Free oxygen radicals
Reactive oxygen species (ROS) are generally very small molecules which are highly reactive, and include oxygen ions, free radicals and peroxides (Pic. 1) both inorganic and organic. ROS form as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling. However, during times of environmental stress ROS levels can increase dramatically, which can result in significant damage to cell structures. This cumulates into a situation known as oxidative stress (OS).
Oxidative stress is a disturbance in the balance between the production of reactive oxygen species (free radicals) and antioxidant defenses. Cells are normally able to defend themselves against ROS damage through the use of enzymes such as superoxide dismutases and catalases. Small molecule antioxidants such as ascorbic acid (vitamin C), uric acid, and glutathione also play important roles as cellular antioxidants. Antioxidants neutralize free radicals by donating one of their own electrons. The antioxidant nutrients themselves don’t become free radicals by donating an electron because they are stable in either form. When this capacity of neutralizing ROS is overloaded, oxidative stress results.
The effects of ROS on cell metabolism have been well documented in a variety of species. These include not only roles in programmed cell death (apoptosis), but also positive effects such as the induction of host defence genes and mobilisation of ion transport systems. This is implicating them more frequently with roles in redox signaling or oxidative signaling. In particular, platelets involved in wound repair and blood homeostasis (the balance of the blood flow) release ROS to recruit additional platelets to sites of injury. These also provide a link to the immune system via the recruitment of leukocytes.
Reactive oxygen species are implicated in cellular activity to a variety of inflammatory responses including cardiovascular disease. Generally, harmful effects of reactive oxygen species on the cell are most often:
The structural modifications in the molecules of nucleic acids, proteins and lipids caused by increased concentration of reactive oxygen species may lead to various metabolic changes that may contribute to the development of neurological diseases, cardiovascular diseases, cancer, and irreversible post-inflammatory damage to various organs, among others.
ROS affect multiple physiological processes from oocyte maturation (Pic. 3) to fertilization, embryo development and pregnancy. It has been suggested that OS modulates the age-related decline in fertility.
Each month, a cohort of oocytes begin to grow and develop in the ovary, but meiosis I (a specialized type of cell division that reduces the chromosome number by half, creating an egg cell or sperm cell) resumes in only one of them, the dominant oocyte.
This process is targeted by an increase in ROS and inhibited by antioxidants.
In contrast, the progression of meiosis II (a specialized type of cell division that reduces the chromosome number by half, creating sperms and eggs) is promoted by antioxidants, suggesting that there is a complex relationship between ROS and antioxidants in the ovary. The increase in steroid production in the growing follicle resulting in ROS formation. Reactive oxygen species produced by the pre-ovulatory follicle are considered important inducers for ovulation (the release of egg from the ovaries).
Oxygen deprivation stimulates follicular formation of new blood vessels, which is important for adequate growth and development of the ovarian follicle.
Any disruption in these processes can lead to irregular ovulation, which can decrease the possibility of natural conception. Because without ovulation, there is no egg to be fertilized.
ROS play an important role during pregnancy and normal parturition and in initiation of preterm labor. There is growing literature on the effects of OS in female reproduction with involvement in the pathophysiology of preeclampsia, free radical-induced birth defects and other situations such as abortions.
Numerous studies have shown that OS plays a role in the pathophysiology of infertility and assisted fertility. There is some evidence of its role in endometriosis (a condition in which the layer of tissue that normally covers the inside of the uterus, grows outside it) tubal and peritoneal factor infertility and unexplained infertility.
During reproduction, ROS are involved in many important mechanisms of sperm physiology. ROS are involved in the sperm nucleus condensation, and in regulating the number of germ cells by induction of apoptosis (programmed cell death) or the growth of spermatogonia (the male precursor of germ cells, capable of infinite cell division).
In the mature sperm, ROS play an important role in the capacitation (the change undergone by sperm in the female reproductive tract that enables them to penetrate and fertilize an egg), acrosome reaction (a sperm must first fuse with the plasma membrane and then penetrate the female egg in order to fertilize it) and sperm motility, and they can also function as signaling molecules.
ROS must be maintained at appropriate levels to ensure appropriate physiological function while preventing pathological damage to the sperms. In order to ensure appropriate fertilization, high levels of ROS cause sperm pathologies such as loss of sperm motility and viability. ROS is thought to affect sperm membranes and sperm DNA.
There are many agents that cause an increase in testicular oxidative stress, such as environmental toxins, or conditions such as varicocele (an abnormal enlargement of the venous plexus in the scrotum), orchitis (an inflammation of testicles), cryptorchidism (undescended testes), and aging, all of which leads to an increase in germ cell apoptosis and hypospermatogenesis (abnormally decreased production of sperms). ROS-induced DNA damage may also potentiate germ cell apoptosis, leading to a decrease in sperm count and thus to the decline of semen quality, both of which are associated with male infertility.
In males, the role of ROS in pathologies has long been recognized as a significant contributor to infertility. Men with high ROS levels or DNA damaged sperm are likely to be infertile. The contribution of oxidative stress to male infertility has been well documented and extensively studied.
On the other hand, the role of ROS in female infertility continues to emerge as a topic of interest, and thus, the majority of conducted studies provide indirect and inconclusive evidence regarding the oxidative effects on female reproduction.
Excessive ROS production and resulting oxidative stress may contribute to aging and several diseased states affecting female reproduction. Endothelial dysfunction secondary to oxidative stress contributes to the development of obstetric complications. ROS and oxidative stress can negatively affect embryo implantation and may influence the development of reproductive disorders such as endometriosis and preeclampsia. These effects have been reported to improve with the aid of antioxidants, and thus could minimize the associated risk for infertility.