Molecular aspects of aneuploidy in preimplantation human embryos: A mini-review

Abstract

Objective Focus and analyze on the two aneuploidy types (meiotic and mitotic) in preimplantation human embryos, their causes and possible molecular mechanisms involved. Design Mini-review. Materials and Methods Search performed in MEDLINE database under the keywords; aneuploidy, molecular mechanisms, preimplantation embryos. Results Aneuploidy is the major obstacle in order to achieve successful pregnancies in IVF world. Specifically, more than 50% of preimplantation embryos are aneuploid and unable to achieve pregnancies and live births. In reproductive aged women, aneuploidy rate in oocytes, caused by an error-prone meiotic chromosome segregation mechanism, is reaching 20-30%, in contrast to human sperm, that only 1-8% have an abnormal chromosomal content. Meiotic aneuploidy can occur from MI non-disjunction, MII non-disjunction and MI or MII pre-division. Maternal age is the major critical factor related to aneuploidy; 50% of the oocytes from advanced age women (≥ 40 years old) are aneuploid due to meiotic errors. Cohesive chromosome connections are weakened with increasing maternal age mainly due to very small amounts of a major cohesin component, the Rec8. Additionally, recombination failure, which varies between chromosomes, can also lead to meiotic aneuploidy. Genomic errors can also arise during post-fertilization mitotic divisions, resulting in embryonic mosaicism. The mechanisms leading to embryonic mosaicism during embryonic mitosis are; non-disjunction, anaphase lagging and endoreplication. Mitotic aneuploidies rise from 63% at the cleavage stage to 95% in blastocyst stage human embryos. Defects in mitotic spindle assembly checkpoint (SAC) can result to high chromosome missegregation levels both in vitro and in vivo. Furthermore, malfunction of cohesins, possibly due to inactivation of STAG2 and/or overexpression of seperase, leads in premature chromosome separation, while delay in their removal may result in non-disjunction. Finally, embryonic mitotic aneuploidy can be caused by extra-nuclear DNA formation (micronucleation) from lagging chromosomes with severe DNA damage and by severe paternal sperm defects. Conclusions The high rate of chromosomal aneuploidies may arise mostly during the first or second meiotic divisions, especially in advanced maternal age women, but also can arise in the postzygotic stage during the mitotic divisions of cleavage stage and blastocyst embryos, resulting in mosaicism. Further work and analysis on the molecular mechanisms that lead to meiotic and mitotic aneuploidy in preimplantation embryos, can reveal improved clinical strategies to reduce the occurrence of aneuploidy and consequently improve the success rates of IVF. Disclosures None. Funding None. Focus and analyze on the two aneuploidy types (meiotic and mitotic) in preimplantation human embryos, their causes and possible molecular mechanisms involved. Mini-review. Search performed in MEDLINE database under the keywords; aneuploidy, molecular mechanisms, preimplantation embryos. Aneuploidy is the major obstacle in order to achieve successful pregnancies in IVF world. Specifically, more than 50% of preimplantation embryos are aneuploid and unable to achieve pregnancies and live births. In reproductive aged women, aneuploidy rate in oocytes, caused by an error-prone meiotic chromosome segregation mechanism, is reaching 20-30%, in contrast to human sperm, that only 1-8% have an abnormal chromosomal content. Meiotic aneuploidy can occur from MI non-disjunction, MII non-disjunction and MI or MII pre-division. Maternal age is the major critical factor related to aneuploidy; 50% of the oocytes from advanced age women (≥ 40 years old) are aneuploid due to meiotic errors. Cohesive chromosome connections are weakened with increasing maternal age mainly due to very small amounts of a major cohesin component, the Rec8. Additionally, recombination failure, which varies between chromosomes, can also lead to meiotic aneuploidy. Genomic errors can also arise during post-fertilization mitotic divisions, resulting in embryonic mosaicism. The mechanisms leading to embryonic mosaicism during embryonic mitosis are; non-disjunction, anaphase lagging and endoreplication. Mitotic aneuploidies rise from 63% at the cleavage stage to 95% in blastocyst stage human embryos. Defects in mitotic spindle assembly checkpoint (SAC) can result to high chromosome missegregation levels both in vitro and in vivo. Furthermore, malfunction of cohesins, possibly due to inactivation of STAG2 and/or overexpression of seperase, leads in premature chromosome separation, while delay in their removal may result in non-disjunction. Finally, embryonic mitotic aneuploidy can be caused by extra-nuclear DNA formation (micronucleation) from lagging chromosomes with severe DNA damage and by severe paternal sperm defects. The high rate of chromosomal aneuploidies may arise mostly during the first or second meiotic divisions, especially in advanced maternal age women, but also can arise in the postzygotic stage during the mitotic divisions of cleavage stage and blastocyst embryos, resulting in mosaicism. Further work and analysis on the molecular mechanisms that lead to meiotic and mitotic aneuploidy in preimplantation embryos, can reveal improved clinical strategies to reduce the occurrence of aneuploidy and consequently improve the success rates of IVF.