Peroxiredoxin 4 knockout results in elevated spermatogenic cell death via oxidative stress

Prx (peroxiredoxin) is a multifunctional redox protein with thioredoxin-dependent peroxidase activity. Prx4 is present as a secretory protein ill Most tissues, whereas in sexually mature testes it is anchored in the ER (endoplasmic reticulum) membrane of spermatogenic cells via an uncleaved N-terminal hydrophobic peptide. We generated a Prx4 knockout mouse to investigate the function of Prx4 in vivo. Prx4 mice lacking Prx4 expression in all cells were obtained by mating Prx(thox/+) female mice with Cre-transgenic male mice that ubiquitously expressed Cre recombinase. The resulting Prx4 male mice were fertile, and most organs were nearly normal in size, except for testicular atrophy. The number deoxynucleotidyl transferase-mediated dUTP nick end labelling-positive spermatogenic cells was higher, in Prx mice than in Prx4 mice and increased remarkably in response it) warming the lower abdomen at 43 degrees C for 15 min. Cells reactive to antibodies against 4-hydroxynonenal and 8-hydroxyguanine were high in the Prx4 ' mice and concomitant with elevated oxidation of lipid and protein thiols. The cauda epididymis of Prx4 mice contained round spermatocytes, which were not found in Prx4 mice, and displayed oligozoospermia. However, mature spermatozoa from the epididymis of Prx mice exhibited normal fertilization in vitro. Taken together, these results indicate that spermatogenic cells lacking Prx4 are more Susceptible to cell death Via oxidative damage than their wild-type counterparts. Our results Suggest that the presence of Prx4, most likely the membrane-bound form, is important for spermatogenesis, but not all absolute requisite.