Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Aneuploidy in mammalian oocytes and the impact of maternal ageing

Nature Reviews Molecular Cell Biology volume 24, pages 27–44 (2023)Cite this article

Subjects

Abstract

During fertilization, the egg and the sperm are supposed to contribute precisely one copy of each chromosome to the embryo. However, human eggs frequently contain an incorrect number of chromosomes — a condition termed aneuploidy, which is much more prevalent in eggs than in either sperm or in most somatic cells. In turn, aneuploidy in eggs is a leading cause of infertility, miscarriage and congenital syndromes. Aneuploidy arises as a consequence of aberrant meiosis during egg development from its progenitor cell, the oocyte. In human oocytes, chromosomes often segregate incorrectly. Chromosome segregation errors increase in women from their mid-thirties, leading to even higher levels of aneuploidy in eggs from women of advanced maternal age, ultimately causing age-related infertility. Here, we cover the two main areas that contribute to aneuploidy: (1) factors that influence the fidelity of chromosome segregation in eggs of women from all ages and (2) factors that change in response to reproductive ageing. Recent discoveries reveal new error-causing pathways and present a framework for therapeutic strategies to extend the span of female fertility.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Meiosis of human oocytes.
Fig. 2: Chromosome segregation in mammalian oocytes.
Fig. 3: Assembly of the meiotic spindle in mammalian oocytes.
Fig. 4: Domains and components of the mammalian meiotic spindle.
Fig. 5: Age-associated defects in chromosome segregation in mammalian oocytes.
Fig. 6: Factors implicated in mammalian oocyte ageing.

Similar content being viewed by others

References

  1. Gruhn, J. R. et al. Chromosome errors in human eggs shape natural fertility over reproductive life span. Science 365, 1466–1469 (2019). Aneuploidy rates in human oocytes exhibit a U-shaped relationship with respect to maternal age where chromosomes and the types of errors they experience are revealed to be different in young and older oocytes.

    Article  CAS  Google Scholar 

  2. Hou, Y. et al. Genome analyses of single human oocytes. Cell 155, 1492–1506 (2013).

    Article  CAS  Google Scholar 

  3. Ottolini, C. S. et al. Genome-wide maps of recombination and chromosome segregation in human oocytes and embryos show selection for maternal recombination rates. Nat. Genet. 47, 727–735 (2015). First identification of the ‘reverse segregation’ type error in human oocytes, when the sister chromatids of a bivalent separate like in mitosis during meiosis I.

    Article  CAS  Google Scholar 

  4. Bell, A. D. et al. Insights into variation in meiosis from 31,228 human sperm genomes. Nature 583, 259–264 (2020).

    Article  CAS  Google Scholar 

  5. Lu, S. et al. Probing meiotic recombination and aneuploidy of single sperm cells by whole-genome sequencing. Science 338, 1627–1630 (2012).

    Article  CAS  Google Scholar 

  6. Wang, J., Fan, H. C., Behr, B. & Quake, S. R. Genome-wide single-cell analysis of recombination activity and de novo mutation rates in human sperm. Cell 150, 402–412 (2012).

    Article  CAS  Google Scholar 

  7. Cimini, D., Tanzarella, C. & Degrassi, F. Differences in malsegregation rates obtained by scoring ana-telophases or binucleate cells. Mutagenesis 14, 563–568 (1999).

    Article  CAS  Google Scholar 

  8. Thompson, S. L. & Compton, D. A. Chromosome missegregation in human cells arises through specific types of kinetochore-microtubule attachment errors. Proc. Natl Acad. Sci. USA 108, 17974–17978 (2011).

    Article  CAS  Google Scholar 

  9. Knouse, K. A., Wu, J., Whittaker, C. A. & Amon, A. Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc. Natl Acad. Sci. USA 111, 13409–13414 (2014).

    Article  CAS  Google Scholar 

  10. Pacchierotti, F., Adler, I. D., Eichenlaub-Ritter, U. & Mailhes, J. B. Gender effects on the incidence of aneuploidy in mammalian germ cells. Environ. Res. 104, 46–69 (2007).

    Article  CAS  Google Scholar 

  11. Templado, C., Vidal, F. & Estop, A. Aneuploidy in human spermatozoa. Cytogenet. Genome Res. 133, 91–99 (2011).

    Article  CAS  Google Scholar 

  12. Magli, M. C. et al. Paternal contribution to aneuploidy in preimplantation embryos. Reprod. Biomed. Online 18, 536–542 (2009).

    Article  CAS  Google Scholar 

  13. Tang, W. W. C., Kobayashi, T., Irie, N., Dietmann, S. & Surani, M. A. Specification and epigenetic programming of the human germ line. Nat. Rev. Genet. 17, 585–600 (2016).

    Article  CAS  Google Scholar 

  14. Haering, C. H., Farcas, A. M., Arumugam, P., Metson, J. & Nasmyth, K. The cohesin ring concatenates sister DNA molecules. Nature 454, 297–301 (2008).

    Article  CAS  Google Scholar 

  15. Burkhardt, S. et al. Chromosome cohesion established by Rec8-cohesin in fetal oocytes is maintained without detectable turnover in oocytes arrested for months in mice. Curr. Biol. 26, 678–685 (2016).

    Article  CAS  Google Scholar 

  16. Tachibana-Konwalski, K. et al. Rec8-containing cohesin maintains bivalents without turnover during the growing phase of mouse oocytes. Genes Dev. 24, 2505–2516 (2010). Alongside Burkhardt et al.15, this study demonstrates that REC8-containing cohesin is not re-installed along chromosomes after S-phase of PGC establishment in fetal development.

    Article  CAS  Google Scholar 

  17. Láscarez-Lagunas, L., Martinez-Garcia, M. & Colaiácovo, M. SnapShot: meiosis – prophase I. Cell 181, 1442–1442.e1 (2020).

    Article  Google Scholar 

  18. Alleva, B. & Smolikove, S. Moving and stopping: regulation of chromosome movement to promote meiotic chromosome pairing and synapsis. Nucleus 8, 613–624 (2017).

    Article  CAS  Google Scholar 

  19. Park, S. U., Walsh, L. & Berkowitz, K. M. Mechanisms of ovarian aging. Reproduction 162, R19–R33 (2021).

    Article  CAS  Google Scholar 

  20. Williams, C. J. & Erickson, G. F. In Morphology and Physiology of the Ovary (Endotext, 2000).

  21. Li, R. & Albertini, D. F. The road to maturation: somatic cell interaction and self-organization of the mammalian oocyte. Nat. Rev. Mol. Cell Biol. 14, 141–152 (2013).

    Article  CAS  Google Scholar 

  22. Anderson, E. & Albertini, D. F. Gap junctions between the oocyte and companion follicle cells in the mammalian ovary. J. Cell Biol. 71, 680–686 (1976).

    Article  CAS  Google Scholar 

  23. Hutt, K. J. & Albertini, D. F. An oocentric view of folliculogenesis and embryogenesis. Reprod. Biomed. Online 14, 758–764 (2007).

    Article  CAS  Google Scholar 

  24. Kitajima, T. S., Ohsugi, M. & Ellenberg, J. Complete kinetochore tracking reveals error-prone homologous chromosome biorientation in mammalian oocytes. Cell 146, 568–581 (2011).

    Article  CAS  Google Scholar 

  25. Terret, M. E. et al. The meiosis I-to-meiosis II transition in mouse oocytes requires separase activity. Curr. Biol. 13, 1797–1802 (2003).

    Article  CAS  Google Scholar 

  26. Holubcová, Z., Blayney, M., Elder, K. & Schuh, M. Error-prone chromosome-mediated spindle assembly favors chromosome segregation defects in human oocytes. Science 5, 1143–1147 (2015). Alongside Haverfield et al.47, live imaging of human oocytes undergoing meiotic division reveals instability of meiotic spindles and incorrect kinetochore–microtubule attachments that promote aneuploidy.

    Article  Google Scholar 

  27. Tyc, K. M., McCoy, R. C., Schindler, K. & Xing, J. Mathematical modeling of human oocyte aneuploidy. Proc. Natl Acad. Sci. USA 117, 10455–10464 (2020).

    Article  CAS  Google Scholar 

  28. Clift, D. & Marston, A. L. The role of shugoshin in meiotic chromosome segregation. Cytogenet. Genome Res. 133, 234–242 (2011).

