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.

Meiosis as an Evolutionary Adaptation for DNA Repair

“…During spermatogenesis in the mouse, DNA repair capability declines after meiosis is complete, allowing accumulation of DNA damage (Marchetti & Wyrobek, 2008). Lewis & Aitken (2005) reviewed evidence that DNA damages in the germ line of men are associated with poor semen quality, low fertilization rates, impaired pre-implantation development, increased abortion, and elevated incidence of disease in the offspring including childhood cancer.…”

Differential sensitivity of male germ cells to mainstream and sidestream tobacco smoke in the mouse

“…The paucity of information on the reproductive effects of paternal exposure to second hand smoke has so far prevented the determination of whether there is an association between second hand smoke and male reproductive dysfunction (California The objectives of this study were to use a mouse model to investigate whether male exposure to MS or SS smoke affected the function and genetic integrity of sperm, fertilization and early embryonic development rates, and whether the effects differed between the two types of smoke. We targeted the last two weeks of spermatogenesis because they are characterized by: (i) a progressive reduction in the ability of male germ cells to carry out DNA repair (Marchetti and Wyrobek, 2008); (ii) an extensive remodeling of the sperm chromatin that results in the replacement of histones with protamines (Kimmins and Sassone-Corsi, 2005;Leduc et al, 2008); and (iii) the acquisition of motility and fertilizing capacity as sperm transverse the epididymis (Soler et al, 1994). We report that SS smoke exposure has deleterious effects on the male germline and that the effects differ from those induced by MS smoke.…”

Exposure to Diagnostic Radiological Procedures and the Risk of Childhood Acute Lymphoblastic Leukemia

“…In humans, this would be equivalent to exposure about 30 to 47 days before conception (42). In addition, in the later stages of development, male germ cells lose the ability to repair DNA damage (43) and the risk of chromosomal aberrations in the offspring may depend on the efficiency of subsequent maternal repair of the DNA of the zygote (44). Therefore, to investigate if paternal X-rays are associated with the risk of ALL in the child, it may be necessary to identify exposures in the few months before conception and, perhaps, to include maternal genotype in the analyses.…”