title: DNA repair decline during mouse spermiogenesis results in the accumulation of heritable DNA damage.
abstract: The postmeiotic 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 3 weeks of spermiogenesis affected the accumulation of DEB-induced heritable damage in early spermatids (21-15 days before fertilization (dbf)), late spermatids (14-8dbf) and sperm (7-1dbf). 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 2 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 postmeiotic 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.
authors.affiliation: Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA. fmarchetti@lbl.gov
authors.forename: Francesco
authors.initials: F
authors.lastname: Marchetti
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wyrobek
mesh_terms: D000818:Animals; D002869:Chromosome Aberrations; D004249:DNA Damage; D004260:DNA Repair; D004852:Epoxy Compounds / Q000633:toxicity; D008297:Male; D051379:Mice; D013087:Spermatids / Q000166:cytology / Q000187:drug effects*; D013091:Spermatogenesis / Q000187:drug effects / Q000235:genetics*; D013997:Time Factors
chemical_list: D004852:Epoxy Compounds; C007366:diepoxybutane