Role of sperm DNA damage in creating de-novo mutations in human offspring: the ‘post-meiotic oocyte collusion’ hypothesis

Aitken, Robert J.

doi:10.1016/j.rbmo.2022.03.012

Cited by 31 publications

(32 citation statements)

References 162 publications

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“…If there is any deficiency or inaccuracy in the repair process by the oocyte, it has the potential to create de novo mutations in the embryo, thereby fixing paternal DNA damage. This observation could provide evidence to support the idea that assisted conception procedures have the potential to increase the mutational load passed down to the offspring [ 29 ]. Although zygotes are able to recognize DNA damage, they have the potential to protect themselves from cell death through antiapoptotic protection, which may provide an opportunity for DNA repair and continued embryogenesis [ 30 ].…”

Section: Cell Cycle Checkpointsmentioning

confidence: 62%

Checkpoint Kinase 1 Is a Key Signal Transducer of DNA Damage in the Early Mammalian Cleavage Embryo

Baran

Mayer

2023

IJMS

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After fertilization, remodeling of the oocyte and sperm genome is essential for the successful initiation of mitotic activity in the fertilized oocyte and subsequent proliferative activity of the early embryo. Despite the fact that the molecular mechanisms of cell cycle control in early mammalian embryos are in principle comparable to those in somatic cells, there are differences resulting from the specific nature of the gene totipotency of the blastomeres of early cleavage embryos. In this review, we focus on the Chk1 kinase as a key transduction factor in monitoring the integrity of DNA molecules during early embryogenesis.

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Section: Cell Cycle Checkpointsmentioning

confidence: 62%

Checkpoint Kinase 1 Is a Key Signal Transducer of DNA Damage in the Early Mammalian Cleavage Embryo

Baran

Mayer

2023

IJMS

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“…116 However, we would argue that a more common mechanism for inducing de novo mutations in the offspring is the defective repair of sperm DNA damage in the oocyte following fertilization in accordance with the post-meiotic oocyte collusion hypothesis described above. 81 As a result of such mechanisms, the presence of DNA damage (particularly oxidative DNA adducts) in spermatozoa would be expected in increase the incidence de novo mutations in the newly formed embryo and, through such mechanisms, have a long-term impact on the health trajectory of the progeny. Such a mechanism has been clearly demonstrated in the Gpx5 knockout mouse where the selective induction of oxidative DNA damage in epididymal spermatozoa has been clearly linked with the occurrence of miscarriages and developmental defects in the offspring of wild-type female mice mated to GPx5 KO males over 1 year of age.…”

Section: What Does Sperm Dna Damage Mean?mentioning

confidence: 99%

“…Indeed, the AUA/ASRM guidelines 112 acknowledge that “ it is possible that very high levels of sperm DNA fragmentation will have a more substantial adverse impact on pregnancy outcomes with IVF as well as an increased risk of miscarriages .” However, it is also theoretically possible that lower levels of sperm DNA damage may still influence the health and wellbeing of the progeny even when pregnancy and parturition are apparently normal, through the induction of genetic and epigenetic mutations in the embryo. It is now well established that the paternal genome represents the source of most de novo mutations in our species and that such mutations arise as a result of defective DNA damage repair 81 . To resolve this important issue, it is now critical that studies are performed exploring the association between DNA damage in spermatozoa and the mutational load carried by the offspring.…”

Section: Dna Damage In Spermatozoamentioning

confidence: 99%

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

Aitken

Lewis

2023

Andrology

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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.

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“…Collectively, the above data suggest that ejaculated spermatozoa with high DNA damage may adversely impact ICSI reproductive outcomes, particularly when the oocyte DNA repair capacity is defective. 55,56 Traditionally, ICSI is performed with viable spermatozoa isolated from ejaculates through semen processing techniques. Conventional sperm preparation techniques, such as density gradient centrifugation and swim-up, are the classical approaches for this purpose.…”

Section: Clinical Implications Of Sperm Dna Damage In Medically Assis...mentioning

confidence: 99%

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

2023

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Intracytoplasmic sperm injection (ICSI) using surgically retrieved spermatozoa outside the classic context of azoospermia has been increasingly used to overcome infertility. The primary indications include high levels of sperm DNA damage in ejaculated spermatozoa and severe oligozoospermia or cryptozoospermia, particularly in couples with ICSI failure for no apparent reason. Current evidence suggests that surgically retrieved spermatozoa for ICSI in the above context improves outcomes, mainly concerning pregnancy and miscarriage rates. The reasons are not fully understood but may be related to the lower levels of DNA damage in spermatozoa retrieved from the testis compared with ejaculated counterparts. These findings are consistent with the notion that excessive sperm DNA damage can be a limiting factor responsible for the failure to conceive. Using testicular in preference of low‐quality ejaculated spermatozoa bypasses post‐testicular sperm DNA damage caused primarily by oxidative stress, thus increasing the likelihood of oocyte fertilization by genomically intact spermatozoa. Despite the overall favorable results, data remain limited, and mainly concern males with confirmed sperm DNA damage in the ejaculate. Additionally, information regarding the health of ICSI offspring resulting from the use of surgically retrieved spermatoa of non‐azoospermic males is still lacking. Efforts should be made to improve the male partner's reproductive health for safer ICSI utilization. A comprehensive andrological evaluation aiming to identify and treat the underlying male infertility factor contributing to sperm DNA damage is essential for achieving this goal.

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Role of sperm DNA damage in creating de-novo mutations in human offspring: the ‘post-meiotic oocyte collusion’ hypothesis

Cited by 31 publications

References 162 publications

Checkpoint Kinase 1 Is a Key Signal Transducer of DNA Damage in the Early Mammalian Cleavage Embryo

Checkpoint Kinase 1 Is a Key Signal Transducer of DNA Damage in the Early Mammalian Cleavage Embryo

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

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

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