Chromosomal mosaicism : underlying mechanisms and consequences for early human embryo development

M. da Avó Ribeiro dos Santos

Research output: ThesisDoctoral thesis 1 (Research UU / Graduation UU)

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Abstract

In humans, reproduction is considered a relatively inefficient process, when compared with other mammalian species and the chance of achieving a spontaneous pregnancy after timed intercourse is at the most 20-30%. Chromosome segregation errors are a well-known inherent feature of cell division in human preimplantation embryos produced by in vitro fertilization (IVF). The occurrence of such errors, which results in embryos containing chromosomally abnormal (aneuploid) cells, is believed to be the main cause for the reported inefficiency of human reproduction, as it may lead to pre-clinical pregnancy losses. In this thesis we start by evaluating the impact of ovarian stimulation administrated to patients undergoing IVF on the development of IVF-derived human embryos. We conclude that although the use of ovarian stimulation is considered relatively safe, further studies are needed to increase the knowledge on this subject and reduce potential effects on embryo development and implantation. Subsequently, we investigated the significance of chromosomal aneuploidy and mosaicism for the developmental potential of human preimplantation embryos. The chromosomal constitution and development of embryos from compaction to the peri-implantation was assessed from day 4 up to day 8 post-fertilization. Our results showed a decrease in the incidence of chromosomal mosaicism over time, with an estimate 80% of day 4 versus 42% of day 8 embryos classified as chromosomally mosaic. We suggest that the developmental arrest of a significant proportion of mosaic embryos on day 4 together with the cell death or reduced proliferation of aneuploid cells within an embryo may be responsible for the observed decrease in mosaicism over time. Our work further indicates that lower levels of chromosomal mosaicism are compatible with embryo implantation, with unknown consequences for further development and later health. The molecular mechanisms that give rise to aneuploidy and chromosomal mosaicism in human preimplantation embryos remain poorly understood. We investigated the behavior of the chromosomal passenger complex (CPC) in human oocytes and embryos compared to what is known in somatic cells. The CPC is an important component of the mitotic checkpoint, as it regulates chromosome segregation, preventing chromosome missegregation and aneuploidy. Our data shows that during the first three embryonic cell divisions Aurora C is the most prominent kinase of the CPC. Aurora B, the kinase variant described in somatic cells, only becomes predominant at the blastocyst stage. Investigation of the upstream pathways regulating localization of the CPC to the centromeres of chromosomes during mitosis showed differences from the mechanisms described in somatic cells. Our results further suggest that these differences may be related to the epigenetic asymmetry known to exist between maternally- and paternally-derived chromatin in human zygotes. We hypothesize that these differences aid in assuring correct CPC localization to centromeres of all chromosomes, independent of their parental origin. Further systematic analysis of the consequences of the differences described in this thesis will contribute to a better understanding of the origins of aneuploidy in early human embryos. Ultimately, that knowledge may allow optimizing the production and selection of IVF embryos and improve success rates after IVF.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Utrecht University
Supervisors/Advisors
  • Fauser, Bart, Primary supervisor
  • Laven, J.S.E., Supervisor, External person
  • Baart, E.B., Co-supervisor, External person
Award date11 Jan 2013
Publisher
Print ISBNs9789039358726
Publication statusPublished - 11 Jan 2013

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