Treatment of Ca(2+) channel blockers (CCB) to relieve hypertension causes reversible male infertility, suggesting deregulation of Ca(2+) homeostasis in testis is closely related with male infertility. To investigate the possible toxicity of therapeutic application of CCB in childhood, the effect of nifedipine and ethosuximide, an L-type and T-type CCB, respectively, on the spermatogenesis and testicular gene expression was examined. Following the intraperitoneal injection of either drug for 7 days to 18 days on old mice, the paired testes weights were significantly lower in mice treated with nifedipine (> or = 10 mg/kg/day) or ethosuximide (100 mg/kg/day) than vehicle controls. In mice given high drug dosing (100 mg/kg), seminiferous tubules showed immaturity with spermatogenic arrest at elongating spermatid stage and poorly developed lumen. Unexpectedly, the expression of activator isoform of transcription factor cAMP-responsive element modulator (CREM) mRNA increased together with transition protein 2 and protamine 2 mRNA in drug-treated mice testes, suggesting that CCB may deregulate expression of activator isoform of CREM in male germ cells and that spermatogenic defect following CCB treatment may attribute to ectopic expression of CREM-dependent gene battery in testis. Therapeutic application of CCB in childhood should be cautious because of their potential to cause spermatogenic defect and altered gene expression in testis.

& b-catenin is a multifunctional molecule that functions in intercellular adhesion and signal transduction during assembly of AJs between Sertoli cells as well as between Sertoli cells and germ cells. To assess changes in the testicular b-catenin in male infertility conditions, testicular tissues from obstructive azoospermia with normal spermatogenesis, spermatogenic arrest (SA) and Sertoli cell-only syndrome (SCO) patients were examined for immunohistochemical localization of b-catenin. In normal spermatogenic tissue, expression of b-catenin was largely found in the Sertoli cell-germ cell (primarily spermatocytes) contact areas. Interestingly, perinuclear localization of b-catenin was found in spermatocytes and spermatids. In spermatogenic arrest, b-catenin in cell contact areas between Sertoli cells and germ cells was greatly decreased, but perinuclear b-catenin in spermatocytes was not. In SCO, weak or negligible immunoreactivity of b-catenin was found in cell contacts between Sertoli cells. Nuclear localization of b-catenin was found in myotubular cells in all samples. Taken together, altered expression of b-catenin in cell contacts within the seminiferous epithelia in spermatogenic arrest and SCO suggests that interactions between Sertoli cells and germ cell are crucial for expression of b-catenin, and thus functional development of AJs in seminiferous epithelia in human testis. It should be also emphasized that perinuclear b-catenin in germ cells may play a specific role in spermatogenesis.