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Title: 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 chromosomalaberrations 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 amore » 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.« less

Authors:
; ;
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
Life Sciences Division
OSTI Identifier:
926275
Report Number(s):
LBNL-45E
TRN: US200807%%614
DOE Contract Number:  
DE-AC02-05CH11231; L0555
Resource Type:
Journal Article
Journal Name:
DNA Repair
Additional Journal Information:
Journal Volume: http://dx.doi.org/10.1016/j.dnarep.2007.12.011
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; CAPACITY; CHROMOSOMAL ABERRATIONS; CHRONIC EXPOSURE; DNA; DNA DAMAGES; DNA REPAIR; FERTILIZATION; GENETICS; GERM CELLS; MALES; MUTAGENS; ORIGIN; REPAIR; SPERMATOGENESIS; SPERMATOZOA; TOBACCO SMOKES; ZYGOTES; diepoxybutane zygote chromosomal aberrations

Citation Formats

Marchetti, Francesco, Marchetti, Francesco, and Wryobek, Andrew J. DNA repair decline during mouse spermiogenesis results in the accumulation of heritable DNA damage. United States: N. p., 2008. Web. doi:10.1016/j.dnarep.2007.12.011.
Marchetti, Francesco, Marchetti, Francesco, & Wryobek, Andrew J. DNA repair decline during mouse spermiogenesis results in the accumulation of heritable DNA damage. United States. doi:10.1016/j.dnarep.2007.12.011.
Marchetti, Francesco, Marchetti, Francesco, and Wryobek, Andrew J. Thu . "DNA repair decline during mouse spermiogenesis results in the accumulation of heritable DNA damage". United States. doi:10.1016/j.dnarep.2007.12.011. https://www.osti.gov/servlets/purl/926275.
@article{osti_926275,
title = {DNA repair decline during mouse spermiogenesis results in the accumulation of heritable DNA damage},
author = {Marchetti, Francesco and Marchetti, Francesco and Wryobek, Andrew J},
abstractNote = {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 chromosomalaberrations 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.},
doi = {10.1016/j.dnarep.2007.12.011},
journal = {DNA Repair},
number = ,
volume = http://dx.doi.org/10.1016/j.dnarep.2007.12.011,
place = {United States},
year = {2008},
month = {2}
}