Paternal exposure to cyclophosphamide induces DNA damage and alters the expression of DNA repair genes in the rat preimplantation embryo

Harrouk, Wafa; Codrington, Alexis M.; Vinson, Robert K.; Robaire, Bernard; Hales, Barbara F.

doi:10.1016/s0921-8777(00)00053-7

Cited by 99 publications

(58 citation statements)

References 44 publications

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“…Some researchers noticed induction of tp53 expresion and some other failed to detect any increase after UV irradiation, treatment with hydroxyurea or with chemotherapeutic agents with effect on mammalian cells (Liu et al 2011). The overexpression of repairing genes that we have observed in oocytes at LRS is compatible with a higher repairing effort, required to repair the genomic lesions promoted during oogenesis in suboptimal conditions (Harrouk et al 2000). The increased expression of rad1, also involved in the telomere-length maintenance (Khair et al 2010), is a common surveillance mechanism activated in trout in response to genotoxic stress such as UV light or ionizing radiation (Bozdarov et al 2013), whereas the downregulation of tp53 generates a more tolerant environment to genotoxic stress.…”

Section: Discussionsupporting

confidence: 64%

Impact of sperm DNA damage and oocyte-repairing capacity on trout development

González-Rojo¹,

Lombó²,

Herráez³

2016

Reproduction

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Section: Discussionsupporting

confidence: 64%

Impact of sperm DNA damage and oocyte-repairing capacity on trout development

González-Rojo¹,

Lombó²,

Herráez³

2016

Reproduction

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“…Animals received food and water ad libitum and were maintained on a 12-h light͞12-h dark photoperiod. After one week of acclimatization, male rats were randomly assigned to one of two treatment groups (n ϭ 10 per group) and gavaged with saline or 6 mg͞kg per day of cyclophosphamide six times per week for 4-5 weeks (17)(18)(19)(20). This treatment regime ensures the targeting of sperm chromatin organization and packaging during spermiogenesis (9).…”

Section: Methodsmentioning

confidence: 99%

“…The transmission of DNA damage incurred in the male genome during 4 weeks of cyclophosphamide administration (20) significantly disrupted the rate of zygotic development after in vivo fertilization (Fig. 1).…”

Section: Paternal Cyclophosphamide Exposure Disrupts Zygotic Developmmentioning

confidence: 97%

Epigenetic programming in the preimplantation rat embryo is disrupted by chronic paternal cyclophosphamide exposure

Barton

Robaire

Hales

2005

Proc. Natl. Acad. Sci. U.S.A.

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Preconceptional paternal exposure to cyclophosphamide, a widely used anticancer agent, leads to increases in embryo loss, malformations, and behavioral deficits in offspring; these abnormalities are transmissible to subsequent generations [Auroux, M., Dulioust, E., Selva, J. & Rince, P. (1990) Mutat. Res. 229, 189 -200]. Little information exists on the mechanisms underlying this male-mediated developmental toxicity. We assessed the impact of paternal cyclophosphamide exposure on the dynamic regulation of histone H4 acetylation at lysine 5 and DNA methylation in preimplantation rat embryos. Zygotes sired by drug-treated males displayed advanced developmental progression, increased pronuclear areas, and disruption of the epigenetic programming of both parental genomes. Early postfertilization zygotic pronuclei were hyperacetylated; by mid-zygotic development, male pronuclei were dramatically hypomethylated, whereas female pronuclei were hypermethylated. Micronuclei were substantially elevated, and histone H4 acetylation at lysine 5 localization to the nuclear periphery was disrupted in two-cell embryos fertilized by cyclophosphamideexposed spermatozoa. This finding demonstrates that paternal exposure to this drug induces aberrant epigenetic programming in early embryos. We hypothesize that disturbances in epigenetic programming contribute to heritable instabilities later in development, emphasizing the importance of epigenetic risk assessment after chemotherapy.pronuclear cross-talk ͉ zygote ͉ histone acetylation ͉ DNA methylation

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“…However, it has been established that premutational lesions in sperm DNA are effectively repaired within a few hours of fertilization (Generoso et al, 1979;Brandriff and Pedersen, 1981). The recognition and repair of premutational damage in the fertilized egg is also accompanied by a suppression of DNA synthesis in both the irradiated male and nonirradiated female pronuclei and alters the expression of DNA repair genes in the preimplantation embryo (Harrouk et al, 2000). It would therefore appear that radiation-induced damage to sperm DNA could later trigger a cascade of epigenetic events in the fertilized egg, similar to that in the repairproficient diploid spermatogonia and finally result in epigenetic modifications.…”

Section: The Mechanisms Of Transgenerational Instabilitymentioning

confidence: 99%

Radiation-induced transgenerational instability

Dubrova

2003

Oncogene

155

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To date, the analysis of mutation induction has provided an irrefutable evidence for an elevated germline mutation rate in the parents directly exposed to ionizing radiation and a number of chemical mutagens. However, the results of numerous publications suggest that radiation may also have an indirect effect on genome stability, which is transmitted through the germ line of irradiated parents to their offspring. This review describes the phenomenon of transgenerational instability and focuses on the data showing increased cancer incidence and elevated mutation rates in the germ line and somatic tissues of the offspring of irradiated parents. The possible mechanisms of transgenerational instability are also discussed.

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Paternal exposure to cyclophosphamide induces DNA damage and alters the expression of DNA repair genes in the rat preimplantation embryo

Cited by 99 publications

References 44 publications

Impact of sperm DNA damage and oocyte-repairing capacity on trout development

Impact of sperm DNA damage and oocyte-repairing capacity on trout development

Epigenetic programming in the preimplantation rat embryo is disrupted by chronic paternal cyclophosphamide exposure

Radiation-induced transgenerational instability

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