Deficiency of peroxiredoxin 6 or inhibition of its phospholipase A2 activity impair the in vitro sperm fertilizing competence in mice

Abstract

Prdx6 −/− male mice are subfertile, and the deficiency or inactivation of Peroxiredoxins (PRDXs) is associated with human male infertility. We elucidate the impact of the lack of PRDX6 or inhibition of its calcium-independent phospholipase A2 (Ca2+-iPLA2) activity by MJ33 on fertilization competence of mouse spermatozoa. Sperm motility, viability, fertilization and blastocyst rates were lower in Prdx6 −/− spermatozoa than in C57BL/6J wild-type (WT) controls (p ≤ 0.05). MJ33 inhibited the PRDX6 Ca2+-iPLA2 activity and reduced these parameters in WT spermatozoa compared with controls (p ≤ 0.05). Levels of lipid peroxidation and of superoxide anion (O2 •─) were higher in Prdx6 −/− than in WT spermatozoa (p ≤ 0.05). MJ33 increased the levels of lipid peroxidation and mitochondrial O2 •─ production in treated versus non-treated WT spermatozoa. Acrosome reaction, binding to zona pellucida and fusion with the oolemma were lower in Prdx6 −/− capacitated spermatozoa than WT capacitated controls and lower in WT spermatozoa treated with the PRDX6 inhibitor. In conclusion, the inhibition of the PRDX6 Ca2+-iPLA2 activity promotes an oxidative stress affecting viability, motility, and the ability of mouse spermatozoa to fertilize oocytes. Thus, PRDX6 has a critical role in the protection of the mouse spermatozoon against oxidative stress to assure fertilizing competence.

The phospholipase A2 activity of peroxiredoxin 6 [S]

“…Spermatozoa from Prdx6 null mice have impaired fertilizing ability that is accentuated during aging (105,106) and treatment of sperm from wild type mice with MJ33 decreased their motility, viability, and fertilization rates (153). These results suggest that the decrease in fertility with aging in mice is related to decreased expression of aiPLA 2 activity.…”

Cytosolic phospholipase A 2 and F 2 isoprostanes are involved in semen quality and human infertility—A study on leucocytospermia, varicocele and idiopathic infertility

“…Therefore, understanding PLA 2 role in human semen may help in the knowledge and treatment of male infertility; the relevance of a peroxiredoxin 6-linked phospholipase A 2 activity in sperm fertilising competence has been demonstrated in mice (Moawad et al, 2017).…”

Protective Role of Peroxiredoxins against Reactive Oxygen Species in Neonatal Rat Testicular Gonocytes

“…One of the main differences we found with our studies on PRDXs in spermatozoa is related to the role of the PRDX6 iPLA 2 activity. While this activity is critical for the survival and fertilizing ability of spermatozoa by repairing oxidized membranes [10][11][12], our results with MJ33 suggest that the PLA 2 activity of PRDX6 plays a role in gonocyte survival mainly in the presence of exogenous oxidative stress. Yet, the increased cell death observed after treating gonocytes for 18 h with 50 µM MJ33 suppressing PRDX6 iPLA 2 activity implies that impairing the repair of oxidized membranes in gonocytes can jeopardize PND3 gonocyte survival over time.…”

“…While ROS are needed for sperm capacitation, due to their regulatory role in the phosphorylation of key proteins, their levels must be tightly controlled to prevent damaging oxidative stress, mainly by PRDX1 and 6 in rat [8][9][10]. In mice, PRDX6 deficiency or inhibition of its PLA 2 activity were found to impair in vitro sperm fertilizing competence [11]. Low levels of PRDX6 were observed in infertile men, positioning PRDX6 as the first line of defense against oxidative stress in human spermatozoa [12].…”