    Article  CAS  Google Scholar 

  29. Keating, L., Touati, S. A. & Wassmann, K. A PP2A-B56-centered view on metaphase-to-anaphase transition in mouse oocyte meiosis I. Cells 9, 390 (2020).

    Article  CAS  Google Scholar 

  30. Marston, A. L. Shugoshins: tension-sensitive pericentromeric adaptors safeguarding chromosome segregation. Mol. Cell. Biol. 35, 634–648 (2015).

    Article  Google Scholar 

  31. Chaigne, A. et al. F-actin mechanics control spindle centring in the mouse zygote. Nat. Commun. 7, 10253 (2016).

    Article  CAS  Google Scholar 

  32. Scheffler, K. et al. Two mechanisms drive pronuclear migration in mouse zygotes. Nat. Commun. 12, 841 (2021).

    Article  CAS  Google Scholar 

  33. Reichmann, J. et al. Dual-spindle formation in zygotes keeps parental genomes apart in early mammalian embryos. Science 361, 189–193 (2018).

    Article  CAS  Google Scholar 

  34. Schulz, K. N. & Harrison, M. M. Mechanisms regulating zygotic genome activation. Nat. Rev. Genet. 20, 221–234 (2019).

    Article  CAS  Google Scholar 

  35. Nagaoka, S. I., Hassold, T. J. & Hunt, P. A. Human aneuploidy: mechanisms and new insights into an age-old problem. Nat. Rev. Genet. 13, 493–504 (2012).

    Article  CAS  Google Scholar 

  36. Dumont, J. et al. A centriole- and RanGTP-independent spindle assembly pathway in meiosis I of vertebrate oocytes. J. Cell Biol. 176, 295–305 (2007).

    Article  CAS  Google Scholar 

  37. Schuh, M. & Ellenberg, J. Self-organization of MTOCs replaces centrosome function during acentrosomal spindle assembly in live mouse oocytes. Cell 130, 484–498 (2007).

    Article  CAS  Google Scholar 

  38. Szollosi, D., Calarco, P. & Donahue, R. P. Absence of centrioles in the first and second meiotic spindles of mouse oocytes. J. Cell Sci. 11, 521–541 (1972).

    Article  CAS  Google Scholar 

  39. Hertig, A. T. & Adams, E. C. Studies on the human oocyte and its follicle. I. Ultrastructural and histochemical observations on the primordial follicle stage. J. Cell Biol. 34, 647–675 (1967).

    Article  CAS  Google Scholar 

  40. Simerly, C. et al. Separation and loss of centrioles from primordidal germ cells to mature oocytes in the mouse. Sci. Rep. 8, 12791 (2018).

    Article  Google Scholar 

  41. Manandhar, G., Schatten, H. & Sutovsky, P. Centrosome reduction during gametogenesis and its significance. Biol. Reprod. 1, 2–13 (2005).

    Article  Google Scholar 

  42. Wu, Q., Li, B., Liu, L., Sun, S. & Sun, S. Centrosome dysfunction: a link between senescence and tumor immunity. Signal. Transduct. Target. Ther. 5, 107 (2020).

    Article  Google Scholar 

  43. Baumann, C., Wang, X., Yang, L. & Viveiros, M. M. Error-prone meiotic division and subfertility in mice with oocyte-conditional knockdown of pericentrin. J. Cell Sci. 130, 1251–1262 (2017).

    CAS  Google Scholar 

  44. Clarke, P. R. & Zhang, C. Spatial and temporal coordination of mitosis by Ran GTPase. Nat. Rev. Mol. Cell Biol. 9, 464–477 (2008).

    Article  CAS  Google Scholar 

  45. Carazo-Salas, R. E. et al. Generation of GTP-bound ran by RCC1 is required for chromatin-induced mitotic spindle formation. Nature 400, 178–181 (1999).

    Article  CAS  Google Scholar 

  46. So, C. et al. Mechanism of spindle pole organization and instability in human oocytes. Science 375, eabj3944 (2022). This study identifies low levels of KIFC1 as a contributing factor to spindle instability in human oocytes.

    Article  CAS  Google Scholar 

  47. Haverfield, J. et al. Tri-directional anaphases as a novel chromosome segregation defect in human oocytes. Hum. Reprod. 32, 1293–1303 (2017).

    Article  CAS  Google Scholar 

  48. Battaglia, D. E., Goodwin, P., Klein, N. A. & Soules, M. R. Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Hum. Reprod. 11, 2217–2222 (1996).

    Article  CAS  Google Scholar 

  49. Roeles, J. & Tsiavaliaris, G. Actin-microtubule interplay coordinates spindle assembly in human oocytes. Nat. Commun. 10, 4651 (2019).

    Article  Google Scholar 

  50. Xue, Z. et al. Genetic programs in human and mouse early embryos revealed by single-cell RNA sequencing. Nature 500, 593–597 (2013).

    Article  CAS  Google Scholar 

  51. Wu, J. et al. Chromatin analysis in human early development reveals epigenetic transition during ZGA. Nature 557, 256–260 (2018).

    Article  CAS  Google Scholar 

  52. Leng, L. et al. Single-cell transcriptome analysis of uniparental embryos reveals parent-of-origin effects on human preimplantation development. Cell Stem Cell 25, 697–712.e6 (2019).

    Article  CAS  Google Scholar 

  53. She, Z. Y. & Yang, W. X. Molecular mechanisms of kinesin-14 motors in spindle assembly and chromosome segregation. J. Cell Sci. 130, 2097–2110 (2017).

    Article  CAS  Google Scholar 

  54. Mogessie, B. & Schuh, M. Actin protects mammalian eggs against chromosome segregation errors. Science 357, eaal1647 (2017).

    Article  Google Scholar 

  55. Schuh, M. & Ellenberg, J. A new model for asymmetric spindle positioning in mouse oocytes. Curr. Biol. 18, 1986–1992 (2008).

    Article  CAS  Google Scholar 

  56. Azoury, J. et al. Spindle positioning in mouse oocytes relies on a dynamic meshwork of actin filaments. Curr. Biol. 18, 1514–1519 (2008).

    Article  CAS  Google Scholar 

  57. Weber, K. L., Sokac, A. M., Berg, J. S., Cheney, R. E. & Bement, W. M. A microtubule-binding myosin required for nuclear anchoring and spindle assembly. Nature 431, 325–329 (2004).

    Article  CAS  Google Scholar 

  58. Hirano, Y. et al. Structural basis of cargo recognition by the myosin-X MyTH4-FERM domain. EMBO J. 30, 2734–2747 (2011).

    Article  CAS  Google Scholar 

  59. Crozet, F., da Silva, C., Verlhac, M. H. & Terret, M. E. Myosin-X is dispensable for spindle morphogenesis and positioning in the mouse oocyte. Development 148, dev199364 (2021).

    Article  CAS  Google Scholar 

  60. Grudzinskas, J. G. & Yovich, J. L. in Gametes – The Oocyte (Cambridge University Press, 1995).

  61. Kyogoku, H. & Kitajima, T. S. Large cytoplasm is linked to the error-prone nature of oocytes. Dev. Cell 41, 287–298.e4 (2017).

    Article  CAS  Google Scholar 

  62. Lane, S. I. R. & Jones, K. T. Chromosome biorientation and APC activity remain uncoupled in oocytes with reduced volume. J. Cell Biol. 216, 3949–3957 (2017). Alongside Kyogoku & Kitajima61, this study demonstrates how the oocyte cytoplasmic volume influences spindle dynamics and the efficacy of the spindle assembly checkpoint to ensure correct chromosome alignment.

    Article  CAS  Google Scholar 

  63. So, C. et al. A liquid-like spindle domain promotes acentrosomal spindle assembly in mammalian oocytes. Science 364, eaat9557 (2019).

    Article  CAS  Google Scholar 

  64. Yoshida, S. et al. Prc1-rich kinetochores are required for error-free acentrosomal spindle bipolarization during meiosis I in mouse oocytes. Nat. Commun. 11, 2652 (2020).

    Article  CAS  Google Scholar 

  65. Bieling, P., Telley, I. A. & Surrey, T. A minimal midzone protein module controls formation and length of antiparallel microtubule overlaps. Cell 142, 420–432 (2010).

    Article  CAS  Google Scholar 

  66. Brunet, S. et al. Meiotic regulation of TPX2 protein levels governs cell cycle progression in mouse oocytes. PLoS One 3, e3338 (2008).

