Total

lOO

TOTAL NORMAL (%)

l8

the origin of the chromosome 21 errors, and the opposite tendencies for chromosome 16 and 18 errors (see Table 5.9). The chromosome 13 error pattern was similar to that of chromosome 21, originating with a comparable frequency from meiosis I and meiosis II, and the chromosome 22-specific pattern was similar to the chromosome 16 pattern, originating predominantly in meiosis II (50.8% meiosis II errors vs. 30.8% meiosis I errors), in contrast to chromosome 18 errors, deriving more frequently from meiosis I (60.2% from meiosis I vs 29.7% from meiosis II). The comparison of these direct data to the data derived from DNA polymorphism studies, obtained from liveborn babies and spontaneous abortions with similar aneuploidies, will be of relevance for understanding of possible differences in viability of aneuploid embryos of different origin.

5.1.2 Mitotic Errors in Cleaving Embryos in Relation to Meiosis Errors

As shown above, approximately half of meiosis II errors are observed in the oocytes with prior errors in meiosis I. As a result of such sequential errors, almost one third of the resulting zygotes may have been considered normal (euplolid), provided that the preceding errors in meiosis I and meiosis II have no effect on the further preimplantation developments of the corresponding embryos. To investigate if these meiosis errors could affect the sequential mitotic divisions in the resulting zygotes and if these apparently euploid zygotes may develop into chromosomally normal embryo acceptable for embryo transfer in PGD cycles, follow-up testing of these embryos was carried out at the cleavage stage. As seen from Table 5.10 of 100 embryos tested overall, only 18%, deriving from the apparently balanced zygotes, were euploid for all five chromosomes analyzed, while the remaining majority were with chromosomal abnormalities [37, 38].

All of the chromosomally normal (euploid for five chromosomes tested) embryos appeared to result from zygotes with only one chromosomal error rescue, with none resulting from the zygotes balanced for two chromosomes. The fact that only a few resulting embryos (11%) were abnormal for the same chromosome, for which sequential meiosis I and meiosis II led to the balanced set, may suggest that the observed sequential errors in female meiosis may be attributable to the meiotic apparatus abnormality overall, rather than to a single chromosome segregation defect, which may further lead to a general defect of mitotic apparatus of the resulting embryos. This seems to be in agreement also with the observed types of aneuploi-dies detected in the resulting embryos, which in 79.3% of cases were represented by complex errors, including mosaicism (Figure 5.11), known to be highly prevalent at the cleavage stage [17, 18].

As the average reproductive age of the patients from whom the oocytes were obtained was approximately 38.5 years, the observed genomic instability in mitotic divisions of the apparently balanced zygotes following meiosis II rescue may be age-related. Although the mechanism by which the age factor may lead to these changes is not known, the underlying mechanisms of the aging process involve increasing errors in the mitotic machinery of dividing cells and chromosomal abnormalities. It was also suggested that deviations in the cytoplasmic organization, such as mitochondrial distribution, may reduce mei-otic competence of oocytes and predispose the embryos to common cleavage abnormalities [23, 39-41]. The relationship between these cytoplas-mic changes and the nuclear organization during maturation and fertilization of oocytes may

Figure 5.11. Sequential chromosome 21 errors in meiosis I and II resulting in an abnormal mosaic embryo. (A and B) FISH images of PB1 and PB2 after hybridization with the MultiVysion PB panel probe. (A) A normal number of signals for each chromosome (double dots) are detected in PB1 with the exception of three signals for chromosome 21 (green arrows). (B) Four instead of five signals are detected in PB2, with a missing green signal for chromosome 21, suggesting the normal number for all five chromosomes in the resulting oocyte. (C to E) Mosaicism in the embryo for chromosomes 13,21, and 22. (C) FISH image of an interphase nucleus from the resulting embryo with normal number of signals, including chromosome 21 (green arrows). (D) FISH image of a second nucleus from the same embryo, in which three signals for chromosome 13 (red arrows) and chromosome 21 (green arrows) are present with a normal number of signals for chromosomes 16,18, and 22. (E) FISH image of third interphase nucleus from the same embryo, in which three signals for chromosome 22 (yellow arrows) and only one signal for chromosome 13 (redarrow) are present, together with two signals for chromosomes 16,18 and 21. The observed mosaicism may be associated with the sequential errors of chromosome 21 in meiosis I and meiosis II.

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