Key Event Title
|Level of Biological Organization|
Key Event Components
|abnormal chromosome number||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Tubulin binding and aneuploidy||AdverseOutcome|
Key Event Description
An aneuploid offspring is an organism born with an incorrect number of chromosomes (which is present in all of their cells) [reviewed in Marchetti et al. 2015].
In most cases, the aneuploid condition will result in the death of the conceptus at different stages of embryo-fetal development depending on the chromosome involved in the aneuploidy. When aneuploid fetuses survive to birth, they will originate offspring affected by aneuploid syndromes, characterized by variable symptoms depending on the specific chromosome involved. The health consequences of a trisomic condition are well established in both humans and mice. Each of the 19 autosomal trisomies of the mouse has been produced and the survival and phenotype of each trisomy characterized [Epstein 1988]. Growth retardation is almost invariably present and congenital malformations are frequently detected. Trisomic fetuses generally survive until at least mid gestation. However, with the exception of trisomy 19 and to a lesser extent trisomy 16 and 18, all die prior to parturition. The precise cause of death of the trisomic embryos is not known. In some instances it appears to be related to extremely poor embryonic growth and development. Aneuploid mouse zygotes are karyotypically unstable during preimplantation development leading to a state of chaotic mosaic aneuploidy within the blastocyst [Lightfoot et al. 2006]. In contrast to the survival of trisomic embryos and fetuses until at least mid gestation, mouse autosomal monosomies are lethal in the pre- or peri-implantation period, with only rare survivors until day 6 of gestation [Magnuson et al. 1985]. Due to dosage compensation mechanisms, aneuploidies of the sex chromosomes in the mouse are viable [Russell 1976].
Survival data of aneuploidies in humans generally match those in mice: aneuploidies of the sex chromosomes are viable, all autosomal monosomies and most trisomies die before birth, with the exception of trisomy 13, 18 and 21 that, in some cases, survive until shortly after birth or much longer (as in the case of Down syndrome). Even in the case of trisomy 21, the most viable of the human trisomies, an estimated 80% or more fetuses die in utero [Hecht and Hecht 1987]. Aneuploid conditions compatible with life present a range of adverse health effects from infertility (e.g., Klinefelter syndrome due to XXY karyotype) to severe mental and physical impairment and reduced life span (e.g., Edwards Syndrome due to trisomy 18).
How It Is Measured or Detected
Diagnostic laboratories around the world use both phenotypic and molecular approaches to determine whether an individual is aneuploid. These are well-established methods that have been used for decades. INSERT HOW YOU MEASURE ANEUPLOID OFFSPRING.
The prevalence of chromosome segregation errors during female meiosis is clearly supported by the application of state-of-the-art genomic approaches, such as Comparative Genomic Hybridization (CGH), array-Comparative Genomic Hybridization (aCGH), and SNP-arrays [Handyside 2012; Nagaoka et al. 2012].
Consider the following criteria when describing each method: 1. Is the assay fit for purpose? Yes 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? Directly 3. Is the assay repeatable? Yes 4. Is the assay reproducible? Yes
Domain of Applicability
Aneuploid offspring have been measured in mouse and humans, but can occur in any sexually reproducing species.
Regulatory Significance of the Adverse Outcome
Various international regulatory agencies have established policies and practices for the assessment and management of heritable mutagenic hazards. Indeed, heritable effects are an important regulatory endpoint noted by agencies around the world [Yauk et al. 2015].
The World Health Organization (WHO)/International Programme on Chemical Safety (IPCS) developed a harmonized scheme for mutagenicity testing. In this document the relationship between somatic cell mutagenicity and germ cell risk is summarized as: “For substances that give positive results for mutagenic effects in somatic cells in vivo, their potential to affect germ cells should be considered. If there is toxicokinetic or toxicodynamic evidence that germ cells are actually exposed to the somatic mutagen or its bioactive metabolites, it is reasonable to assume that the substance may also pose a mutagenic hazard to germ cells and thus a risk to future generations.” [Eastmond et al. 2009].
Thus, assessment of heritable mutagenic hazards such as aneuploidy, are an important regulatory endpoint. During drug and chemical development, agents that induce aneuploidy would not be developed further. There is currently not a specific example that can be referenced of a regulatory decision based on this adverse outcome.
The development of AOPs related to mutagenicity in germ cells is expected to aid the identification of potential hazards to germ cell genomic integrity and support regulatory efforts to protect population health.
Eastmond DA, Hartwig A, Anderson D, Anwar WA, Cimino MC, Dobrev I, Douglas GR, Nohmi T, Phillips DH, Vickers . 2009. Mutagenicity testing for chemical risk assessment: update of the WHO/IPCS Harmonized Scheme, Mutagenesis, 24:341-349.
Epstein CJ. 1988. Mouse model systems for the study of aneuploidy. In: Vig BK, Sandberg AA, editors. Aneuploidy, Part B: Induction and Test Systems: Alan R. Liss, Inc. p 9-49.
Hecht F, Hecht BK. 1987. Aneuploidy in humans: dimesions, demography, and dangers of abnormal numbers of chromosomes. In: Vig BK, Sandberg AA, editors. Aneuploidy, Part A: Incidence and Etiology: Alan R. Liss, Inc. p 9-49.
Lightfoot DA, Kouznetsova A, Mahdy E, Wilbertz J, Hoog C. 2006. The fate of mosaic aneuploid embryos during mouse development. Dev Biol 289:384-394.
Magnuson T, Debrot S, Dimpfl J, Zweig A, Zamora T, Epstein CJ. 1985. The early lethality of autosomal monosomy in the mouse. J Exp Zool 236:353-360.
Marchetti A, Massarotti A, Yauk CL, Pacchierotti F, Russo A. Submitted. The adverse outcome pathway (AOP) for chemical binding to tubulin in oocytes leading to aneuploid offspring. Environ Mol Mutagen.
Russell LB. 1976. Numerical sex-chromosome anomalies in mammals: Their spontaneous occurrence and use in mutagenesis studies. In: Hollaender A, editor. Chemical Mutagens Principles and Methods for their Detection, vol 4. New York: Plenum Press. p 55-91.
Yauk CL, Aardema MJ, Benthem Jv, Bishop JB, Dearfield KL, DeMarini DM, Dubrova YE, Honma M, Lupski JR, Marchetti F, Meistrich ML, Pacchierotti F, Stewart J, Waters MD, Douglas GR. 2015. Approaches for identifying germ cell mutagens: Report of the 2013 IWGT workshop on germ cell assays. Mutat Res Genet Toxicol Environ Mutagen. 783:36-54.