    Article  Google Scholar 

  67. Lefebvre, C. et al. Meiotic spindle stability depends on MAPK-interacting and spindle-stabilizing protein (MISS), a new MAPK substrate. J. Cell Biol. 157, 603–613 (2002).

    Article  CAS  Google Scholar 

  68. Pfender, S., Kuznetsov, V., Pleiser, S., Kerkhoff, E. & Schuh, M. Spire-type actin nucleators cooperate with formin-2 to drive asymmetric oocyte division. Curr. Biol. 21, 955–960 (2011).

    Article  CAS  Google Scholar 

  69. Holubcová, Z., Howard, G. & Schuh, M. Vesicles modulate an actin network for asymmetric spindle positioning. Nat. Cell Biol. 15, 937–947 (2013).

    Article  Google Scholar 

  70. Schuh, M. An actin-dependent mechanism for long-range vesicle transport. Nat. Cell Biol. 13, 1431–1436 (2011).

    Article  CAS  Google Scholar 

  71. Cheeseman, L. P., Boulanger, J., Bond, L. M. & Schuh, M. Two pathways regulate cortical granule translocation to prevent polyspermy in mouse oocytes. Nat. Commun. 7, 13726 (2016).

    Article  CAS  Google Scholar 

  72. Larson, S. M. et al. Cortical mechanics and meiosis II completion in mammalian oocytes are mediated by myosin-II and Ezrin-Radixin-Moesin (ERM) proteins. Mol. Biol. Cell 21, 3182–3192 (2010).

    Article  CAS  Google Scholar 

  73. Simerly, C., Nowak, G., De Lanerolle, P. & Schatten, G. Differential expression and functions of cortical myosin IIa and IIb isotypes during meiotic maturation, fertilization, and mitosis in mouse oocytes and embryos. Mol. Biol. Cell 9, 2509–2525 (1998).

    Article  CAS  Google Scholar 

  74. Bennabi, I. et al. Artificially decreasing cortical tension generates aneuploidy in mouse oocytes. Nat. Commun. 11, 1649 (2020). This study reveals that mouse oocytes with low cortical tension exhibit defects in chromosome alignment due to increased transposition of myosin 2 from the cortex and into the cytoplasm.

    Article  CAS  Google Scholar 

  75. Yanez, L. Z., Han, J., Behr, B. B., Pera, R. A. R. & Camarillo, D. B. Human oocyte developmental potential is predicted by mechanical properties within hours after fertilization. Nat. Commun. 7, 10809 (2016). This study proposes that non-invasive membrane viscoelasticity measurements can predict developmental competence of human zygotes.

    Article  CAS  Google Scholar 

  76. Musacchio, A. The molecular biology of spindle assembly checkpoint signaling dynamics. Curr. Biol. 25, R1002–R1018 (2015).

    Article  CAS  Google Scholar 

  77. Vallot, A. et al. Tension-induced error correction and not kinetochore attachment status activates the SAC in an Aurora-B/C-dependent manner in oocytes. Curr. Biol. 28, 130–139.e3 (2018).

    Article  CAS  Google Scholar 

  78. Brunet, S., Pahlavan, G., Taylor, S. & Maro, B. Functionality of the spindle checkpoint during the first meiotic division of mammalian oocytes. Reproduction 126, 443–450 (2003).

    Article  CAS  Google Scholar 

  79. Wassmann, K., Niault, T. & Maro, B. Metaphase I arrest upon activation of the Mad2-dependent spindle checkpoint in mouse oocytes. Curr. Biol. 13, 1596–1608 (2003).

    Article  CAS  Google Scholar 

  80. Rodriguez-Bravo, V. et al. Nuclear pores protect genome integrity by assembling a premitotic and mad1-dependent anaphase inhibitor. Cell 156, 1017–1031 (2014).

    Article  CAS  Google Scholar 

  81. Galli, M. & Morgan, D. O. Cell size determines the strength of the spindle assembly checkpoint during embryonic development. Dev. Cell 36, 344–352 (2016).

    Article  CAS  Google Scholar 

  82. Kolano, A., Brunet, S., Silk, A. D., Cleveland, D. W. & Verlhac, M. H. Error-prone mammalian female meiosis from silencing the spindle assembly checkpoint without normal interkinetochore tension. Proc. Natl Acad. Sci. USA 109, E1858–E1867 (2012).

    Article  CAS  Google Scholar 

  83. Lane, S. I. R., Yun, Y. & Jones, K. T. Timing of anaphase-promoting complex activation in mouse oocytes is predicted by microtubule-kinetochore attachment but not by bivalent alignment or tension. Development 139, 1947–1955 (2012).

    Article  CAS  Google Scholar 

  84. Sebestova, J., Danylevska, A., Novakova, L., Kubelka, M. & Anger, M. Lack of response to unaligned chromosomes in mammalian female gametes. Cell Cycle 11, 3011–3018 (2012).

    Article  CAS  Google Scholar 

  85. Levasseur, M. D., Thomas, C., Davies, O. R., Higgins, J. M. G. & Madgwick, S. Aneuploidy in oocytes is prevented by sustained CDK1 activity through degron masking in cyclin B1. Dev. Cell 48, 672–684 (2019).

    Article  CAS  Google Scholar 

  86. Thomas, C. et al. A prometaphase mechanism of securin destruction is essential for meiotic progression in mouse oocytes. Nat. Commun. 12, 4322 (2021). Alongside Levasseur et al.85, this study demonstrates how the triggering of anaphase is delayed by oocytes using degron masking strategies and expression of an excess of APC/C substrates.

    Article  CAS  Google Scholar 

  87. Rosen, L. E. et al. Cohesin cleavage by separase is enhanced by a substrate motif distinct from the cleavage site. Nat. Comm. https://doi.org/10.1038/s41467-019-13209-y (2019).

    Article  Google Scholar 

  88. Davey, N. E. & Morgan, D. O. Building a regulatory network with short linear sequence motifs: lessons from the degrons of the anaphase-promoting complex. Mol. Cell 64, 12–23 (2016).

    Article  CAS  Google Scholar 

  89. Hassold, T., Jacobs, P., Kline, J., Stein, Z. & Warburton, D. Effect of maternal age on autosomal trisomies. Ann. Hum. Genet. 44, 29–36 (1980).

    Article  CAS  Google Scholar 

  90. Ruth, K. S. et al. Genetic insights into biological mechanisms governing human ovarian ageing. Nature 596, 393–397 (2021). This study identifies 290 genetic loci associated with age at natural menopause, including genes involved in DNA-damage response pathways.

    Article  CAS  Google Scholar 

  91. Franasiak, J. M. et al. The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil. Steril. 101, 656–663.e1 (2014).

    Article  Google Scholar 

  92. Magnus, M. C., Wilcox, A. J., Morken, N. H., Weinberg, C. R. & Håberg, S. E. Role of maternal age and pregnancy history in risk of miscarriage: prospective register based study. BMJ 364, l869 (2019).

    Article  Google Scholar 

  93. Hassold, T. & Chiu, D. Maternal age-specific rates of numerical chromosome abnormalities with special reference to trisomy. Hum. Genet. 70, 11–17 (1985).

    Article  CAS  Google Scholar 

  94. Haering, C. H. et al. Structure and stability of Cohesin’s Smc1-kleisin interaction. Mol. Cell 15, 951–964 (2004).

    Article  CAS  Google Scholar 

  95. Lister, L. M. et al. Age-related meiotic segregation errors in mammalian oocytes are preceded by depletion of cohesin and Sgo2. Curr. Biol. 20, 1511–1521 (2010). This study established a link between the age-related increase in chromosome segregation errors during meiotic divisions and changes to chromosome structure due to REC8 cohesin loss in oocytes from older mice.

    Article  CAS  Google Scholar 

  96. Liu, L. & Keefe, D. L. Defective cohesin is associated with age-dependent misaligned chromosomes in oocytes. Reprod. Biomed. Online 16, 103–112 (2008). This study detected low levels of cohesin proteins on the chromosomes in oocytes of prematurely senescent mice and implicated defective cohesin in increased chromosome segregation errors during maternal ageing.

    Article  CAS  Google Scholar 

  97. Chiang, T., Schultz, R. M. & Lampson, M. A. Age-dependent susceptibility of chromosome cohesion to premature separase activation in mouse oocytes. Biol. Reprod. 85, 1279–1293 (2011).

