OVEREXPRESSION OF ANDROGEN-BINDING PROTEIN SEX HORMONE-BINDING GLOBULIN IN MALE TRANSGENIC MICE - TISSUE DISTRIBUTION AND PHENOTYPIC DISORDERS/

The rat androgen-binding protein/sex hormone-binding globulin (ABP/SHB G) gene in transgenic mice was previously shown to be specifically exp ressed in the testes. This study verifies a Sertoli cell location of A BP and translation of testicular ABP mRNA in the transgenic mice by di hydrotestosterone (DHT)binding assays and immunohistochemistry. DHT-bi nding activities in the testis and epididymis of the hemizygous transg enic mice were elevated 20-fold as compared to activity in the wildtyp e tissues. DHT-binding activities were also elevated in blood plasma a t least 25- to 50-fold in the transgenic mice; binding was undetectabl e in the plasma from control mice. Immunohistochemical analysis reveal ed that the transgenic testicular ABP was primarily in the cytoplasm o f Sertoli cells and lumen of the seminiferous tubules. In some tubules , intense staining also was associated with spermatids, After transpor t to the epididymis, there were large amounts of immunoreactive ABP in ternalized in the epithelium of the initial segment and proximal caput . The increased levels of plasma and testicular ABP had no effect on l evels of testosterone; there was a 30-fold range of plasma and testicu lar testosterone levels in the wild-type and transgenic mice. Increase d ABP levels in the transgenic mice were associated with structural an d functional abnormalities in the testis. Abnormal spermatogenesis res ulted in extensive structural changes in the transgenic testis; the de gree of the defect varied from near normality to the loss of most germ cells. In the affected mice, seminiferous tubules had smaller diamete rs and decreased numbers of germ cells, particularly in the spermatid stages of differentiation, Pyknotic nuclei and multinucleated cells we re associated with the spermatids in the defective tubules, but not in the wild-type tubules, Consequently, mice with the spermatogenic diso rder had reduced epididymal sperm numbers. The variable spermatogenic disorder was associated with variable male fertility. The homozygous t ransgenic male and female mice also had a serious motor dysfunction af fecting their hind limbs. This study demonstrates how the transgenic m ouse model can be used to study ABP's function, and the data support s everal hypotheses on its function in the testis and epididymis.