Indian Journal of Experimental Biology Vol 48, May 2010, pp. 425-435 Review Article Free radicals: Their beneficial and detrimental effects on sperm function Shiva Kothari 1 , Aaron Thompson 1 , Ashok Agarwal 1 * & Stefan S du Plessis 2 1 Center for Reproductive Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk A19.1, Cleveland, Ohio 44195, USA 2 Division of Medical Physiology, Faculty of Health Sciences, University of Stellenbosch, South Africa Free radicals are molecules with one or more unpaired electron(s) commonly found in seminal plasma. Physiologically, free radicals control sperm maturation, capacitation and hyperactivation, the acrosome reaction, and sperm-oocyte fusion. Pathologically, free radicals induce lipid peroxidation, DNA damage and apoptosis of spermatozoa. The present review deals with both the beneficial and detrimental effects of free radicals on sperm function. Keywords: Apoptosis, Acrosome reaction, Capacitation, DNA damage, Free radical, Sperm function Free radicals are molecules with one or more unpaired electron(s) 1 . These highly reactive molecules attack the nearest stable molecule to obtain an electron. Subsequently, the targeted molecule becomes a free radical itself and initiates a cascade of events that can ultimately lead to cellular damage 2 . However, at physiological levels, free radicals also help preserve homeostasis by acting as signal transducers 3 . There are two common forms of free radicals namely, reactive oxygen species (ROS) and reactive nitrogen species (RNS). Examples of ROS include the superoxide anion (O 2 - ), hydrogen peroxide (H 2 O 2 ), the extremely reactive hydroxyl radical (OH . ) and the peroxyl radical (HO 2 - ) 4 . RNS are often considered to be a subclass of ROS 4 and include nitric oxide (NO), nitrous oxide (N 2 O), peroxynitrite (NO 3 - ), nitroxyl anion (HNO) and peroxynitrous acid (HNO 3 ) 1,5 . Antioxidants act as free radical scavengers that help to keep free radicals at homeostatic levels in order to maintain physiologic function and prevent pathological effects due to development of oxidative stress (OS) 6 . OS is a state when there is an imbalance between ROS and the scavenging properties of antioxidants. Under these circumstances ROS outnumber antioxidants due to either increased ROS levels, decreased antioxidant properties, or a combination of both. Physiologically, free radicals control sperm maturation, capacitation and hyperactivation, the acrosome reaction (AR), and sperm-oocyte fusion. Pathologically, free radicals induce lipid peroxidation (LPO), DNA damage and apoptosis. The pathological effects of free radicals on sperm function have been described extensively in the literature, but a discussion physiological roles of free radicals in sperm function is required for better understanding of the phenomena. It is, therefore, the aim of the present review article is to explore both the beneficial and detrimental role of free radicals on sperm function. Sources of ROS in seminal plasma ROS that ultimately end up in the seminal plasma and exert their effects on spermatozoa can be generated from or originate from various sources that can either be endogenous or exogenous. Endogenous sources of ROS Semen consists of different types of cells such as mature and immature spermatozoa, round cells from different stages of spermatogenesis, leukocytes and epithelial cells. Of these, leukocytes (neutrophils and macrophages) and immature spermatozoa are the two main sources of ROS 7,8 . Peroxidase positive leukocytes — Peroxidase positive leukocytes include polymorphonuclear leukocytes (PMN) (50-60% of all leukocytes) and macrophages (20-30% of all leukocytes) 9,10 . These peroxidase positive leukocytes originate from the prostate and seminal vesicles 11 . As one of the main mechanisms to combat pathogens, leukocytes produce high levels of ROS 12 . More specifically, when activated during disease states, peroxidase positive leukocytes produce ROS through the nicotinamide _________________ *Correspondent author Telephone: 216-444-9485 Fax: 216-445-6049 E-mail: Agarwaa@ccf.org