    Article  CAS  Google Scholar 

  98. Chiang, T., Duncan, F. E., Schindler, K., Schultz, R. M. & Lampson, M. A. Evidence that weakened centromere cohesion is a leading cause of age-related aneuploidy in oocytes. Curr. Biol. 20, 1522–1528 (2010). This study reported that the displacement of REC8 cohesin from chromosomes promotes chromosome segregation errors in oocytes from older mice.

    Article  CAS  Google Scholar 

  99. Merriman, J. A., Jennings, P. C., Mclaughlin, E. A. & Jones, K. T. Effect of aging on superovulation efficiency, aneuploidy rates, and sister chromatid cohesion in mice aged up to 15 months. Biol. Reprod. 86, 49 (2012).

    Article  Google Scholar 

  100. Jessberger, R. Age-related aneuploidy through cohesion exhaustion. EMBO Rep. 13, 539–546 (2012).

    Article  CAS  Google Scholar 

  101. Duncan, F. E. et al. Chromosome cohesion decreases in human eggs with advanced maternal age. Aging Cell 11, 1121–1124 (2012).

    Article  CAS  Google Scholar 

  102. Sakakibara, Y. et al. Bivalent separation into univalents precedes age-related meiosis I errors in oocytes. Nat. Commun. 6, 7550 (2015).

    Article  Google Scholar 

  103. Patel, J., Tan, S. L., Hartshorne, G. M. & McAinsh, A. D. Unique geometry of sister kinetochores in human oocytes during meiosis I may explain maternal age-associated increases in chromosomal abnormalities. Biol. Open. 5, 178–184 (2015).

    Article  Google Scholar 

  104. Lagirand-Cantaloube, J. et al. Loss of centromere cohesion in aneuploid human oocytes correlates with decreased kinetochore localization of the sac proteins Bub1 and Bubr1. Sci. Rep. 7, 44001 (2017).

    Article  CAS  Google Scholar 

  105. Zielinska, A. P., Holubcova, Z., Blayney, M., Elder, K. & Schuh, M. Sister kinetochore splitting and precocious disintegration of bivalents could explain the maternal age effect. Elife 4, e11389 (2015). Alongside Sakakibara et al.103 and Patel et al.104, these studies identified multiple age-related changes in chromosome architecture in human oocytes that cause errors in chromosome-spindle interactions.

    Article  Google Scholar 

  106. Yun, Y., Lane, S. I. R. & Jones, K. T. Premature dyad separation in meiosis II is the major segregation error with maternal age in mouse oocytes. Development 141, 199–208 (2014).

    Article  CAS  Google Scholar 

  107. Angell, R. R. Predivision in human oocytes at meiosis I: a mechanism for trisomy formation in man. Hum. Genet. 86, 383–387 (1991).

    Article  CAS  Google Scholar 

  108. Kim, J. et al. Meikin is a conserved regulator of meiosis-I-specific kinetochore function. Nature 517, 466–471 (2015).

    Article  CAS  Google Scholar 

  109. Maier, N. K., Ma, J., Lampson, M. A. & Cheeseman, I. M. Separase cleaves the kinetochore protein Meikin at the meiosis I/II transition. Dev. Cell 56, 2192–2206.e8 (2021).

    Article  CAS  Google Scholar 

  110. Gryaznova, Y. et al. Kinetochore individualization in meiosis I is required for centromeric cohesin removal in meiosis II. EMBO J. 40, e106797 (2021).

    Article  CAS  Google Scholar 

  111. Ogushi, S. et al. Loss of sister kinetochore co-orientation and peri-centromeric cohesin protection after meiosis I depends on cleavage of centromeric REC8. Dev. Cell 56, 3100–3114.e4 (2021). Together with Gryaznova et al.111, this study identifies two distinct populations of cohesin near to kinetochores, including pericentromeric cohesin that keeps sister chromatids together in meiosis II and centromeric cohesin that must be destroyed before pericentromeric cohesin.

    Article  CAS  Google Scholar 

  112. Watanabe, Y. Geometry and force behind kinetochore orientation: Lessons from meiosis. Nat. Rev. Mol. Cell Biol. 13, 370–382 (2012).

    Article  CAS  Google Scholar 

  113. Mihajlović, A. I., Haverfield, J. & FitzHarris, G. Distinct classes of lagging chromosome underpin age-related oocyte aneuploidy in mouse. Dev. Cell 56, 2273–2283.e3 (2021).

    Article  Google Scholar 

  114. Kouznetsova, A., Kitajima, T. S., Brismar, H. & Höög, C. Post-metaphase correction of aberrant kinetochore-microtubule attachments in mammalian eggs. EMBO Rep. 20, e47905 (2019).

    Article  Google Scholar 

  115. Zielinska, A. P. et al. Meiotic Kinetochores fragment into multiple lobes upon Cohesin loss in aging eggs. Curr. Biol. 29, 3749–3765.e7 (2019).

    Article  CAS  Google Scholar 

  116. Winship, A. L., Stringer, J. M., Liew, S. H. & Hutt, K. J. The importance of DNA repair for maintaining oocyte quality in response to anti-cancer treatments, environmental toxins and maternal ageing. Hum. Reprod. Update 24, 119–134 (2018).

    Article  CAS  Google Scholar 

  117. Bedoschi, G., Navarro, P. A. & Oktay, K. Chemotherapy-induced damage to ovary: mechanisms and clinical impact. Future Oncol. 12, 2333–2334 (2016).

    Article  CAS  Google Scholar 

  118. Stringer, J. M., Winship, A., Zerafa, N., Wakefield, M. & Hutt, K. Oocytes can efficiently repair DNA double-strand breaks to restore genetic integrity and protect offspring health. Proc. Natl Acad. Sci. USA 117, 11513–11522 (2020).

    Article  CAS  Google Scholar 

  119. Marangos, P. et al. DNA damage-induced metaphase I arrest is mediated by the spindle assembly checkpoint and maternal age. Nat. Commun. 6, 8706 (2015).

    Article  CAS  Google Scholar 

  120. Collins, J. K., Lane, S. I. R., Merriman, J. A. & Jones, K. T. DNA damage induces a meiotic arrest in mouse oocytes mediated by the spindle assembly checkpoint. Nat. Commun. 6, 8553 (2015).

    Article  CAS  Google Scholar 

  121. Titus, S. et al. Individual-oocyte transcriptomic analysis shows that genotoxic chemotherapy depletes human primordial follicle reserve in vivo by triggering proapoptotic pathways without growth activation. Sci. Rep. 11, 407 (2021).

    Article  CAS  Google Scholar 

  122. Rémillard-Labrosse, G. et al. Human oocytes harboring damaged DNA can complete meiosis I. Fertil. Steril. 113, 1080–1089.e2 (2020).

    Article  Google Scholar 

  123. Lucifero, D., Mertineit, C., Clarke, H. J., Bestor, T. H. & Trasler, J. M. Methylation dynamics of imprinted genes in mouse germ cells. Genomics 79, 530–538 (2002).

    Article  CAS  Google Scholar 

  124. Lucifero, D., Mann, M. R. W., Bartolomei, M. S. & Trasler, J. M. Gene-specific timing and epigenetic memory in oocyte imprinting. Hum. Mol. Genet. 13, 839–849 (2004).

    Article  CAS  Google Scholar 

  125. Kageyama, S. I. et al. Alterations in epigenetic modifications during oocyte growth in mice. Reproduction 133, 85–94 (2007).

    Article  CAS  Google Scholar 

  126. Ge, Z. J., Schatten, H., Zhang, C. L. & Sun, Q. Y. Oocyte ageing and epigenetics. Reproduction 149, R103–R114 (2015).

    Article  CAS  Google Scholar 

  127. Janssen, S. M. & Lorincz, M. C. Interplay between chromatin marks in development and disease. Nat. Rev. Genet. 23, 137–153 (2021).

    Article  Google Scholar 

  128. Kim, J. M., Liu, H., Tazaki, M., Nagata, M. & Aoki, F. Changes in histone acetylation during mouse oocyte meiosis. J. Cell Biol. 162, 37–46 (2003).

    Article  CAS  Google Scholar 

  129. Akiyama, T., Kim, J. M., Nagata, M. & Aoki, F. Regulation of histone acetylation during meiotic maturation in mouse oocytes. Mol. Reprod. Dev. 69, 222–227 (2004).

