Aop:106

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AOP Title

Chemical binding to tubulin in oocytes leading to aneuploid offspring
Short name: Tubulin binding and aneuploidy

Authors

Francesco Marchetti 1*, Alberto Massarotti 2, Carole L. Yauk 1, Francesca Pacchierotti 3, Antonella Russo 4

1 Environmental Health Science and Research Bureau, Health Canada, Ottawa, Canada. 2 Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale “A. Avogadro”, Novara, Italy. 3 Unit of Radiation Biology and Human Health, Laboratory of Toxicology, ENEA CR Casaccia, Rome, Italy. 4 Department of Biology, University of Padova, Padova, Italy.

  • Correspondence to: Francesco Marchetti, Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON K1A 0K9, Canada. E-mail: francesco.marchetti@hc-sc.gc.ca

Status

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This AOP page was last modified on 12/11/2016.

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Abstract

Aneuploidy, an abnormal number of chromosomes, arising during meiosis in germ cells represents the most common chromosomal abnormality at birth and is the leading cause of pregnancy loss in humans. Aneuploidy can affect any chromosome, and data in rodents suggest that neither aneuploid sperm nor aneuploid oocytes are selected against at fertilization. Therefore, an increase in germ cell aneuploidy is expected to result in an increase in aneuploid pregnancies. The etiology of human aneuploidy is still not well understood, although there is strong evidence supporting a preferential occurrence during female meiosis I and a positive correlation with maternal age. There is extensive evidence in animal models that chemicals can induce aneuploidy by interfering with the proper functioning of the meiotic spindle and other aspects of chromosome segregation. Over 15 chemicals have been shown to induce aneuploidy in mammalian oocytes and the majority of these chemicals interfere with microtubule dynamics during meiosis. In addition to these animals studies, there is also one reported case in which environmental exposure to trichlorfon, an organophosphate insecticide, resulted in a cluster of Down syndrome cases among women in an Hungarian community. The present AOP focuses on the induction of aneuploidy in mammalian oocytes as a consequence of chemical binding to tubulin (MIE). In this AOP, chemicals that bind to tubulin lead to the depolymerization of microtubules (KE1). Extensive microtubule depolymerisation leads to meiotic spindle disorganization (KE2), which in turns lead to altered chromosome dynamics (KE3) and the generation of aneuploidy oocytes (KE4). Aneuploidy oocytes can be fertilized and generate aneuploidy offspring (AO). There is ample empirical evidence supporting this AOP and the overall weight of evidence is strong.


Background (optional)

Aneuploidy is associated with serious human health effects. Approximately 10–30% of human zygotes, 50% of spontaneous abortions, and 0.3% of human newborns are aneuploid [Hassold et al. 2007; Nagaoka et al. 2012]. Cytogenetic analyses of human oocytes and preimplantation embryos have reported frequencies of aneuploidy in excess of 50% [Magli et al. 2001; Munne 2002; Kuliev et al. 2003]. In these studies, the overall aneuploidy frequency is estimated from the analysis of a subset of chromosomes, which may affect the accuracy of the estimate.

Aneuploidy can affect any chromosome [Nagaoka et al. 2012], although there is evidence that acrocentric chromosomes may be more frequently involved in aneuploidy than metacentric chromosomes [Nicolaidis and Petersen 1998; Hassold et al. 2007; Gianaroli et al. 2010]. In humans, only trisomies for a few autosomal chromosomes (13, 18 and 21) and aneuploidies of the sex chromosomes are compatible with life. These aneuploidies have important developmental, neurological and reproductive effects. Trisomy 21 or Down syndrome, with an occurrence of ~1/720 births, is the most common genetic abnormality in newborns [Hassold et al. 2007].

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Tubulin, Binding

Key Events

Event Support for Essentiality
Microtubule, Depolymerization
Spindle, Disorganization
Meiotic chromosome dynamics, Altered
Chromosome number, Altered

Adverse Outcome

Adverse Outcome
Aneuploid offspring, Increase

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Tubulin, Binding Directly Leads to Microtubule, Depolymerization Strong
Microtubule, Depolymerization Directly Leads to Spindle, Disorganization Moderate
Chromosome number, Altered Directly Leads to Aneuploid offspring, Increase Strong
Tubulin, Binding Indirectly Leads to Chromosome number, Altered Strong
Spindle, Disorganization Directly Leads to Meiotic chromosome dynamics, Altered Moderate
Meiotic chromosome dynamics, Altered Directly Leads to Chromosome number, Altered Weak

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Life Stage Applicability

Life Stage Evidence Links
Adult, reproductively mature Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
Mus musculus Mus musculus Strong NCBI
Homo sapiens Homo sapiens Moderate NCBI
Hamster Moderate

Sex Applicability

Sex Evidence Links
Female Strong

Graphical Representation

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Overall Assessment of the AOP

Domain of Applicability

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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The present AOP should be considered specific to female germ cells exposed in the peri-ovulation period. The majority of data on this AOP were derived from experiments in mice. The available results on aneuploidy induction induced by the prototype tubulin-binding chemical colchicine in oocytes of species other than Mus musculus are qualitatively consistent with mouse data, in agreement with the similarities in the mechanism of action across several Phyla and the high degree of homology of tubulin across species. Evidence for microtubule depolymerization and spindle disorganization has been obtained in human oocytes exposed in culture to colchicine. This suggests that the MIE and KEs are conserved and would occur in human oocytes also. Therefore, the AOP should apply to any species that produce eggs.

Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Weight of Evidence Summary

Summary Table
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Quantitative Considerations

Summary Table
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Considerations for Potential Applications of the AOP (optional)

References