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Sperm DNA damage/fragmentation: problems that evade the eyes

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Male factor infertility accounts for half of the couples seeking fertility treatment, but not all causes can be explained. Within this group, 5-10% men have high amount of sperm DNA fragmentation despite having normal semen parameters. Studies have shown that sperm DNA fragmentation is correlated with poor reproductive outcomes, such as miscarriages, chromosomal abnormalities, congenital malformations, genetic disorders and neurological defects.

Today, DNA fragmentation tests are not yet considered as a routine analysis in fertility investigation, but should they be?

Why do DNA fragmentations occur?

There are many reasons as to why DNA fragmentations occur. Intrinsic factors are generally defects in the process of sperm production. For example, small breaks and nicks are induced in the DNA structure during normal maturation but these are later fixed by repair mechanisms. DNA damage checkpoints should also be in place to prevent damaged sperm from proceeding any further. However, defects in the repair and monitoring process could potentially result in permanent DNA fragmentation in ejaculated sperm.

Reactive oxidative species are the chief culprit in a process known as oxidative stress. They are extremely unstable particles that can damage genetic materials. Normally, our cells are equipped with antioxidant molecules that counteract such damage, but they could be overwhelmed by excessive oxidative stress. For example, the following could lead to the production of reactive oxidative species and consequently, DNA damage:

  • X rays and radiotherapy

  • Ultraviolet light (UV)

  • Cigarette smoking

  • herbicides

  • alcohol abuse

  • chronic stress

  • drugs (eg. acetaminophen)

  • chemotherapy

  • environmental pollution

Age is an important factor as some studies have suggested that men with advanced age are more prone to DNA fragmentation. Those under the age of 35 years were found to have considerably lower DNA damage as well as oxidative stress levels.

Higher DNA fragmentation levels are also observed in various medical conditions, including varicocele, microbial infections (such as Chlamydia) and leucocytospermia.

Can men with DNA fragmentation conceive naturally or through assisted reproductive technologies (ARTs)?

The probability of natural conception declines as the level of DNA damage increases. Studies have shown that if the level of DNA fragmentation is higher than 30%, then the chance of natural conception is almost zero. Therefore, if you or your partner have difficulty falling pregnant for more than 1 year of having regular, unprotected sex, diagnostic check-ups and ARTs should be considered.

Among the various ART techniques, intrauterine insemination has been shown to have low success if sperm DNA fragmentation is higher than 30%. In vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) are thought to be better approaches, but their success rates also depend on how much DNA damage exists in the sperm. Before ICSI, advanced sperm selection could help choose a sperm that appears the most promising. For example, under high magnification, scientists could see into the sperm heads where detrimental vacuoles may be present.

Once fertilised, DNA damage continues to affect embryo growing quality. While low level of DNA damage seems to be well tolerated, high fragmentation rate (>30%) is associated with lower blastocyst and pregnancy rates.

What treatment might help?

Sperm are delicate cells that are highly susceptible to oxidative stress. Previous reports have suggested that oral antioxidant treatment may reduce the elevated levels of sperm DNA fragmentation in ejaculated sperm. Adjusting the diet to include more antioxidant-rich foods may also be helpful to some extent. However, large clinical trials on this approach are yet to be conducted.

To date, in-depth research regarding the precise pathophysiological mechanisms underlying DNA damage is largely lacking. This limits the development of potential treatments for DNA repair. The true clinical value of using sperm DNA fragmentation as a prognostic predictor of treatment outcome and embryo quality are also areas that need further research.

Reference

Zini, Armand, & Agarwal, Ashok. (2018). A Clinician's Guide to Sperm DNA and Chromatin Damage. Springer International Publishing. https://doi.org/10.1007/978-3-319-71815-6