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Cytoplasm Mediates Both Development and Oxidation-Induced Apoptotic Cell Death in Mouse Zygotes¹

^a Department of Obstetrics/Gynecology, Brown University, Women and Infants Hospital, Providence,Rhode Island 02905 ^b Marine Biological Laboratory, Woods Hole, Massachusetts 02543

ABSTRACT

Eggs must be the major locus of reproductive aging in women, because donation of eggs from younger to middle-aged women abrogates the effects of age on fertility. Oxidative stress, mitochondrial dysfunction, and apoptosis are associated with senescence. To develop an animal model of egg senescence, we treated mouse zygotes with 175 µM H₂O₂ that induced mitochondrial dysfunction and developmental arrest, followed by delayed cell death, consistent with apoptosis. We reconstructed zygotes with nuclei and cytoplasm from treated or untreated zygotes, then followed development and apoptotic cell death in the reconstituted embryos. Pronuclear exchange between untreated, normal zygotes served as nuclear transfer controls. Rates of cleavage and development to morula and blastocysts were significantly lower (P < 0.01) in zygotes reconstituted from untreated pronuclei and H₂O₂-stressed cytoplasts than those of nuclear transfer controls. Instead, the arrested, reconstituted zygotes displayed TUNEL staining at a similar rate to that of H₂O₂-treated controls, suggesting that apoptotic potential could be transferred cytoplasmically. On the other hand, rates of cleavage and development to morula and blastocyst of the reconstituted zygotes, derived from stressed pronuclei and untreated cytoplasm, were significantly increased (P < 0.05), compared to those of H₂O₂-treated, control zygotes, indicating that healthy cytoplasm could partly rescue pronuclei from oxidative stress. Although oxidation stressed both nuclei and cytoplasm, cytoplasm was more sensitive than nuclei to oxidative stress. It is suggested that cytoplasm, most likely mitochondria, plays a central role in mediating both development and apoptotic cell death induced by oxidative stress in mouse zygotes.

FOOTNOTES

First decision: 8 December 1999.

¹ This work was supported in part by the NIH (K081099) and Women and Infants Hospital/Brown Faculty Research Fund.

² Correspondence: David Keefe, Women & Infants Hospital, Brown University, Dept. of Ob/Gyn, 101 Dudley Street, Providence, RI 02905. FAX: 401 453 7599; dkeefe{at}smtp.wihri.org

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