DNA Repair Decline During Mouse Spermiogenesis Results in the Accumulation of Heritable DNA Damage

Abstract

The post-meiotic phase of mouse spermatogenesis (spermiogenesis) is very sensitive to the genomic effects of environmental mutagens because as male germ cells form mature sperm they progressively lose the ability to repair DNA damage. We hypothesized that repeated exposures to mutagens during this repair-deficient phase result in the accumulation of heritable genomic damage in mouse sperm that leads to chromosomal aberrations in zygotes after fertilization. We used a combination of single or fractionated exposures to diepoxybutane (DEB), a component of tobacco smoke, to investigate how differential DNA repair efficiencies during the three weeks of spermiogenesis affected the accumulation of DEB-induced heritable damage in early spermatids (21-15 days before fertilization, dbf), late spermatids (14-8 dbf) and sperm (7-1 dbf). Analysis of chromosomal aberrations in zygotic metaphases using PAINT/DAPI showed that late spermatids and sperm are unable to repair DEB-induced DNA damage as demonstrated by significant increases (P<0.001) in the frequencies of zygotes with chromosomal aberrations. Comparisons between single and fractionated exposures suggested that the DNA repair-deficient window during late spermiogenesis may be less than two weeks in the mouse and that during this repair-deficient window there is accumulation of DNA damage in sperm.Finally, the dose-response study in sperm indicated a linear response for both single and repeated exposures. These findings show that the differential DNA repair capacity of post-meioitic male germ cells has a major impact on the risk of paternally transmitted heritable damage and suggest that chronic exposures that may occur in the weeks prior to fertilization because of occupational or lifestyle factors (i.e, smoking) can lead to an accumulation of genetic damage in sperm and result in heritable chromosomal aberrations of paternal origin.

Low-dose carbon ion irradiation effects on DNA damage and oxidative stress in the mouse testis

“…And accordingly, the serious damage may become depleted of germ cells or irreversibly damage (Boekelheide, 2005), resulting in spermatogenic failure (Table 1). Furthermore, DNA repair decline during mouse spermatogenesis may cause the accumulation of heritable DNA damage (Marchetti and Wyrobek, 2008). Therefore, further studies are needed to confirm whether there was a limited time to repair damage completely and to avoid genetic and reproductive risks induced by heavy-ion radiation.…”

Programmed Genetic Instability: A Tumor-Permissive Mechanism for Maintaining the Evolvability of Higher Species through Methylation-Dependent Mutation of DNA Repair Genes in the Male Germ Line

“…The effects of repair gene targeting depend critically on the extent of functional inhibition and the presence or otherwise of associated mutations; in general, mild (e.g., haploinsufficient) CT/repair defects tend to increase mutation while decreasing apoptosis ( Frank et al 2005 ; Smilenov et al 2005 ) and may even enhance fitness and lifespan ( Siegl-Cachedenier et al 2007 ), whereas severe repair defects tend to cause increased apoptosis and premature lethality ( Henrie et al 2003 ). Hence, because low-level sperm DNA damage can be repaired after fertilization of repair-proficient oocytes ( Menezo 2006 ; Marchetti et al 2007 ; Fernandez-Gonzalez et al 2008 )—particularly in the setting of prior DNA damage “conditioning” of such oocytes ( Agrawal and Wang 2008 )—mild nondeletional prezygotic male germ line repair defects could plausibly enhance sperm divergence with minimal fertility compromise, thereby safeguarding species’ evolvability while offsetting transgenerational risks of paternally transmitted birth defects ( Marchetti and Wyrobek 2008 ) or cancer ( Zenzes et al 1999 ; Yauk et al 2007 ). This conclusion is further supported by the finding that chronic exposure of spermatogonia to low-dose damage greatly reduces genetic damage induced by an acute second hit ( Cai et al 1993 ; Koana et al 2007 ).…”

Monoallelic gene expression and mammalian evolution

“…Many more mutations are therefore likely to accrue in the male germline especially with ageing but only the mammalian oocyte is capable of repairing DNA throughout oogenesis 36, 37. Moreover, de novo mutations and chromosomal structural aberrations are known to be transmitted by sperm since their DNA repair capacity also declines during the post‐meiotic phase of spermatogenesis 38, 39. Females inheriting a paternal X, which may have been subjected to DNA damage during spermatogenesis, have this X chromosome silenced by imprinting and therefore not expressed in female placental development, while the male placenta only inherits a maternal X.…”