Contemporary evidence on the physiological role of reactive oxygen species in human sperm function

Abstract

Reactive oxygen species (ROS) play an important role in male fertility. Overproduction of reactive oxygen species (ROS) has been associated with a variety of male fertility complications, including leukocytospermia, varicocele and idiopathic infertility. The subsequent oxidative insult to spermatozoa can manifest as insufficient energy metabolism, lipid peroxidation and DNA damage, leading to loss of motility and viability. However, various studies have demonstrated that physiological amounts of ROS play important roles in the processes of spermatozoa maturation, capacitation, hyperactivation and acrosome reaction. It is therefore crucial to define and understand the delicate oxidative balance in male reproductive cells and tissues for a better understanding of both positive as well as negative impact of ROS production on the fertilizing ability. This review will discuss the specific physiological roles, mechanisms of action and effects that ROS have on the acquisition of structural integrity and physiological activity of spermatozoa.

Figures

Fig. 1

Biochemical pathway proposed to regulate sperm capacitation and hyperactivation. The process is initiated by an influx of Ca2+ and HCO3 −, possibly caused by the inactivation of an ATP-dependent Ca2+ regulatory channel (PMCA) and alkalization of the cytosol. Both Ca2+ and reactive oxygen species (ROS), specifically O2 −, activate adenylate cyclase (AC), which produces cyclic adenosine monophosphate (cAMP). cAMP activates downstream protein kinase A (PKA). PKA triggers a membrane bound NADPH oxidase to stimulate greater ROS production. In addition, PKA triggers phosphorylation of serine (Ser) and tyrosine (Tyr) residues that, in addition to other inter-connected pathways, lead to the activation of protein tyrosine kinase (PTK). PTK phosphorylates Tyr residues of the fibrous sheath surrounding the axoneme, the cytoskeletal component of the flagellum. ROS, specifically hydrogen peroxide (H2O2), increases the amount of Tyr phosphorylation by promoting PTK activity and inhibiting phosphotyrosine phosphatase (PTPase) activity, which normally de-phosphorylates Tyr residues. The enhanced Tyr phosphorylation observed in capacitation is the last known step in the process, but intermediate steps or other (in)direct methods may be involved

Fig. 2

Biochemical pathway proposed to regulate the acrosome reaction (AR). Induction of the AR can occur by physiological and non-physiological activators, including the zona pellucida (ZP), progesterone, or reactive oxygen species (ROS). Subsequent release of Ca2+ from the acrosomal calcium store generated during capacitation causes the cleavage of phosphatidylinosital-4,5-biphosphate (PIP2), which forms diacylglycerol (DAG) and inosital triphosphate (IP3). The latter activates actin-severing proteins, which leads to the fusion of the acrosomal and plasma membranes, and eventual acrosomal exocytosis. DAG later activates protein kinase C (PKC), causing a second, greater influx of Ca2+ and activation of phospholipase A2 (PLA2). The release of large amounts of membrane fatty acids increases the fluidity of the plasma membrane necessary for later fusion with the oocyte