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Oxidative stress and male infertility

Key Points

  • Male infertility is a complex lifestyle-related disorder

  • Oxidative stress has adverse effects on the structural and functional integrity of sperm and is a major cause of defective sperm function and male infertility

  • Oxidative stress causes damage to both mitochondrial and nuclear DNA and also affects the sperm epigenome, resulting in infertility, recurrent pregnancy loss, poor pregnancy outcomes and an increased disease burden in the offspring

  • Spermatozoa are most vulnerable to oxidative stress and oxidative DNA damage (ODD) as these cells have limited antioxidant defence mechanisms and a limited capacity for detection and repair of DNA damage

  • A number of intrinsic and extrinsic factors can regulate oxidative stress, and these must be maintained at moderate levels for optimal sperm function and the maintenance of cellular homeostasis and redox-sensitive signal-transduction pathways

  • Simple lifestyle modifications and interventions can substantially reduce levels of testicular inflammation, oxidative stress and ODD and improve the quality of life of infertile couples

Abstract

DNA damage, largely owing to oxidative stress, is a leading cause of defective sperm function. High levels of oxidative stress result in damage to sperm DNA, RNA transcripts, and telomeres and, therefore might provide a common underlying aetiology of male infertility and recurrent pregnancy loss, in addition to congenital malformations, complex neuropsychiatric disorders, and childhood cancers in children fathered by men with defective sperm cells. Spermatozoa are highly vulnerable to oxidative stress owing to limited levels of antioxidant defence and a single, limited DNA-damage detection and repair mechanism. Oxidative stress is predominantly caused by a host of lifestyle-related factors, the majority of which are modifiable. Antioxidant regimens and lifestyle modifications could both be plausible therapeutic approaches that enable the burden of oxidative-stress-induced male factor infertility to be overcome. Lifestyle interventions including yoga and meditation can substantially improve the integrity of sperm DNA by reducing levels of oxidative DNA damage, regulating oxidative stress and by increasing the expression of genes responsible for DNA repair, cell-cycle control and anti-inflammatory effects. Oxidative stress is caused by various modifiable factors, and the use of simple interventions can decrease levels of oxidative stress, and therefore reduce the incidence of both infertility and complex diseases in the resultant offspring.

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Figure 1: Causes and consequences of seminal oxidative stress and oxidative DNA damage.

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All authors contributed equally to all aspects of the preparation of this manuscript.

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Correspondence to Rima Dada.

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Glossary

Free radical

A free radical is an atom or molecule that is highly reactive because it contains an unpaired electron in the outer shell.

Capacitation

A process that sperm undergo as they travel through the woman's reproductive tract. Capacitation enables the sperm to penetrate the egg.

Oxidative stress

Results from an imbalance between the intracellular production of free radicals and the cellular defence mechanisms.

Antioxidant

Any substance that prevents or reduces damage caused by free-radicals (highly reactive chemicals containing oxygen) that attack other molecules and modify their chemical structure.

DNA fragmentation

Splitting of DNA strands into shorter pieces by endonucleolytic DNA cleavage at multiple sites. This process includes internucleosomal DNA fragmentation, which, along with chromatin condensation, is considered a hallmark of apoptosis.

Assisted reproductive techniques

(ART). All treatments or procedures that include the in vitro handling of both human oocytes and sperm or of embryos for the purpose of establishing a pregnancy.

Meditation

A practice of concentrated focus upon a sound, object, visualization, such as the breath, movement, or attention itself in order to increase awareness of the present moment, reduce stress, promote relaxation, and enhance personal and spiritual growth.

Yoga

A Hindu spiritual and ascetic discipline, a part of which, including breath control, simple meditation, and the adoption of specific bodily postures, is widely practiced for health and relaxation purposes.

Protamines

Proteins that bind with DNA in sperm cells, replacing histones and allowing chromosomes to become more highly condensed than is possible with histones.

Spermatogenesis

The production of sperm within the seminiferous tubules.

Asthenozoospermia

Low sperm motility.

Telomere length

A telomere is a region of repetitive nucleotide sequences at each end of a chromosome, which protect the end of the chromosome from deterioration or from fusion with neighbouring chromosomes. Telomere length decreases with advancing cellular age, thus strategies that reduce the rate of telomere shortening might delay the cellular ageing process.

DNA methylation

Attachment of methyl (−CH3) groups to DNA, most commonly to cytosine bases.

Azoospermia

Semen containing no sperm, either because the testicles cannot produce sperm or because of a blockage in the reproductive tract.

Sertoli cell

A testicular cell responsible for nurturing the spermatids (immature sperm). These cells secrete inhibin, a hormone that regulates follicule-stimulating hormone (FSH) production by the pituitary gland. When stimulated by FSH, the Sertoli cell initiates spermatogenesis.

Genomic integrity

The active maintenance of all the genetic elements in the cells of an organism (including DNA, RNA and epigenetic determinants and appropriate developmental gene expression) for proper dynamic function.

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Bisht, S., Faiq, M., Tolahunase, M. et al. Oxidative stress and male infertility. Nat Rev Urol 14, 470–485 (2017). https://doi.org/10.1038/nrurol.2017.69

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