DNA damage in testicular germ cells and spermatozoa. When and how is it induced? How should we measure it? What does it mean?

Abstract

This review surveys the causes and consequences of DNA damage in the male germ line from spermatogonial stem cells to fully differentiated spermatozoa. Within the stem cell population, DNA integrity is well maintained as a result of excellent DNA surveillance and repair; however, a progressive increase in background mutation rates does occur with paternal age possibly as a result of aberrant DNA repair as well as replication error. Once a germ cell has committed to spermatogenesis, it responds to genetic damage via a range of DNA repair pathways or, if this process fails, by the induction of apoptosis. When fully‐differentiated spermatozoa are stressed, they also activate a truncated intrinsic apoptotic pathway which results in the activation of nucleases in the mitochondria and cytoplasm; however, the physical architecture of these cells prevents these enzymes from translocating to the nucleus to induce DNA fragmentation. Conversely, hydrogen peroxide released from the sperm midpiece during apoptosis is able to penetrate the nucleus and induce DNA damage. The base excision repair pathway responds to such damage by cleaving oxidized bases from the DNA, leaving abasic sites that are alkali‐labile and readily detected with the comet assay. As levels of oxidative stress increase and these cells enter the perimortem, topoisomerase integrated into the sperm chromatin becomes activated by SUMOylation. Such activation may initially facilitate DNA repair by reannealing double strand breaks but ultimately prepares the DNA for destruction by nucleases released from the male reproductive tract. The abasic sites and oxidized base lesions found in live spermatozoa are mutagenic and may increase the mutational load carried by the offspring, particularly in the context of assisted conception. A variety of strategies are described for managing patients expressing high levels of DNA damage in their spermatozoa, to reduce the risks such lesions might pose to offspring health.

Surgically retrieved spermatozoa for ICSI cycles in non‐azoospermic males with high sperm DNA fragmentation in semen

“…28 In particular, oxidatively induced DNA damage is not regionalized owing to the persistence of histones throughout the sperm head chromatin, thus making sperm DNA oxidation a critical candidate for reproductive failure. 29 The mechanistic link between oxidative stress and sperm DNA damage is beyond the scope of the present article, but Aitken and Lewis 30 have elegantly elaborated on it. In their article, the authors have explained when and how DNA damage is induced in testicular germ cells and spermatozoa, and how it should be measured.…”

“…The finding that DNA damage is usually greater in epididymal/ejaculated spermatozoa than in testicular spermatozoa implies that post-testicular sperm DNA damage can occur and that the epididymis might be a challenging environment for spermatozoa, particularly if their chromatin has not been adequately remodeled and compacted during spermiogenesis. 30 Other mechanisms might also be implicated in the differential quality of testicular and ejaculated spermatozoa of men with infertility, including epigenetic dysregulation of genes associated with fertilization, embryo development, and sperm DNA damage. 78,79 In one report, the mRNA levels of annexinA2 (ANXA2), sperm protein 17 (SP17), plasma serine protease inhibitor (SERPINA5), and peroxiredoxin-2 (PRDX2) genes were differentially expressed in infertile men than fertile controls, and the former exhibited increased sperm DNA damage rates in the neat semen.…”

“…Accordingly, it seems plausible that the DNA damage observed in ejaculated spermatozoa represents cells that escaped apoptosis or have become damaged during post‐testicular transit through the male reproductive tract. The finding that DNA damage is usually greater in epididymal/ejaculated spermatozoa than in testicular spermatozoa implies that post‐testicular sperm DNA damage can occur and that the epididymis might be a challenging environment for spermatozoa, particularly if their chromatin has not been adequately remodeled and compacted during spermiogenesis 30 …”

Sperm DNA integrity: a special issue exploring the causes, consequences, and treatment of DNA damage in human spermatozoa

“…Whatever the cause of the DNA damage, there is a growing volume of data to indicate that it has clinical significance—not so much for the process of conception itself but for the viability, health, and wellbeing of the offspring 2 . Thus, this Special Issue includes an excellent study by Busnelli et al 24 .…”

“…Since the pioneering studies by Don Evenson and colleagues first opened our eyes to the existence of DNA damage in subpopulations of human spermatozoa, 1 important questions have been raised concerning the causes, clinical significance, and resolution of this phenomenon 2 . In this Special Issue of Andrology, we have brought together a collection of cutting‐edge research articles and reviews, reflecting the most recent advances in this area.…”