An ultrastructural and cytological study of preimplantation development of the mouse

Calarco, Patricia G.; Brown, Edward H.

doi:10.1002/jez.1401710303

Cited by 219 publications

(77 citation statements)

References 33 publications

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“…DNA polymerase gamma, the enzyme responsible for replication of mitochondrial DNA, is severely inhibited by these compounds in cell-free assays (1,4,5,9,15,22). These observations may be particularly relevant to the embryo lethality noted with AZT, since the period of maximal cytotoxicity seen in embryos (between ovulation and blastocyst formation) closely coincides with a period of mitochondrial morphologic evolution in the mouse embryo (3,18). The morphologic maturation of the mitochondria at the blastocyst stage may correspond to the disappearing sensitivity of the embryo to the lethal effects of the drug once implantation has occurred.…”

Section: Discussionmentioning

confidence: 87%

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: 87%

Effect of zidovudine on preimplantation murine embryos

Toltzis

Mourton

Magnuson

1993

Antimicrob Agents Chemother

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“…4A) and the structure reaches a stable state, depending on the conditions. The blastocyst cavity is an intercellular space in the mammalian embryo, created by the directional fluid secretion of the outer layer cells (Aziz and Alexandre, 1991;Calarco and Brown, 1969;Wiley and Eglitis, 1981). This secretion most likely occurs in essentially all outer blastomeres with apicobasal epithelial polarity, thus initiating multiple small cavitations (Motosugi et al, 2005), and these multiple cavities coalesce with each other to form one large cavity.…”

Section: Resultsmentioning

confidence: 99%

Computer simulation of emerging asymmetry in the mouse blastocyst

et al. 2008

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The mechanism of embryonic polarity establishment in mammals has long been controversial. Whereas some claim prepatterning in the egg, we recently presented evidence that mouse embryonic polarity is not established until blastocyst and proposed the mechanical constraint model. Here we apply computer simulation to clarify the minimal cellular properties required for this morphology. The simulation is based on three assumptions: (1) behavior of cell aggregates is simulated by a 3D vertex dynamics model; (2) all cells have equivalent mechanical properties; (3) an inner cavity with equivalent surface properties is gradually enlarged. However, an initial attempt reveals a requirement for an additional assumption: (4) the surface of the cavity is firmer than intercellular surfaces, suggesting the presence of a basement membrane lining the blastocyst cavity, which is indeed confirmed by published data. The simulation thus successfully produces a structure recapitulating the mouse blastocyst. The axis of the blastocyst, however, remains variable, leading us to an additional assumption: (5) the aggregate is enclosed by a capsule, equivalent to the zona pellucida in vivo. Whereas a spherical capsule does not stabilize the blastocyst axis, an ellipsoidal capsule eventually orients the axis in accordance with its longest diameter. These predictions are experimentally verified by time-lapse recordings of mouse embryos. During simulation, equivalent cells form two distinct populations composed of smaller inner cells and larger outer cells. These results reveal a unique feature of early mammalian development: an asymmetry may emerge autonomously in an equivalent population with no need for a priori intrinsic differences.

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“…The periphery of the NPB changes at the same time and a new structure, the nucleonema, composed of ribonucleoproteins (RNPs), begins to emerge from the NPBs [5,16]. During further embryonic development, the NPBs gradually disappear and at the early blastocyst stage, the nucleolus becomes morphologically identical to the somatic one [11].…”

mentioning

confidence: 99%