homozygous transgenic male and female mice also had a serious motor dysfunction affecting their hind limbs. This study demonstrates how the transgenic mouse model can be used to study ABP's function, and the data support several hypotheses on its function in the testis and epididymis.

Effect of intra-testicular melatonin injection on testicular functions, local and general immunity of a tropical rodent Funambulus pennanti

“…2). Androgen binding protein was detected as a single major band between 45 and 50 kDa in the testes, which precisely corresponds to the predicted molecular mass of the receptor, i.e., 47 kDa [24,25]. AR percent expression in testes decreased significantly (P \ 0.01) after 10 days treatment (MI-10D) and a further decrease was noted following treatment for 20 days (MI-20D) (P \ 0.01) when compared with the control group (Fig.…”

Effects of Maternal Exposure to Low Doses of DES on Testicular Steroidogenesis and Spermatogenesis in Male Rat Offspring

“…Transgenic mice overexpressing rat androgen-binding protein in their testes show progressive abnormalities of spermatogenesis, eventually leading to infertility [51,52]. ABP-transgenic mice have increased total intratesticular testosterone concentrations but decreased free testosterone levels, suggesting that the decrease in the availability of free testosterone lowers germ cell numbers and reduces fertility [53].…”

Developmentally distinct in vivo effects of FSH on proliferation and apoptosis during testis maturation

“…Yes; Sertoli cells (Skinner et al 1989, Danzo 1995, Larriba et al 1995, Joseph et al 1997 Yes; (Arkblad et al 2002) No…”

“…(McLean et al 2002) and in vivo studies to be one of the wide variety of transcriptional regulators of StAR mRNA synthesis (Gregory & De Phillip 1998, Manna et al 2003. Cyclin D2 and androgen binding protein (ABP) are additional Sertoli cell proteins up-regulated by FSH that are required for normal testicular function (Skinner et al 1989, Danzo 1995, Larriba et al 1995, Sicinski et al 1996, Joseph et al 1997, while protein C inhibitor, also required for spermatogenesis (Uhrin et al 2000, Odet et al 2003, appears to be synthesized only in germ cells and Leydig cells (Odet et al 2003). In vivo confirmation of the negative regulation by FSH of genes encoding insulin-like growth factor binding protein-3 (IGFBP-3) (Smith et al 1990, Rappaport & Smith 1995, Khan et al 2002, HNF-3/ forkhead (Wolfrum et al 2003), transferring (Kaestner et al 1998), endothelin-1 (Fantoni et al 1993, Tripiciano et al 1999) and cathepsin-L (Penttila et al 1995, Wright et al 2003) is presented.…”