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 in 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−/ymice lacking Prx4 expression in all cells were obtained by mating Prx4flox/+female mice with Cre-transgenic male mice that ubiquitously expressed Cre recombinase. The resulting Prx4−/ymale mice were fertile, and most organs were nearly normal in size, except for testicular atrophy. The number of deoxynucleotidyl transferase-mediated dUTP nick end labelling-positive spermatogenic cells was higher in Prx4−/ymice than in Prx4+/ymice and increased remarkably in response to warming the lower abdomen at 43 °C for 15 min. Cells reactive to antibodies against 4-hydroxynonenal and 8-hydroxyguanine were high in the Prx4−/ymice and concomitant with elevated oxidation of lipid and protein thiols. The cauda epididymis of Prx4−/ymice contained round spermatocytes, which were not found in Prx4+/ymice, and displayed oligozoospermia. However, mature spermatozoa from the epididymis of Prx4−/ymice 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 an absolute requisite. [ABSTRACT FROM AUTHOR]