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Paternally Transmitted Chromosomal Aberrations in Mouse Zygotes Determine Their Embryonic Fate¹

Biology and Biotechnology Research Program,³ Lawrence Livermore National Laboratory, Livermore, California 94550 National Institute of Environmental Health Sciences,⁴ Research Triangle Park, North Carolina 27709 Comprehensive Cancer Center,⁵ University of California San Francisco, San Francisco, California 94120

The developmental consequences of chromosomal aberrations in embryos include spontaneous abortions, morphological defects, inborn abnormalities, and genetic/chromosomal diseases. Six germ-cell mutagens with different modes of action and spermatogenic stage sensitivities were used to investigate the relationship between the types of cytogenetic damage in zygotes with their subsequent risk of postimplantation death and of birth as a translocation carrier. Independent of the mutagen used, over 98% of paternally transmitted aberrations were chromosome type, rather than chromatid type, indicating that they were formed during the period between exposure of male germ cells and initiation of the first S phase after fertilization. There were consistent one-to-one agreements between the proportions of a) zygotes with unstable aberrations and the frequencies of dead embryos after implantation (slope = 0.87, confidence interval [CI]: 0.74, 1.16) and b) zygotes with reciprocal translocations and the frequency of translocation carriers at birth (slope = 0.74, CI: 0.48, 2.11). These findings suggest that chromosomal aberrations in zygotes are highly predictive of subsequent abnormal embryonic development and that development appears to proceed to implantation regardless of the presence of chromosomal abnormalities. Our findings support the hypothesis that, for paternally transmitted chromosomal aberrations, the fate of the embryo is already set by the end of G1 of the first cell cycle of development.

¹ Funding support from NIH ES 09117-03 and NIEHS IAG Y1 ES 8016-5. This work was performed under the auspices of the U.S. Department of Energy by the University of California, Lawrence Livermore National Laboratory, under Contract W-7405-Eng-48.

² Correspondence: Francesco Marchetti, Biology and Biotechnology Research Program, L-448, Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, CA 94550. FAX: 925 424 3130; marchetti2{at}llnl.gov

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