Skip Navigation


ToxSci Advance Access originally published online on September 13, 2007
Toxicological Sciences 2007 100(2):495-503; doi:10.1093/toxsci/kfm242
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow All Versions of this Article:
100/2/495    most recent
kfm242v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Barton, T. S.
Right arrow Articles by Hales, B. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Barton, T. S.
Right arrow Articles by Hales, B. F.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

DNA Damage Recognition in the Rat Zygote Following Chronic Paternal Cyclophosphamide Exposure

Tara S. Barton*, Bernard Robaire*,{dagger} and Barbara F. Hales*,1

* Department of Pharmacology and Therapeutics {dagger} Department of Obstetrics and Gynecology, McGill University, 3655 Promenade Sir-William-Osler, Montreal, Quebec H3G 1Y6, Canada

1 To whom correspondence should be addressed. Fax: (514) 398-7120. E-mail: barbara.hales{at}mcgill.ca.

Received August 1, 2007; accepted September 5, 2007


  Abstract

The detrimental effects of preconceptional paternal exposure to the alkylating anticancer agent, cyclophosphamide, include aberrant epigenetic programming, dysregulated zygotic gene activation, and abnormalities in the offspring that are transmitted to the next generation. The adverse developmental consequences of genomic instabilities transmitted via the spermatozoon emphasize the need to elucidate the mechanisms by which the early embryo recognizes DNA damage in the paternal genome. Little information exists on DNA damage detection in the zygote. We assessed the impact of paternal cyclophosphamide exposure on phosphorylated H2AX ({gamma}H2AX) and poly(ADP-ribose) polymerase-1(PARP-1), biomarkers of DNA damage, to determine the capacity in the rat zygote to recognize genomic damage and initiate a response to DNA lesions. An amplified biphasic {gamma}H2AX response was triggered in the paternal pronucleus in zygotes sired by drug-treated males; the maternal genome was not affected. PARP-1 immunoreactivity was substantially elevated in both parental genomes, coincident with the second phase of {gamma}H2AX induction in embryos sired by cyclophosphamide-exposed spermatozoa. Thus, paternal exposure to a DNA damaging agent rapidly activates signals implemental for DNA damage recognition in the zygote. Inefficient repair of DNA lesions may lead to persistent alterations of the histone code and chromatin integrity, resulting in aberrant embryogenesis. We propose that the response of the early embryo to disturbances in spermatozoal genomic integrity plays a vital role in determining its outcome.

Key Words: histone modifications; developmental toxicity; embryo; spermatozoa; {gamma}H2AX; poly(ADP-ribosyl)ation.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
A. Derijck, G. van der Heijden, M. Giele, M. Philippens, and P. de Boer
DNA double-strand break repair in parental chromatin of mouse zygotes, the first cell cycle as an origin of de novo mutation
Hum. Mol. Genet., July 1, 2008; 17(13): 1922 - 1937.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.