    Article  CAS  Google Scholar 

  130. Hamatani, T. et al. Age-associated alteration of gene expression patterns in mouse oocytes. Hum. Mol. Genet. 13, 2263–2278 (2004).

    Article  CAS  Google Scholar 

  131. Yue, M. X. et al. Abnormal DNA methylation in oocytes could be associated with a decrease in reproductive potential in old mice. J. Assist. Reprod. Genet. 29, 643–650 (2012).

    Article  Google Scholar 

  132. Manosalva, I. & González, A. Aging changes the chromatin configuration and histone methylation of mouse oocytes at germinal vesicle stage. Theriogenology 74, 1539–1547 (2010).

    Article  CAS  Google Scholar 

  133. Shao, G. B. et al. Aging alters histone H3 lysine 4 methylation in mouse germinal vesicle stage oocytes. Reprod. Fertil. Dev. 27, 419–426 (2015).

    Article  CAS  Google Scholar 

  134. Castillo-Fernandez, J. et al. Increased transcriptome variation and localised DNA methylation changes in oocytes from aged mice revealed by parallel single-cell analysis. Aging Cell 19, e13278 (2020).

    Article  CAS  Google Scholar 

  135. Manosalva, I. & González, A. Aging alters histone H4 acetylation and CDC2A in mouse germinal vesicle stage oocytes. Biol. Reprod. 81, 1164–1171 (2009).

    Article  CAS  Google Scholar 

  136. Akiyama, T., Nagata, M. & Aoki, F. Inadequate histone deacetylation during oocyte meiosis causes aneuploidy and embryo death in mice. Proc. Natl Acad. Sci. USA 103, 7339–7344 (2006).

    Article  CAS  Google Scholar 

  137. Van Den Berg, I. M. et al. Defective deacetylation of histone 4 K12 in human oocytes is associated with advanced maternal age and chromosome misalignment. Hum. Reprod. 26, 1181–1890 (2011).

    Article  Google Scholar 

  138. De La Fuente, R. et al. Major chromatin remodeling in the germinal vesicle (GV) of mammalian oocytes is dispensable for global transcriptional silencing but required for centromeric heterochromatin function. Dev. Biol. 275, 447–458 (2004).

    Article  Google Scholar 

  139. Shay, J. W. & Wright, W. E. Telomeres and telomerase: three decades of progress. Nat. Rev. Genet. 20, 299–309 (2019).

    Article  CAS  Google Scholar 

  140. Vaiserman, A. & Krasnienkov, D. Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. Front. Genet. 11, 630186 (2021).

    Article  Google Scholar 

  141. Uysal, F., Kosebent, E. G., Toru, H. S. & Ozturk, S. Decreased expression of TERT and telomeric proteins as human ovaries age may cause telomere shortening. J. Assist. Reprod. Genet. 38, 429–441 (2021).

    Article  Google Scholar 

  142. Yamada-Fukunaga, T. et al. Age-associated telomere shortening in mouse oocytes. Reprod. Biol. Endocrinol. 11, 108 (2013).

    Article  Google Scholar 

  143. Lim, C. J. & Cech, T. R. Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization. Nat. Rev. Mol. Cell Biol. 22, 283–298 (2021).

    Article  CAS  Google Scholar 

  144. Liu, L., Blasco, M. A. & Keefe, D. L. Requirement of functional telomeres for metaphase chromosome alignments and integrity of meiotic spindles. EMBO Rep. 3, 230–234 (2002).

    Article  CAS  Google Scholar 

  145. Nakagawa, S. & FitzHarris, G. Intrinsically defective microtubule dynamics contribute to age-related chromosome segregation errors in mouse oocyte meiosis-I. Curr. Biol. 27, 1040–1047 (2017). This study reveals that aged mouse oocytes exhibit defects in spindle assembly and stability, factors that further contribute to chromosome alignment errors in oocytes from aged mice.

    Article  CAS  Google Scholar 

  146. Volarcik, K. et al. The meiotic competence of in-vitro matured human oocytes is influenced by donor age: evidence that folliculogenesis is compromised in the reproductively aged ovary. Hum. Reprod. 13, 154–160 (1998).

    Article  CAS  Google Scholar 

  147. van der Reest, J., Nardini Cecchino, G., Haigis, M. C. & Kordowitzki, P. Mitochondria: their relevance during oocyte ageing. Ageing Res. Rev. 70, 101378 (2021).

    Article  Google Scholar 

  148. Pan, H., Ma, P., Zhu, W. & Schultz, R. M. Age-associated increase in aneuploidy and changes in gene expression in mouse eggs. Dev. Biol. 316, 397–407 (2008).

    Article  CAS  Google Scholar 

  149. He, Y., Li, X., Gao, M., Liu, H. & Gu, L. Loss of HDAC3 contributes to meiotic defects in aged oocytes. Aging Cell 18, e13036 (2019).

    Article  CAS  Google Scholar 

  150. Bolcun-Filas, E., Rinaldi, V. D., White, M. E. & Schimenti, J. C. Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway. Science 343, 533–536 (2014).

    Article  CAS  Google Scholar 

  151. Li, Q. & Engebrecht, J. A. BRCA1 and BRCA2 tumor suppressor function in meiosis. Front. Cell Dev. Biol. 9, 668309 (2021).

    Article  Google Scholar 

  152. Almansa-Ordonez, A., Bellido, R., Vassena, R., Barragan, M. & Zambelli, F. Oxidative stress in reproduction: a mitochondrial perspective. Biology 9, 269 (2020).

    Article  CAS  Google Scholar 

  153. Meli, R., Monnolo, A., Annunziata, C., Pirozzi, C. & Ferrante, M. C. Oxidative stress and BPA toxicity: an antioxidant approach for male and female reproductive dysfunction. Antioxidants 9, 405 (2020).

    Article  CAS  Google Scholar 

  154. Igosheva, N. et al. Maternal diet-induced obesity alters mitochondrial activity and redox status in mouse oocytes and zygotes. PLoS One 5, e10074 (2010).

    Article  Google Scholar 

  155. Jia, Z. et al. Resveratrol reverses the adverse effects of a diet-induced obese murine model on oocyte quality and zona pellucida softening. Food Funct. 9, 2623–2633 (2018).

    Article  CAS  Google Scholar 

  156. Boots, C. E., Boudoures, A., Zhang, W., Drury, A. & Moley, K. H. Obesity-induced oocyte mitochondrial defects are partially prevented and rescued by supplementation with co-enzyme Q10 in a mouse model. Hum. Reprod. 31, 2090–2097 (2016).

    Article  CAS  Google Scholar 

  157. Finkel, T. & Holbrook, N. J. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247 (2000).

    Article  CAS  Google Scholar 

  158. Perkins, A. T., Das, T. M., Panzera, L. C. & Bickel, S. E. Oxidative stress in oocytes during midprophase induces premature loss of cohesion and chromosome segregation errors. Proc. Natl Acad. Sci. USA 113, E6823–E6830 (2016).

    Article  CAS  Google Scholar 

  159. Al-Zubaidi, U. et al. Mitochondria-targeted therapeutics, MitoQ and BGP-15, reverse aging-associated meiotic spindle defects in mouse and human oocytes. Hum. Reprod. 36, 771–784 (2021).

    Article  CAS  Google Scholar 

  160. Tatone, C. et al. Evidence that carbonyl stress by methylglyoxal exposure induces DNA damage and spindle aberrations, affects mitochondrial integrity in mammalian oocytes and contributes to oocyte ageing. Hum. Reprod. 26, 1843–1859 (2011).

    Article  CAS  Google Scholar 

  161. Liu, Y. et al. Resveratrol protects mouse oocytes from methylglyoxal-induced oxidative damage. PLoS One 8, e77960 (2013).

    Article  CAS  Google Scholar 

  162. Dalton, C. M., Szabadkai, G. & Carroll, J. Measurement of ATP in single oocytes: impact of maturation and cumulus cells on levels and consumption. J. Cell. Physiol. 229, 353–361 (2014).

    Article  CAS  Google Scholar 

  163. Dumollard, R. et al. Sperm-triggered [Ca2+] oscillations and Ca2+ homeostasis in the mouse egg have an absolute requirement for mitochondrial ATP production. Development 131, 3057–3067 (2004).

