Oxidative stress: Major executioner in disease pathology, role in sperm DNA damage and preventive strategies: Beyond the Abstract

Imbalance in reactive oxygen species production (ROS) and antioxidant defenses in the cell there by leading to a state of oxygen paradox is defined by a cellular condition known as oxidative stress (OS), which interferes with the essential cellular processes, inactivates essential metabolic enzymes and disrupt various cellular signaling pathways.(1) ROS are constantly produced in the cell during physiological conditions and serves beneficial as well as deleterious impact on the cellular system depending upon their relative concentrations.

At lower, moderate or physiological levels, ROS serves crucial role in various biological processes and serves as inter and intra-cellular signaling intermediates, messengers of information to nucleolus, messengers of metabolism and essential immune functions whereas at higher levels ROS generate OS which has detrimental impact on cellular physiology. OS is associated with chronic and regressive ailments such as accelerated ageing, cancer, autoimmune dysfunction, cardiovascular disease, neurological disorders, pulmonary diseases, rheumatoid arthritis, nephropathy, ocular diseases, disease of the reproductive system (male and female infertility) etc.(2)

OS impairs the structural and functional integrity of spermatozoa leading to peroxidative damage to the sperm plasma membrane, DNA fragmentation in sperm nuclear/mitochondrial genome and causes dysregulation in levels of mRNAs/transcripts.(3) ROS which include superoxide anions (O2•), hydrogen peroxide (H2O2), peroxyl (ROO•), and hydroxyl (OH•) radicals are the highly reactive oxidizing agents and their major source of production in spermatozoa include activated leukocytes in the seminal plasma and the mitochondria in the spermatozoa itself. Low/moderate levels of ROS are required by spermatozoa for the activation of several redox-sensitive physiological processes, such as sperm capacitation and hyperactivation, whereas supraphysiological ROS levels impede sperm membrane fluidity and permeability and causes sperm DNA damage.(4) Significance of ROS in sperm hyperactivation was further supported by a study which demonstrated that in vitro incubation of spermatozoa with low concentration of OH triggered sperm hyperactivation.(5)

OS induced sperm DNA damage is associated with several pathologies such as male infertility, recurrent pregnancy loss (RPL), congenital malformations and high frequency of childhood disorders including childhood cancers.(6) The exact mechanism of how OS negatively affects the sperm function is largely unknown but is mainly attributed to peroxidative damage to axoneme and depletion of intracellular ATP levels, followed by generation of 4‑hydroxynonenal and malondialdehyde owing to oxidation of lipid membrane components and fragmentation of both nuclear and mitochondrial DNA.(7) Sperm plasma membrane is most accessible to OS induced injury because of the high content of polyunsaturated fatty acids (PUFAs) which provides exuberant sites for free radical induced damage.(8) It also has a limited cytosolic space with minimal antioxidants post spermiogenesis. Sperm harbors a truncated DNA damage detection and repair system which makes sperm further vulnerable to accumulate oxidatively induced damage to both mitochondrial and nuclear DNA.(9) Seminal plasma is well endowed with enzymatic antioxidants (such as superoxide dismutase and catalase) and non-enzymatic antioxidants (such as pyruvate and ascorbic acid), which scavenge ROS and protect spermatozoa from OS, specifically after leaving the testicles.

Seminal plasma is also well-endowed with enzymatic antioxidants such as catalase, superoxide dismutase and glutathione peroxidase and non-enzymatic antioxidants (pyruvate, ascorbic acid, α-tocopherol, glutathione, taurine, hypotaurine, L-carnitine, coenzyme Q10, vitamins A, E, C, and B complex) and micronutrients such as zinc, selenium, copper and iron. However, the total antioxidant capacity in infertile men has been documented to be lower than in their fertile counterparts. Antioxidants reduce cellular levels of ROS in two ways: firstly, by inactivating the ROS produced by various metabolic activities and rendering it inactive and unable to generate lipid peroxidative damage to the sperm plasma membrane; and secondly, by decreasing the level of enzymatic ROS production. Deficiencies in enzymatic or non-enzymatic antioxidant systems are associated with OS and oxidative DNA damage as the absence of either of these systems leads to the accumulation of excessive levels of ROS, which damage the sperm mitochondrial and nuclear genome, therefore rendering it unable to fertilize the oocyte.(10)

Administration of various antioxidants or their combinations (in food or in supplement form) by increasing dietary intake of fruits/vegetables highly enriched in polyphenolic antioxidants or by using synthetic form of antioxidants may exert beneficiary effect on the human health and may help in reducing OS burden through their effect on nuclear DNA is controversial. However, indiscriminate and sustained usage of antioxidants results in sperm DNA decondensation and ultimately results in “Reductive Stress” impairing numerous redox sensitive metabolic processes and also impairs pronucleus formation at fertilization.(11) OS is caused by exogenous and endogenous factors that can be modified by a healthy lifestyle and adoption of simple lifestyle interventions like yoga and meditation.(12-13) 

OS induced pathologies are caused by factors that could be easily modified by maintaining healthy habits like intake of fruits and vegetables, cessation of smoking and reducing intake of alcoholic beverages, avoiding pesticide exposure, reducing psychological stress and avoiding excessive usage of mobile phones and integrating yoga and meditation into our lifestyle which may improve the quality of life (QOL) and help in cessation of OS and its sequelae.(14) Yoga is an emerging integrative health discipline and a profound science of inner well-being which can positively modulate mind and body and has been shown to improve clinical profile of patients with various pathologies and complex and chronic lifestyle diseases including glaucoma, depression, obesity, hypertension, asthma, type II diabetes, and cancer.(15-16)

Meditation is a set of cognitive practices involving intentional and self-regulated focusing of attention with an aim to relax and pacify both the mind and the body.(17) Yoga and meditation based lifestyle intervention (YMLI) practices are an adjunct to modern therapy includes regulation of diet, mental attitude and the practice of specific techniques such as asanas (postures), breathing practices (pranayamas) and meditation, to attain the highest level of consciousness and thus, leading to individual’s well-being. YMLI reduces psychological stress, anxiety, depression, decreases levels of salivary cortisol, slows down cellular ageing and enhances QOL, cognitive abilities and increases long term cardio-vagal tone.(18) Studies from our lab have documented that YMLI based lifestyle intervention can reduce OS, improves sperm DNA integrity and can reduce the incidence of paternally transmitted genetic and epigenetic abnormalities.(19)

This intervention also increases expression of DNA repair genes, decreases the levels of inflammatory cytokines such as Interleukin-6 (IL-6), Mitogen activated protein kinase 10 (MAPK10), MAPK15 and upregulates the levels of anti-inflammatory cytokines such as IL-2 and IL-4.(16) Dhawan et al. have documented normalization of levels of sperm transcripts critical for early embryonic development following short term YMLI.(20) YMLI based lifestyle intervention can reduce rate of cellular ageing, enhances telomerase levels and its activity and aids in maintenance of telomere length, genomic stability and chromosomal integrity.(21) This may further aid in maintenance of spermatogonial proliferation and production of sperm with low levels of DNA damage and thereby, enhance the male fertility. Thus, YMLI is an integrated approach to reduce the number of couples opting for assisted conception due to male factor infertility and thereby assist in achieving optimal physical, mental and reproductive health and improve carry home live birth rate and reduce disease burden in the next generation. 

Written by: Shilpa Bisht, MSc, Madhuri Tolahunase : MSc, Dinesh Tomar; MSc and Rima Dada, MD, PhD

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