Abstract
Sperm DNA fragmentation is a recognized factor in male infertility with direct implications for embryo development, implantation and pregnancy outcomes. Historically, standard semen analysis has not included assessments of DNA integrity, creating a clear need for advanced diagnostic tools. DNA damage can arise through pathways such as apoptosis, oxidative stress and exposure to environmental toxins, all of which compromise reproductive potential. Several methodologies exist for measuring sperm DNA fragmentation, including the sperm chromatin structure assay, terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), the Comet assay and sperm chromatin dispersion, each of which has unique advantages and limitations. Novel automated imaging platforms incorporating machine learning algorithms have emerged, enabling high-throughput, single-sperm assessment and reducing subjectivity associated with manual scoring. Species differences further complicate the understanding of DNA stability and sperm quality, especially in livestock and models of artificial insemination; nonetheless, physiological similarities between humans and species close to humans provide useful translational insights. Emerging sperm selection technologies, including microfluidics, hyaluronic acid affinity systems and magnetic-activated cell sorting, show promise in reducing DNA fragmentation, improving reproductive outcomes and decreasing pregnancy loss. As the field progresses toward increasingly personalized fertility treatments, measures of DNA integrity will remain central to optimizing assisted reproduction success rates across species.
Key points
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Sperm DNA fragmentation is a major factor affecting male fertility, and can affect embryo development, embryo implantation and, ultimately, living offspring; none of these factors is usually defined by a standard semen analysis.
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DNA damage can be induced by oxidative stress, apoptosis and environmental toxins, which contribute to sperm DNA fragmentation, which in turn reduces reproductive capability in both humans and livestock species.
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Assays such as the sperm chromatin structure assay, terminal deoxynucleotidyl transferase dUTP nick end labelling, Comet and sperm chromatin dispersion are unique methodologies to identify sperm DNA fragmentation. Each has advantages, disadvantages and importance based on the clinical or research initiative.
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Species-specific differences in sperm DNA integrity make it very difficult to use standard thresholds, particularly in artificial insemination and breeding programmes, but thresholds are relatively consistent within humans as a species.
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New sperm selection techniques, particularly microfluidics and magnetic-activated cell sorting are now being used to enhance fertility outcomes in assisted reproduction, and can help to reduce sperm DNA fragmentation through enhanced selection of high-quality sperm with intact DNA.
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New therapeutic approaches, such as extracellular vesicles, stem cell-derived components and specific antioxidant treatments, seem to have substantial promise in reducing sperm DNA fragmentation. These strategies work by improving sperm quality, decreasing oxidative stress and promoting mechanisms that repair DNA.
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Dabiri, M., Goss, D.M., Ramasamy, R. et al. Sperm DNA fragmentation and its influence on mammalian reproduction. Nat Rev Urol (2026). https://doi.org/10.1038/s41585-025-01123-6
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DOI: https://doi.org/10.1038/s41585-025-01123-6
