Cyclosphamide in the F0 male rat: physical and behavioral changes in three successive adult generations

Auroux, M; Dulioust, Emmanuel Jb.; Selva, J.; Rince, P.

doi:10.1016/0027-5107(90)90093-j

Cited by 58 publications

(19 citation statements)

References 42 publications

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“…Furthermore, if one considers the possible explanations for initial alterations due to cryopreservation (whether these be nuclear mutations, mitochondrial mutations, or epigenetic changes), it would in fact, be surprising to find clear-cut and constant phenotypes because the number, as well as the precise localization, of these events could differ from one mouse to another. Thus, here as in other experiments where low teratogenic or mutagenic risks were assessed (24,25), subtle and complex effects might actually represent an appreciable part of the induced phenotypical changes. Although such effects are more difficult to assess and explain, they must retain our attention.…”

Section: Discussionmentioning

confidence: 99%

“…Behavioral assessments have proven sensitive enough to provide evidence for subtle teratogenic or mutagenic effects (24,25 Gestational ages (number of days between embryo transfer and date of recording) of appearance of nine developmental criteria (means ± SEM): R, righting; HP, hindlimb placing; DCE and DR, disappearance of crossed extensor response and rooting response, respectively; BH, bar holding; VP, vibrissae placing; BG, bulging of gum; AI, appearance of the two incisors of lower mandible; EYO, eyelid opening. C, control mice; CP, cryopreserved mice.…”

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confidence: 99%

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Long-term effects of embryo freezing in mice.

Dulioust

Toyama

Busnel

et al. 1995

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

107

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Embryo cryopreservation does not induce clear-cut anomalies at detectable rates, but several mechanisms exist for nonlethal damage during the freeze-thaw process, and the risk of moderate or delayed consequences has not been extensively investigated. In a long-term study including senescence, we compared cryopreserved and control mice for several quantitative traits. Significant differences were seen in morphophysiological and behavioral features, some of them appearing in elderly subjects. Thus, apart from its immediate toxicity, embryo cryopreservation, without being severely detrimental, may have delayed effects. These results, consistent with other findings, question the neutrality of artificial reproductive technologies and draw attention to the preimplantation stages in developmental toxicology.Embryo freezing is common practice in several species including humans. This technique can be lethal to some embryos but is not considered to have any delayed effect. However, several arguments question such a viewpoint. Several targets of major importance to further development and life are present in the early mammalian embryo: the nuclear DNA, of course, and also the mitochondrial genome (1) and early processes such as those related to imprinting (2, 3), which are completed after fertilization. Freezing-thawing involves dramatic cellular and biochemical changes, such as enzyme inactivation (4-6), ionic disturbances, or attack by free radicals (7-9), that through various pathways could damage these critical components or processes. The current opinion-that embryo freezing has no late consequencesrelies on the negative results of previous experimental studies (10-15) and on common experience in cattle and humans. More recently, however, damage to the genetic material from freezing has been reported (16-18). Furthermore, in domestic species as in humans, investigations have mainly focused on patent defects at birth or in early life. However, for complex organisms in which many genetic changes, especially mitochondrial, may have only mild or delayed effects, such indicators provide only a limited assessment of the broad spectrum of anomalies that could result from mutagenic or toxic action on the early embryo.More detailed investigation and long-term follow-up are necessary to comprehensively assess embryo-freezing consequences in mammals. We report here the results of a study comparing mice derived from cryopreserved and control embryos in several morphophysiological, sensorimotor, and behavioral traits, from birth to senescence. The experiment was done on two different hybrid genotypes: C57BL6/CBA F1 (B6CBA) and C3H/DBA2 F1(C3D2). MATERIALS AND METHODSEmbryo Collection. After superovulation (pregnant mare serum gonadotropin, 5 international units, and human chorionic gonadotropin, 5 international units, 48 hr later), 8-weekold C57BL/6JIco (B6) and C3H/OuJIco (C3) females were mated with CBA/JIco (CBA) and DBA/2JIco (D2) males, respectively. B6CBA and C3D2 embryos were collected in M2 medium (19), at the two...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Long-term effects of embryo freezing in mice.

Dulioust

Toyama

Busnel

et al. 1995

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

107

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“…16). Thus, the greatly altered zygotic DNA methylation pattern observed after paternal cyclophosphamide treatment may contribute to the serious neurological deficits and developmental failure transmitted to three successive generations (18,32).…”

Section: Discussionmentioning

confidence: 99%

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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“…Quanta la nature eta la subtilite des troubles observes, il faut les rapprocher des r6sultats que nous avons d6ja obtenus en provoquant chez le rat m&le des mutations experimentales a I'aide d'antimitotiques mutagenes :la progeniture de ces males presente en effet une alteration de la capacite d'apprendre [5], sous-tendue par une chute de certains des supports biochimiques de la memoire [4].…”

Section: Mutations Facteurs Epig~netiques Et Variations Continues Duunclassified

Age paternel et risques pour la descendance

Auroux

2004

Androl.

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Cyclosphamide in the F0 male rat: physical and behavioral changes in three successive adult generations

Cited by 58 publications

References 42 publications

Long-term effects of embryo freezing in mice.

Long-term effects of embryo freezing in mice.

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

Age paternel et risques pour la descendance

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