Frequency Of Chromosome Errors In Primates

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It is well established that aneuploidy is common in human oocytes and IVF embryos, and that the frequency of these anomalies increases with age, especially after age 25 (Munne and Cohen, 1998; Munne et al., 2002). Several studies have reported frequencies up to 50% for aneuploidy (Gras et al., 1992) and as high as 48% for mosaicism (Munne et al., 2002). In the latter study, as many as 84% of cells in ''chaotic mosaic'' embryos were abnormal. However, all the data are from oocytes and IVP embryos of infertile women, in which occurrence of chromosome anomalies may be especially marked compared with the general population, and may also be exacerbated by gonadotropin stimulation for IVF. Moreover, humans are not suitable experimental subjects for studying the etiology or frequency of aneuploidy in the general population. In order to study these questions, a suitable experimental model is needed, which clearly needs to be a nonhuman primate. However, no study has adequately examined the frequency of aneuploidies in monkey oocytes, either under natural conditions or following ovarian stimulation with gonadotropins.

Aneuploidy is defined as any deviation from the normal number of chromosomes, usually meaning a cell nucleus possessing too many or too few chromosomes. Aneuploidy generally results from nondisjunction events during meiosis, subsequent to ''germinal vesicle'' (GV) breakdown. About 85% of aneuploidy errors in mice derive from meiotic nondisjunction (Hunt and Hassold, 2002). Alternatively, aneuploidy can result from errors subsequent to meiosis, i.e., mitotic nondisjunction during embryo development. This represents about 15% of chromosomal anomalies. One study reported a significant relationship between maternal age and embryo mosaicism caused by mitotic nondisjunction (Munne and Cohen, 1998). In addition, embryos with impaired developmental competence had a higher frequency of chromosome abnormalities. Gross forms of aneuploidy such as polyploidy can also result from polyspermic fertilization or failure of second polar body extrusion. However, these gross errors are easily distinguishable from non-disjunction errors that are more prevalent in primate IVP embryos. It is important to understand the etiology of these high error rates so that more normal embryos can be produced, with consequent improvement in the success rates of human IVF, especially for older women for whom the aneuploidy rate is much higher. There are two main possibilities.

1. High rates of aneuploidy and associated mosaicism in embryos due to aberrant chromosome separation are inherent in humans and other ''Old World'' primates, and this frequency increases with age. If this is true, then little or nothing can be done to decrease the frequencies of these errors. This possibility seems unlikely, partly because such high error rates are not seen in oocytes or embryos from other species examined, such as laboratory or domestic animals. Another reason for doubting this explanation is the source of the information on aneuploidy/mosaicism rates in human oocytes and embryos, as discussed next.

2. The high aneuploidy/mosaicism rates reported in human IVP embryos may result from several factors. (i) The subjects are patients attending IVF clinics; many of these women are infertile, and thus, they are not representative of the general population; (ii) These patients are mostly in the 30-40 years age bracket, and it is likely that the frequency of aneuploidy (nondisjunction) and mosaicism errors in oocytes increases with age (Pellestor et al., 2003); (iii) The patients are stimulated with gonadotropins which raise estra-diol levels much higher than normal (Hughes et al., 1990). This abnormal endocrine environment could adversely affect chromosome separation during meiosis. Recent data in mice indicate that estro-genic compounds that elevate blood estradiol levels greatly increase the nondisjunction frequency (Hunt et al., 2003); (iv) The artificial culture conditions used for embryo production (IVP) may have an impact on genetic quality of embryos by influencing chromosomal segregation during early cleavage (Bean et al., 2002). The mechanism of this effect is not known. Factors (iii) and (iv) may synergize to increase the overall rate of chromosome anomalies. If (iii) is true, then the high rate of aneuploidy/mosaicism seen in many infertile women is potentially treatable by designing new stimulation regimens, or even avoiding gonado-tropin stimulation altogether. This may be especially important for older women who are at higher risk for chromosome anomalies. If (iv) is true, then new embryo culture media are needed to reduce mosaicism frequency.

Without reliable information on the cause(s) of high error rates during chromosomal segregation in humans, it is difficult to know how to proceed in order to ameliorate the condition to produce more normal IVF embryos. It is also entirely plausible that the conditions giving rise to chromosomal anomalies cannot be ameliorated, but again, this will not be elucidated without further studies. It would be useful to know the frequency of aneuploidy/mosaicism in the general human population, but this information is not available, nor is it likely to be. Alternatively, donor oocytes from young women could be examined, but this is not practical because chromosome analysis is destructive and thus precludes use of these oocytes for their primary purpose of embryo production and transfer. Information on oocytes from unstimulated, infertile patients would be helpful, but there are almost no data on this. Because of all these difficulties in obtaining relevant information from humans, the etiology of aneuploidy/mosaicism in primate oocytes and embryos remains a mystery.

The rhesus monkey should prove an ideal model for unraveling this mystery, for several reasons. First, destructive analysis can be done on rhesus oocytes and embryos because this is an experimental model, and complete analysis of all cells is needed to gauge the degree of mosaicism in embryos. Second, we can obtain oocytes from several sources to help determine the etiology of chromosome defects: in vivo matured oocytes from nonstimulated and from gonadotropin-stimulated monkeys, and IVP embryos from IVM or from in vivo matured oocytes. In effect, we can devise a 2 x 2 factorial study with stimulation vs. nonstimulation and in vivo vs. IVP embryos, which is impractical in humans. In these ways, we could compare aneuploidy and mosaicism frequencies, within and across age groups. We would expect to find substantial chromosomal error rates (perhaps 20% or more) in embryos derived from IVM oocytes due to errors in nondisjunction as a result of the artificial conditions during meiosis in vitro. This would help to account for the low developmental competence of primate (monkey and human) IVM oocytes, and help to determine whether the high frequency of aneuploidy observed in oocytes and embryos of older women is inherent or if their oocytes are more susceptible to ART procedures.

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