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PMID: 36604857 Published · ppublish English Journal Article Review

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

Andrology ·Vol. 11 ·No. 8 ·2023-00-00 ·Pages 1545-1557

Aitken RJ, Lewis SEM

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.

Keywords
DNA fragmentation extracellular DNA fertility mutational load nuclease oxidative stress spermatozoa
MeSH Terms
Male Humans Semen Spermatozoa/metabolism Testis DNA Damage DNA/metabolism
Chemicals
DNA
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Aitken Robert John ORCID
Priority Research Centre for Reproductive, Science, College of Engineering, Science and Environment, University of Newcastle, Callaghan, New South Wales, Australia. | Hunter Medical Research Institute (HMRI), New Lambton, New South Wales, Australia.
Lewis Sheena E M ORCID
Queens University Belfast, Belfast, UK. | Examen Ltd., Weavers Court, Belfast, UK.
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Article Info
Journal
Andrology
Abbr.
Andrology
ISSN
2047-2927
DOI
10.1111/andr.13375
Published
2023-00-00
Epub
2023-00-16
Pages
1545-1557
Language
English
Region
England
NLM ID
101585129
Subset
IM
External Links
PubMed source DOI: 10.1111/andr.13375 View journal details
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