    Article  CAS  Google Scholar 

  164. Campbell, K. & Swann, K. Ca2+ oscillations stimulate an ATP increase during fertilization of mouse eggs. Dev. Biol. 298, 225–233 (2006).

    Article  CAS  Google Scholar 

  165. Adhikari, D., Lee, I. W., Yuen, W. S. & Carroll, J. Oocyte mitochondria-key regulators of oocyte function and potential therapeutic targets for improving fertility. Biol. Reprod. 106, 366–377 (2022).

    Article  Google Scholar 

  166. Simsek-Duran, F. et al. Age-associated metabolic and morphologic changes in mitochondria of individual mouse and hamster oocytes. PLoS One 8, e64955 (2013).

    Article  CAS  Google Scholar 

  167. Ben-Meir, A. et al. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell 14, 887–895 (2015).

    Article  CAS  Google Scholar 

  168. Kujjo, L. L. et al. Ceramide and its transport protein (CERT) contribute to deterioration of mitochondrial structure and function in aging oocytes. Mech. Ageing Dev. 134, 43–52 (2013).

    Article  CAS  Google Scholar 

  169. Selesniemi, K., Lee, H. J., Muhlhauser, A. & Tilly, J. L. Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies. Proc. Natl Acad. Sci. USA 108, 12319–12324 (2011).

    Article  CAS  Google Scholar 

  170. Tarín, J. J., Gómez-Piquer, V., Pertusa, J. F., Hermenegildo, C. & Cano, A. Association of female aging with decreased parthenogenetic activation, raised MPF, and MAPKs activities and reduced levels of glutathione S-transferases activity and thiols in mouse oocytes. Mol. Reprod. Dev. 69, 402–410 (2004).

    Article  Google Scholar 

  171. Espey, L. L. Ovulation as an inflammatory reaction: a hypothesis. Biol. Reprod. 22, 73–106 (1980).

    Article  CAS  Google Scholar 

  172. Duffy, D. M., Ko, C., Jo, M., Brannstrom, M. & Curry, T. E. Ovulation: parallels with inflammatory processes. Endocr. Rev. 40, 369–416 (2019).

    Article  Google Scholar 

  173. Miyamoto, K. et al. Effect of oxidative stress during repeated ovulation on the structure and functions of the ovary, oocytes, and their mitochondria. Free Radic. Biol. Med. 49, 674–681 (2010).

    Article  CAS  Google Scholar 

  174. Chao, H. T. et al. Repeated ovarian stimulations induce oxidative damage and mitochondrial DNA mutations in mouse ovaries. Ann. N. Y. Acad. Sci. 1042, 148–156 (2005).

    Article  CAS  Google Scholar 

  175. Murdoch, W. J., Townsend, R. S. & McDonnel, A. C. Ovulation-induced DNA damage in ovarian surface epithelial cells of ewes: prospective regulatory mechanisms of repair/survival and apoptosis. Biol. Reprod. 65, 1417–1424 (2001).

    Article  CAS  Google Scholar 

  176. Riley, J. C. M. & Behrman, H. R. In vivo generation of hydrogen peroxide in the rat corpus luteum during luteolysis. Endocrinology 128, 1749–1753 (1991).

    Article  CAS  Google Scholar 

  177. Aten, R. F., Duarte, K. M. & Behrman, H. R. Regulation of ovarian antioxidant vitamins, reduced glutathione, and lipid peroxidation by luteinizing hormone and prostaglandin F(2α). Biol. Reprod. 46, 401–407 (1992).

    Article  CAS  Google Scholar 

  178. Sawada, M., Carlson, J. C. & Carlson, J. C. Rapid plasma membrane changes in superoxide radical formation, fluidity, and phospholipase A2 activity in the corpus luteum of the rat during induction of luteolysis. Endocrinology 128, 2992–2998 (1991).

    Article  CAS  Google Scholar 

  179. Chatzidaki, E. E. et al. Ovulation suppression protects against chromosomal abnormalities in mouse eggs at advanced maternal age. Curr. Biol. 31, 4038–4051.e7 (2021). This study demonstrates that halting or reducing ovulation cycles reduces chromosome segregation errors in aged mouse oocytes.

    Article  CAS  Google Scholar 

  180. Liu, M. et al. Resveratrol protects against age-associated infertility in mice. Hum. Reprod. 28, 707–717 (2013).

    Article  CAS  Google Scholar 

  181. Xian, Y. et al. Antioxidants retard the ageing of mouse oocytes. Mol. Med. Rep. 18, 1981–1986 (2018).

    CAS  Google Scholar 

  182. Beaujouan, E. Latest-late fertility? Decline and resurgence of late parenthood across the low-fertility countries. Popul. Dev. Rev. 46, 219–247 (2020).

    Article  Google Scholar 

  183. Osterman, M. J. K., Hamilton, B. E., Martin, J. A., Driscoll, A. K. & Valenzuela, C. P. Births: final data for 2020. Natl Vital-. Stat. Rep. 70, 1–50 (2021).

    Google Scholar 

  184. Khandwala, Y. S., Zhang, C. A., Lu, Y. & Eisenberg, M. L. The age of fathers in the USA is rising: an analysis of 168 867 480 births from 1972 to 2015. Hum. Reprod. 32, 2110–2116 (2017).

    Article  Google Scholar 

  185. Wyns, C. et al. ART in Europe, 2017: results generated from European registries by ESHRE. Hum. Reprod. Open 2021, hoab026 (2021).

    Article  CAS  Google Scholar 

  186. Giannopapa, M., Sakellaridi, A., Pana, A. & Velonaki, V. S. Women electing oocyte cryopreservation: characteristics, information sources, and oocyte disposition: a systematic review. J. Midwifery Women’s Health 67, 178–201 (2022).

    Article  Google Scholar 

  187. Yun, Y., Wei, Z. & Hunter, N. Maternal obesity enhances oocyte chromosome abnormalities associated with aging. Chromosoma 128, 413–421 (2019).

    Article  CAS  Google Scholar 

  188. Luzzo, K. M. et al. High fat diet induced developmental defects in the mouse: oocyte meiotic aneuploidy and fetal growth retardation/brain defects. PLoS One 7, e49217 (2012).

    Article  CAS  Google Scholar 

  189. Llonch, S. et al. Single human oocyte transcriptome analysis reveals distinct maturation stage-dependent pathways impacted by age. Aging Cell 20, e13360 (2021).

    Article  CAS  Google Scholar 

  190. Savini, I., Gasperi, V. & Catani, M. V. Oxidative stress and obesity. in Obesity (eds Ahmad, S. & Imam, S.) 65–86 (Springer, 2016).

  191. Zhang, D. et al. Overweight and obesity negatively affect the outcomes of ovarian stimulation and invitro fertilisation: a cohort study of 2628 Chinese women. Gynecol. Endocrinol. 26, 325–332 (2010).

    Article  Google Scholar 

  192. Lashen, H., Fear, K. & Sturdee, D. W. Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study. Hum. Reprod. 19, 1644–1666 (2004).

    Article  CAS  Google Scholar 

  193. Priya, K., Setty, M., Babu, U. V. & Pai, K. S. R. Implications of environmental toxicants on ovarian follicles: how it can adversely affect the female fertility? Environ. Sci. Pollut. Res. Int. 28, 67925–67939 (2021).

    Article  CAS  Google Scholar 

  194. Mesquita, I., Lorigo, M. & Cairrao, E. Update about the disrupting-effects of phthalates on the human reproductive system. Mol. Reprod. Dev. 88, 650–672 (2021).

    Article  CAS  Google Scholar 

  195. Mlynarčíková, A., Kolena, J., Ficková, M. & Scsuková, S. Alterations in steroid hormone production by porcine ovarian granulosa cells caused by bisphenol A and bisphenol A dimethacrylate. Mol. Cell. Endocrinol. 244, 57–62 (2005).

    Article  Google Scholar 

  196. Zhou, W., Liu, J., Liao, L., Han, S. & Liu, J. Effect of bisphenol A on steroid hormone production in rat ovarian theca-interstitial and granulosa cells. Mol. Cell. Endocrinol. 283, 12–18 (2008).

    Article  CAS  Google Scholar 

  197. Hunt, P. A. et al. Bisphenol A alters early oogenesis and follicle formation in the fetal ovary of the rhesus monkey. Proc. Natl Acad. Sci. USA 109, 17525–17530 (2012).

