DNA damage and repair in human oocytes and embryos: a review

Abstract

The genome of all cells is protected at all times by mechanisms collectively known as DNA repair activity (DRA). Such activity is particularly important at the beginning of human life, i.e. at fertilization, immediately after and at the very onset of embryonic development. DRA in early development is, by definition, of maternal origin: the transcripts stored during maturation, need to control the integrity of chromatin, at least until the maternal/zygotic transition at the 4- to 8-cell stage in the human embryo. Tolerance towards DNA damage must be low during this critical stage of development. The majority of DNA damage is due to either apoptosis or reactive oxygen species (ROS). Apoptosis, abortive or not, is a common feature in human sperm, especially in oligoasthenospermic patients and FAS ligand has been reported on the surface of human spermatozoa. The susceptibility of human sperm to DNA damage is well documented, particularly the negative effect of ROS (Kodama et al., 1997; Lopes et al., 1998a, b) and DNA modifying agents (Zenzes et al., 1999; Badouard et al., 2007). DNA damage in sperm is one of the major causes of male infertility and is of much concern in relation to the paternal transmission of mutations and cancer (Zenzes, 2000; Aitken et al., 2003; Fernández-Gonzalez, 2008). It is now clear that DNA damaged spermatozoa are able to reach the fertilization site in vivo (Zenzes et al., 1999), fertilize oocytes and generate early embryos both in vivo and in vitro. The effect of ROS on human oocytes is not as easy to study or quantify. It is a common consensus that the maternal genome is relatively well protected while in the maturing follicle; however damage may occur during the long quiescent period before meiotic re-activation (Zenzes et al., 1998). In fact, during the final stages of follicular growth, the oocyte may be susceptible to damage by ROS. With regards to the embryo there is active protection against ROS in the surrounding environment i.e. in follicular and tubal fluid (El Mouatassim et al., 2000; Guerin et al., 2001). DNA repair activity in the zygote is mandatory in order to avoid mutation in the germ line (Derijck et al., 2008). In this review we focus on the expression of mRNAs that regulate DNA repair capacity in the human oocyte and the mechanisms that protect the embryo against de novo damage.

Predictive value of DNA integrity analysis in idiopathic recurrent pregnancy loss following spontaneous conception

“…Thus, transmutation of paternal genome may compromise embryo quality, viability and maintaining pregnancy, ultimately leading to recurrent pregnancy loss. Oocytes are well equipped to handle DNA damage in sperm by different pathways like direct reversal of damage, singlestrand damage repair, base excision repair, nucleotide excision repair, mismatch repair that repair sperm DNA damages [26,31]. Oocytes can repair sperm DNA damage, but there is a threshold beyond which sperm DNA may not be repaired, and accumulation of ethenonucleosides (type of DNA lesion) in sperm may inhibit nucleotide excision repair mechanism.…”

Sperm with large nuclear vacuoles and semen quality in the evaluation of male infertility

“…There is clinical evidence that the spermatozoa of infertile males have substantially more DNA damage than those of fertile subjects [Zini and Libman 2006]. The mechanisms proposed to resolve the etiology of DNA damage include apoptosis, oxidative stress, and abnormal chromatin packaging [Ménézo et al 2010;Miller et al 2010]. Many studies have indicated that there is a positive relationship between sperm DNA fragmentation and large nuclear vacuoles in the sperm nuclear area [Oliveira et al 2010a;Skowronek et al 2012;Sakkas and Alvarez 2010].…”

Birth defects and congenital health risks in children conceived through assisted reproduction technology (ART): a meeting report

“…", furthered the realization that oocyte quality in mammals was directly coupled to events taking place within the ovarian follicle [4]. Now it is widely accepted that maternal health and the attendant influences of age, lifestyle, environmental exposures and medical interventions, such as controlled ovarian hyperstimulation impact oocyte quality and offspring health and contribute to the origins of birth defects and developmental deficiencies manifest at birth or later stages of life [5][6][7][8].…”