ToxSci Advance Access originally published online on September 13, 2007
Toxicological Sciences 2007 100(2):495-503; doi:10.1093/toxsci/kfm242
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DNA Damage Recognition in the Rat Zygote Following Chronic Paternal Cyclophosphamide Exposure
* Department of Pharmacology and Therapeutics
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
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Abstract |
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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 (
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 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 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; H2AX; poly(ADP-ribosyl)ation.
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