Analysis of Embryotoxic Effects in Preimplantation Embryos

Spielmann, Horst

doi:10.1007/978-1-4684-5332-4_14

Cited by 11 publications

(4 citation statements)

References 66 publications

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“…The system that was employed, namely, the exposure of preblastocyst mouse embryos to potentially toxic substances, has been used to predict the adverse effects of a variety of physical and pharmacologic agents in humans (16). The correlation with human toxicity is variable: cyclophosphamide exposure and chlorambucil exposure, for example, which, similarly to AZT exposure, result in diminution of cell numbers in preimplantation murine embryos, are clearly associated with human risk, while chlorpromazine exposure, which results in a similar phenomenon in mouse blastocysts, has less certain effects during human gestation (2).…”

Section: Discussionmentioning

confidence: 99%

“…Control cells were cultured in the absence of drug side by side with exposed cells and were treated identically but were not subjected to washing. Development to the blastocyst stage was judged successful from light-microscopic appearance (8,16).…”

Section: Methodsmentioning

confidence: 99%

“…Murine embryonic development is sufficiently accessible to in vitro experimental manipulation that all stages can be examined for their susceptibility to drug toxicity by previously established methods (8,16). Fertilized murine oocytes can be readily isolated from the dam at the one-to two-cell stage.…”

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confidence: 99%

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Effect of zidovudine on preimplantation murine embryos

Toltzis

Mourton

Magnuson

1993

Antimicrob Agents Chemother

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It previously has been demonstrated that zidovudine (AZT) is lethal to early murine embryos. The effect of the drug on pre-and postimplantation embryos was examined to delineate the timing of this toxicity and to investigate its possible mechanisms. Embryos exposed in the whole mouse during preblastocyst development were unable to proceed beyond the blastocyst stage. Similarly, when two-cell embryos harvested from unexposed females were exposed to low-concentration (1 ,uM) AZT in vitro over 24 h, development beyond the blastocyst stage was inhibited. In contrast, drug exposure during in vitro blastocyst and postblastocyst development resulted in little or no morphologic toxicity. Further investigation revealed that preblastocyst AZT exposure resulted in the development of blastocysts with significantly lower cell numbers than control embryos.While embryonic exposure to AZT at the blastocyst and postblastocyst stages also resulted in retarded cell division, the effects were milder than those recorded after preblastocyst exposure. These data demonstrate that the critical period of AZT toxicity toward murine embryos is between ovulation and implantation and indicate that AZT directly suppresses cell division in the preimplantation embryo.As the incidence of human immunodeficiency virus (HIV) infection in women increases, growing numbers will be deliberately or inadvertently exposed to zidovudine (AZT) during pregnancy. Recommendations to treat HIV-infected pregnant women with AZT if their CD4 cell counts fall below 200/pul (11) have been made. Moreover, trials to test whether planned antiviral chemotherapy of all pregnant HIV-infected women can interrupt the transmission of virus from mother to child are under way. Traditionally, therapy during pregnancy with any drug has been approached with extreme caution because of concerns about untoward effects upon the embryo or fetus. Therefore, it is important to investigate the toxicity of intragestational administration of HIV antimetabolites in order to enable rational application to humans. It previously has been demonstrated that AZT at concentrations that are readily achievable with conventional human dosing is lethal to murine embryos during early gestation (7,21). Direct exposure of embryos to AZT in vitro resulted in retarded cell division at 0.1 ,ug/ml and cell death at concentrations of 1 ,ug/ml and above (21). Safe administration of AZT during human pregnancy requires that this toxicity be better defined and that its underlying mechanism be determined.The first step in defining the embryo toxicity of AZT is to identify the developmental stage at which this effect occurs. Murine embryonic development is sufficiently accessible to in vitro experimental manipulation that all stages can be examined for their susceptibility to drug toxicity by previously established methods (8, 16). Fertilized murine oocytes can be readily isolated from the dam at the one-to two-cell stage. Two-cell embryos can be cultured in vitro and will develop into blastocysts, the stage immedi...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Effect of zidovudine on preimplantation murine embryos

Toltzis

Mourton

Magnuson

1993

Antimicrob Agents Chemother

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“…Outgrown blastocysts possess two tissues, an outer trophectoderm, which after implantation forms the placenta and extraembryonic membranes, and an inner cell mass (ICM), which gives rise to the fetus (reviewed by Spielman, 1987).…”

Section: Introductionmentioning

confidence: 99%