    Article  CAS  Google Scholar 

  198. Hunt, P. A. et al. Bisphenol a exposure causes meiotic aneuploidy in the female mouse. Curr. Biol. 13, 546–553 (2003). This study shows that exposure to a component of common plastics, BPA, promotes chromosome segregation errors and aneuploidy in mouse oocytes.

    Article  CAS  Google Scholar 

  199. Machtinger, R. et al. Bisphenol-A and human oocyte maturation in vitro. Hum. Reprod. 28, 2735–2745 (2013).

    Article  CAS  Google Scholar 

  200. Pacchierotti, F., Ranaldi, R., Eichenlaub-Ritter, U., Attia, S. & Adler, I. D. Evaluation of aneugenic effects of bisphenol A in somatic and germ cells of the mouse. Mutat. Res. 651, 64–70 (2008).

    Article  CAS  Google Scholar 

  201. Pfeiffer, E., Rosenberg, B., Deuschel, S. & Metzler, M. Interference with microtubules and induction of micronuclei in vitro by various bisphenols. Mutat. Res. 390, 21–31 (1997).

    Article  CAS  Google Scholar 

  202. Yang, L., Baumann, C., De La Fuente, R. & Viveiros, M. M. Mechanisms underlying disruption of oocyte spindle stability by bisphenol compounds. Reproduction 159, 383–396 (2020).

    Article  CAS  Google Scholar 

  203. Can, A., Semiz, O. & Cinar, O. Bisphenol-A induces cell cycle delay and alters centrosome and spindle microtubular organization in oocytes during meiosis. Mol. Hum. Reprod. 11, 389–396 (2005).

    Article  CAS  Google Scholar 

  204. Campen, K. A., Kucharczyk, K. M., Bogin, B., Ehrlich, J. M. & Combelles, C. M. H. Spindle abnormalities and chromosome misalignment in bovine oocytes after exposure to low doses of bisphenol A or bisphenol S. Hum. Reprod. 33, 895–904 (2018).

    Article  CAS  Google Scholar 

  205. Horan, T. S. et al. Replacement bisphenols adversely affect mouse gametogenesis with consequences for subsequent generations. Curr. Biol. 28, 2948–2954.e3 (2018).

    Article  CAS  Google Scholar 

  206. Žalmanová, T. et al. Bisphenol S negatively affects the meotic maturation of pig oocytes. Sci. Rep. 7, 485 (2017).

    Article  Google Scholar 

  207. Calhaz-Jorge, C. et al. Survey on ART and IUI: legislation, regulation, funding and registries in European countries. Hum. Reprod. Open 2020, hoz044 (2020).

    Article  CAS  Google Scholar 

  208. Wagner, M. et al. Single-cell analysis of human ovarian cortex identifies distinct cell populations but no oogonial stem cells. Nat. Commun. 11, 1147 (2020).

    Article  CAS  Google Scholar 

  209. Zhang, H. et al. Adult human and mouse ovaries lack DDX4-expressing functional oogonial stem cells. Nat. Med. 21, 1116–1118 (2015).

    Article  CAS  Google Scholar 

  210. Johnson, J., Canning, J., Kaneko, T., Pru, J. K. & Tilly, J. L. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 428, 145–150 (2004).

    Article  CAS  Google Scholar 

  211. Lei, L. & Spradling, A. C. Female mice lack adult germ-line stem cells but sustain oogenesis using stable primordial follicles. Proc. Natl Acad. Sci. USA 110, 8585–8590 (2013).

    Article  CAS  Google Scholar 

  212. White, Y. A. R. et al. Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Nat. Med. 18, 413–421 (2012).

    Article  CAS  Google Scholar 

  213. Hikabe, O. et al. Reconstitution in vitro of the entire cycle of the mouse female germ line. Nature 539, 299–303 (2016). In this study, fertilizable mouse eggs are generated from stem cells in vitro.

    Article  Google Scholar 

  214. Yamashiro, C. et al. Generation of human oogonia from induced pluripotent stem cells in vitro. Science 362, 356–360 (2018). This study demonstrates that human oocytes, akin to the fetal oocyte stage, can be produced from stem cells in vitro.

    Article  CAS  Google Scholar 

  215. Herbert, M. & Turnbull, D. Progress in mitochondrial replacement therapies. Nat. Rev. Mol. Cell Biol. 19, 71–72 (2018).

    Article  CAS  Google Scholar 

  216. Reardon, S. Genetic details of controversial ‘three-parent baby’ revealed. Nature 544, 17–18 (2017).

    Article  CAS  Google Scholar 

  217. Verlinsky, Y. et al. Analysis of the first polar body: preconception genetic diagnosis. Hum. Reprod. 5, 826–829 (1990).

    Article  CAS  Google Scholar 

  218. Montag, M. Polar body biopsy: a viable alternative to preimplantation genetic diagnosis and screening. Reprod. Biomed. Online 18, 6–11 (2009).

    Article  Google Scholar 

  219. Cimadomo, D. et al. The impact of biopsy on human embryo developmental potential during preimplantation genetic diagnosis. Biomed. Res. Int. 2016, 7193075 (2016).

    Article  Google Scholar 

  220. Palini, S. et al. Genomic DNA in human blastocoele fluid. Reprod. Biomed. Online 26, 603–610 (2013).

    Article  CAS  Google Scholar 

  221. Tobler, K. J. et al. Blastocoel fluid from differentiated blastocysts harbors embryonic genomic material capable of a whole-genome deoxyribonucleic acid amplification and comprehensive chromosome microarray analysis. Fertil. Steril. 104, 418–425 (2015).

    Article  CAS  Google Scholar 

  222. Kuznyetsov, V. et al. Evaluation of a novel non-invasive preimplantation genetic screening approach. PLoS ONE 13, e017262 (2018).

    Article  Google Scholar 

  223. Galluzzi, L. et al. Extracellular embryo genomic DNA and its potential for genotyping applications. Futur. Sci. OA 1, FSO62 (2015).

    Article  Google Scholar 

  224. Wu, H. et al. Medium-based noninvasive preimplantation genetic diagnosis for human α-thalassemias-SEA. Medicine 94, e669 (2015).

    Article  CAS  Google Scholar 

  225. Xu, J. et al. Noninvasive chromosome screening of human embryos by genome sequencing of embryo culture medium for in vitro fertilization. Proc. Natl Acad. Sci. USA 113, 11907–11912 (2016).

    Article  CAS  Google Scholar 

  226. Shamonki, M. I., Jin, H., Haimowitz, Z. & Liu, L. Proof of concept: preimplantation genetic screening without embryo biopsy through analysis of cell-free DNA in spent embryo culture media. Fertil. Steril. 106, 1312–1318 (2016).

    Article  CAS  Google Scholar 

  227. Zmuidinaite, R., Sharara, F. I. & Iles, R. K. Current advancements in noninvasive profiling of the embryo culture media secretome. Int. J. Mol. Sci. 22, 2513 (2021).

    Article  CAS  Google Scholar 

  228. Cavazza, T. et al. Parental genome unification is highly error-prone in mammalian embryos. Cell 184, 2860–2877.e2 (2021).

    Article  CAS  Google Scholar 

  229. Scott, L. Pronuclear scoring as a predictor of embryo development. Reprod. Biomed. Online 6, 201–214 (2003).

    Article  Google Scholar 

  230. Tesarik, J. & Greco, E. The probability of abnormal preimplantation development can be predicted by a single static observation on pronuclear stage morphology. Hum. Reprod. 14, 1318–1328 (1999).

    Article  CAS  Google Scholar 

  231. Coskun, S. et al. Nucleolar precursor body distribution in pronuclei is correlated to chromosomal abnormalities in embryos. Reprod. Biomed. Online 7, 86–90 (2003).

    Article  Google Scholar 

  232. Chaigne, A. et al. A soft cortex is essential for asymmetric spindle positioning in mouse oocytes. Nat. Cell Biol. 15, 958–966 (2013).

    Article  CAS  Google Scholar 

  233. Chaigne, A. et al. A narrow window of cortical tension guides asymmetric spindle positioning in the mouse oocyte. Nat. Commun. 6, 6027 (2015).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors intended to write an accessible article for a wide audience, while introducing as many new findings as possible. We would like to apologize to all the authors whose work could not be cited here due to space constraints. M.S., A.W. and C.C. have received financial support from the Max Planck Society, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) by a DFG Leibniz Prize (SCHU 3047/1-1), an EMBO Post-Doctoral Long-Term Fellowship to A.W., and a Boehringer Ingelheim Fonds PhD Fellowship to C.C. Work was further supported by the DFG under Germany’s Excellence Strategy (EXC 2067/1-390729940).

