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Mice Overexpressing the Mitochondrial Phospholipid Hydroperoxide Glutathione Peroxidase in Male Germ Cells Show Abnormal Spermatogenesis and Reduced Fertility

Department of Histology and Medical Embryology (R.P., G.C., M.S., C.B.); Department of Psychology, Section of Neuroscience (A.B., F.M.), Department of Medical Pathophysiology (A.L., L.G.), Istituto Pasteur-Fondazione Cenci Bolognetti (F.M.), Sapienza University of Rome, 00161 Rome, Italy

Address all correspondence and requests for reprints to: Dr. Carla Boitani, Department of Histology and Medical Embryology, Via A. Scarpa 14, 00161 Roma, Italy. E-mail: carla.boitani{at}uniroma1.it.

To investigate the physiological effects of mitochondrial phospholipid hydroperoxide glutathione peroxidase (mPHGPx) overexpression during early male germ cell differentiation, we have generated transgenic mice bearing the rat mPhgpx coding sequence driven by the mouse synaptonemal complex protein 1 promoter, allowing the transgene to be specifically activated in the testis from the zygotene to diplotene stages of the first meiotic division. Northern/Western blotting and immunocytochemical analyses of endogenous mPHGPx expression during spermatogenesis showed a low enzyme level in middle-late pachytene spermatocytes, but not in earlier meiotic stages, and a significant increase in mPHGPx content in round spermatids. The histological and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling analysis of transgenic testes revealed a number of spermatogenetic defects, including primary spermatocyte apoptosis, haploid cell loss, and seminiferous epithelium disorganization. In line with these features, adult transgenic male mice also displayed a reduction in fertility. Results obtained in this study suggest that mPHGPx expression is tightly regulated in pachytene spermatocytes, with any spatial-temporal increase in mPHGPx expression resulting in damage to spermatogenesis and eventual loss of haploid cells. Present findings in the mouse may be of interest to human male fertility.