Oxidative stress (OS) is a disturbance in the balance between the production of reactive oxygen species (free radicals) and antioxidant defenses.

The generation of free radicals is a continuous physiological process, fulfilling relevant biological functions. The mechanisms of generation of free radicals occur mostly in the mitochondria (structures that create energy to run the cell), cell membranes and cytoplasm. 

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed as unavoidable by-products of metabolism. During the metabolic processes, these radicals act as mediators for the transfer of electrons in various biochemical reactions. 

The continuous production of free radicals during the metabolic processes culminated in the development of antioxidant defense mechanisms (enzymes and substances such as glutathione, metallothionein, vitamin A, vitamin C and vitamin E) (Tab. 1). These are intended to limit the intracellular (inside the cell) levels of these reactive species and control the occurrence of damage caused by them. 

However, excessive production can lead to oxidative damage (Pic. 1). The structural modifications in the molecules of nucleic acids, proteins and lipids caused by increased concentration of reactive oxygen species and/or reactive nitrogen species lead to various metabolic changes that may contribute to the development of neurological diseases, cardiovascular diseases, cancer, among others.

The installation process of oxidative stress arises from an imbalance between oxidants and antioxidants in favor of excessive generation of free radicals or removal speed thereof. This process leads to the oxidation of molecules with consequent loss of its biological functions and/or homeostatic imbalances, whose manifestation is the potential oxidative damage to cells and tissues. Accumulation of ROS/RNS can result in a number of deleterious effects such as lipid peroxidation, protein oxidation and DNA damage.

Symptoms

  • fatigue
  • memory loss and/or brain fog
  • muscle and joint pain
  • decreased eyesight
  • headaches
  • sensitivity to noise
  • susceptibility to infections

Associated diseases

  • Alzheimer’s disease
  • Parkinson’s disease 
  • other neurodegenerative diseases 
  • cardiovascular diseases (Pic. 2)
  • diabetes
  • cancer
  • asthma
  • arthritis
  • preeclampsia (a disorder of pregnancy characterized by the onset of high blood pressure and often a significant amount of protein in the urine)

Complications

Neurodegenerative diseases

Different tissues have different oxygen demands depending on their metabolic needs. The brain is particularly vulnerable to the effects of reactive oxygen species due to its high demand for oxygen, and its abundance of highly peroxidisable substrates. Neurons and astrocytes, the two major types of brain cells, are largely responsible for the brain’s massive consumption of O2 and glucose; indeed, the brain represents only ~2% of the total body weight and yet accounts for more than 20% of the total consumption of oxygen. 

Oxidative stress has been detected in a range of neurodegenerative disease, and evidence suggests that oxidative stress may play a role in disease pathogenesis. Aging has been established as the most important risk factor for the common neurodegenerative diseases, Alzheimer’s disease (AD), and Parkinson’s disease (PD). Most theories of aging centre are on the idea that cumulative oxidative stress leads to mitochondrial mutations, mitochondrial dysfunction, and oxidative damage. 

Pre-eclampsia (PE) 

Pre-eclampsia is a pregnancy-specific hypertension syndrome. In normal pregnancies, there is an increase of free radical production and lipoperoxidation (reactive oxygen species result in the oxidative deterioration of lipids) towards the end of pregnancy when compared with non-pregnant women. In a parallel fashion, total antioxidant capacity (Uric acid, Vitamins C and E) gradually increases during pregnancy, leading to an oxidative balance maintained throughout pregnancy. 

Evidence in recent years has shown that a biochemical imbalance in pre-eclampsia occurs with an increase of oxidative stress and lipoperoxidation and, at the same time, a deficient antioxidant protection.

Risk factors 

  • hyperoxia (occurs when cells, tissues and organs are exposed to an excess supply of oxygen or higher than normal partial pressure of oxygen)
  • tissue injury
  • cigarette smoke
  • stress
  • hypertension
  • inflammation
  • environmental pollutants
  • industrial solvents
  • UV radiation
  • pesticides
  • low intake of antioxidant-rich food
  • processed meat intake

Prevention

Antioxidants from our diet play an important role in helping endogenous antioxidants for the neutralization of oxidative stress. The nutrient antioxidant deficiency is one of the causes of numerous chronic and degenerative pathologies. 

Eating foods that are high in anti-oxidants like beets, kale, berries can help. To promote the production of anti-oxidants it is necessary to eat foods that help body make more glutathione such as asparagus, walnuts, spinach, tomatoes.

Female fertility

ROS affect multiple physiological processes from oocyte maturation 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.

It plays a 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.

Male fertility

During reproduction, ROS are involved in many important mechanisms of sperm physiology.

ROS are involved in the sperm nuclear matter condensation, regulating the number of germ cells by induction of apoptosis (a type of cell death) or the growth of spermatogonia (a type of male germ cell). 

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 OS in pathologies has long been recognized as a significant contributor to infertility. Men with high OS levels or DNA damaged sperm are likely to be infertile. The contribution of OS to male infertility has been well documented and extensively studied.

On the other hand, the role of OS 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 OS may contribute to aging and several diseased states affecting female reproduction. Endothelial dysfunction secondary to OS contributes to the development of obstetric complications. Reactive oxygen and nitrogen species 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.

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