Author information

All authors researched data for the article, contributed substantially to discussion of the content, wrote the article, and edited the manuscript before submission.

Author information

Author notes

  1. These authors contributed equally: Chloe Charalambous, Alexandre Webster.

Authors and Affiliations

  1. Department of Meiosis, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany

    Chloe Charalambous, Alexandre Webster & Melina Schuh

Authors
  1. Chloe Charalambous
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexandre Webster
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Melina Schuh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Melina Schuh.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Molecular Cell Biology thanks Marie-Hélène Verlhac and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Oxidative stress

Arises due to an imbalance between the production of reactive oxygen species (ROS) and the detoxification of ROS through antioxidant pathways. Excessive levels of ROS can lead to an accumulation of damage to macromolecules, including DNA within cells.

Primordial germ cells

(PGCs). An immature germline cell that is established during fetal development, which eventually matures through meiosis into a gamete.

Homologous chromosomes

Maternally and paternally inherited chromosomes similar in genetic content and size, and however not identical as they contain different alleles.

Sister chromatids

An identical chromosome copy of a single homologous chromosome formed through DNA replication. Both sister chromatids are comprised of identical DNA sequences and alleles.

Cohesin complexes

A tripartite ring-like protein complex that can simultaneously link two strands of DNA and can organize chromosomes into bivalent structures in meiosis.

Meiotic recombination

A DNA repair process specific to germ cells where homologous chromosomes exchange strands of DNA and form chiasmata structures. Meiotic recombination creates new gene allele combinations, increasing genetic diversity in the offspring. Structurally, meiotic recombination also links homologous chromosomes together via chiasmata to form bivalent chromosomes that promote accurate chromosome segregation during meiosis I.

Non-crossover

The repair of DNA double-strand breaks through meiotic recombination without reciprocal exchange of large genomic DNA sequences between homologous chromosomes.

Chiasmata

A DNA-protein assembly located at DNA lesions formed by meiotic recombination.

Telomeres

The protected ends of chromosomes that consist of repetitive DNA sequences and associated shelterin protein complexes.

Bivalent chromosome

Chromosome assemblies consisting of two pairs of homologous sister chromatids joined together by cohesin after formation of chiasmata.

Follicular atresia

The degeneration and re-absorption of oocyte-containing follicles within the ovary. A wave of follicular atresia during fetal development reduces follicle numbers before birth and is followed by gradual atresia that occurs continuously throughout reproductive life.

Gap junctions

Inter-cellular membrane channels that connect the oocyte to somatic follicle cells. These channels are used to transfer small molecules from the follicle cells to the oocyte.

Graafian follicle

A large ovarian follicle produced by the later stages of folliculogenesis. At this follicle stage, the prophase-arrested oocyte resumes meiosis.

Luteinizing hormone

A gonadotropin that triggers germ cell maturation in both males and females, triggering ovulation in females.

Pituitary gland

An organ of the endocrine system located at the base of the brain responsible for the release of luteinizing hormone, among other hormones.

Nuclear envelope breakdown

(NEBD). The stage when the oocyte nucleus breaks down and condensed chromosomes are released into the cytoplasm. Also termed germinal vesicle breakdown in oocytes.

REC8

The meiosis-specific α-kleisin subunit of a cohesin complex that is cleaved by separase during anaphase.

Polar body

A cell that is produced during the meiotic divisions of the oocyte. One polar body is produced during each of the two asymmetric meiotic divisions, finally generating a large egg and two small polar bodies. Polar bodies receive chromosomes from the oocyte and are later degraded.

Pronuclei

Transient nuclear membrane structures that form following fertilization to separately hold the chromosomes of the sperm and the meiosis II egg.

Zygotic genome activation

The stage in embryonic development where the genes of the embryo are first transcribed, marking the maternal-to-zygote transition.

Phthalates

A compound used to make plastic more flexible and durable.

Bisphenol A

(BPA). A monomeric compound that is polymerized to produce polycarbonate plastics and resins.

Centrosomes

Organelles comprised of two centrioles surrounded by pericentriolar material that assembles the spindle machinery.

RAN-dependent microtubule assembly pathway

RAN bound to GTP (RAN–GTP) releases spindle-assembly factors bound to importins that are close to chromosomes. In turn, RAN–GTP activates the spindle-assembly factors, leading to local spindle microtubule assembly at chromosomes.

Importins

Proteins that bind to nuclear localization sequences on other proteins and mediate their transfer from the cytoplasm and into the nucleus via nuclear pores that span the nuclear membrane.

Kinetochores

Protein assemblies formed on the centromeres of chromosomes that bind to microtubules to form kinetochore fibres (k-fibres). Inner kinetochore proteins bind to centromeric repeat DNA, forming the constitutive centromeric associated network, while outer kinetochore proteins form the KMN network that engages microtubules.

Merotelic attachments

When a kinetochore is erroneously attached to two or more k-fibres originating from opposite spindle poles.

Lagging chromosomes

A chromosome whose segregation is delayed or that fails to segregate from the spindle mid-zone to the spindle poles during anaphase.

Fluorescence in situ hybridization

A diagnostic method where fluorescently labelled oligonucleotides are annealed onto chromosome regions containing sequence complementarity and analysed by fluorescence light microscopy.

Array comparative genome hybridization

A diagnostic method where fluorescently labelled chromosome fragments from a specimen are competitively annealed to a micro-array chip containing oligonucleotides of a reference genome.

Next-generation sequencing

A diagnostic method where thousands to millions of genomic fragments are annealed to a microarray chip and sanger-sequenced in parallel at single-base resolution.

Blastocoel fluid

Fluid within the blastocyst cavity that is released from the blastocyst during egg freezing.

Kinetochore fibres

(K-fibres). Bundles of microtubules stably attached to kinetochores responsible for pulling chromosomes to spindle poles during anaphase.

NDC80 complex

A component of the outer kinetochore found in all eukaryotes that is comprised of four subunits termed NDC80, NUF2, SPC24 and SPC25.

Spindle assembly checkpoint

(SAC). A cellular surveillance mechanism that prevents or delays entry into anaphase until kinetochores are stably attached to spindle microtubules.

Mitotic checkpoint complex

(MCC). A protein complex formed as part of the SAC that blocks the anaphase-promoting complex/cyclosome from interacting with its co-activator CDC20.

Anaphase-promoting complex/cyclosome

(APC/C). A protein ubiquitin ligase complex responsible for triggering degradation of cell-cycle and other proteins prior to anaphase onset, including cyclin B1 and securin.

Cyclin B1

A regulatory protein of the cell cycle that binds to CDK1, generating the cyclin B1–CDK1 complex that phosphorylates target proteins to promote cell cycle progression.

Securin

An inhibitory protein that binds to and inactivates the cohesin-cleaving enzyme separase. It is degraded by the APC/C prior to entry into anaphase, eventually allowing separase activity.

Metacentric chromosomes

A class of chromosomes with two long arms, with the kinetochore roughly equidistant from both telomeres.

Univalent chromosomes

A bivalent chromosome that has prematurely separated into two homologous chromosomes before anaphase I.

Gonadotropic hormones

Hormones that stimulate the gonads, including luteinizing hormone and follicle-stimulating hormone in females.

CHEK2

Gene encoding a tumour-suppressor serine/threonine kinase that responds to DNA damage by initiating repair, cell cycle arrest and apoptotic signalling.

Reactive oxygen species (ROS)

A class of free radical compounds including superoxide anions, hydrogen peroxide and hydroxyl radicals. At low levels, ROS promote a range of cellular functions but too high levels can cause damage to proteins, lipids and nucleic acids.

Corpus luteum

A compartment of the ovary formed after rupture of a follicle following ovulation. This structure secretes hormones that help establish and maintain pregnancy. If embryo implantation fails to occur, the corpus luteum undergoes degeneration and wound healing.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Charalambous, C., Webster, A. & Schuh, M. Aneuploidy in mammalian oocytes and the impact of maternal ageing. Nat Rev Mol Cell Biol 24, 27–44 (2023). https://doi.org/10.1038/s41580-022-00517-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41580-022-00517-3

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing