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Event: 728

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Increase, Aneuploid offspring

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Increase, Aneuploid offspring

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
abnormal chromosome number increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Tubulin binding and aneuploidy AdverseOutcome Francesco Marchetti (send email) Open for citation & comment EAGMST Under Review

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help
Name
Colchicine

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
Homo sapiens Homo sapiens High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
Adult, reproductively mature High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Female High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

An aneuploid offspring is an organism born with an incorrect number of chromosomes (which is present in all of its cells) [reviewed in Marchetti et al., 2016]. 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. In humans, most

aneuploid embryos survive until the blastocyst stage and are lost around the time of implantation [Fragouli et al., 2013]; however, a decline in the rate of aneuploidy is already observed between early cleavage stage and the blastocyst stage [Fragouli et al., 2014]. 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

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Diagnostic laboratories around the world use both phenotypic and molecular approaches to determine whether an individual is aneuploid. Most commonly, tests during pregnancy are used to determine whether a pregnancy is aneuploid [Rink and Norton, 2016]. These include screening tests such as ultrasound examinations [Benacerraf, 2005; Rao and Plat, 2016]; or diagnostic tests during the first or second trimesters, such as chorionic villus sampling [Hogge et al., 1985; Jenkins and Wapner, 1999], amniocentesis [Crandall and Lebher, 1976; Dacu and Wilroy, 1985], and serum markers [Canick et al., 2006]. These are well-established methods that have been used for decades. Recent developments in genomics approaches allow now the diagnosis of an aneuploid pregnancy by detecting fetal cell-free DNA in the blood of the mother [Bianchi et al., 2014; Gil et al., 2017; Sehnert et al., 2011; Valderramos et al., 2016]. When the diagnosis is done after birth, it may be based on the results of a physical exam. For example, children with Down syndrome have distinct facial features that include a flat face, slanting eyes and a small mouth [Fink et al., 1975; Farkas et al., 2002]. A karyotypical analysis of peripheral blood lymphocytes to confirm the presence of the extra chromosome is also conducted.

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Aneuploid offspring have been measured in mouse and humans, but can occur in any sexually reproducing species.

Evidence for Perturbation by Stressor

Colchicine

Dose of 2.0, 3.0 and 4.0 mg/kg colchicine administered at the time of the induction of ovulation significantly increased hyperhaploid zygotes over the control values at all doses tested. Comparison with the data obtained in oocytes under the same experimental conditions suppor the notion that aneuploid oocytes can be fertilized and the chromosome defect transmitted to the embryo

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. For KEs that are designated as an AO, one additional field of information (regulatory significance of the AO) should be completed, to the extent feasible. If the KE is being described is not an AO, simply indicate “not an AO” in this section.A key criterion for defining an AO is its relevance for regulatory decision-making (i.e., it corresponds to an accepted protection goal or common apical endpoint in an established regulatory guideline study). For example, in humans this may constitute increased risk of disease-related pathology in a particular organ or organ system in an individual or in either the entire or a specified subset of the population. In wildlife, this will most often be an outcome of demographic significance that has meaning in terms of estimates of population sustainability. Given this consideration, in addition to describing the biological state associated with the AO, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to describe regulatory examples using this AO. More help

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., 2015a].

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. However, the UK Committee on Mutagenicity of Chemicals in Foods, Consumer Products and the Environment in its 2007 annual report (https://www.gov.uk/government/collections/com-guidance-statements) did recommend that the risk assessment of certain benzimidazoles be conducted solely on the aneugenic properties of these compounds.

The development of AOPs related to mutagenicity in germ cells [Yauk et al., 2015b; 2016] is expected to aid the identification of potential hazards to germ cell genomic integrity and support regulatory efforts to protect population health.

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Benacerraf BR. 2005. The role of second trimester genetic sonogram in screening for fetal Down Syndrome. Semin Perinatol, 29:386-394.

Bianchi DW, Parker RL, Wentworth J, Madankumar R, Saffer C, Das AF, Craig JA, Chudova DI, Devers PL, Jones KW, Oliver K, Rava RP, Sehnert AJ, CARE Study Group. 2014. DNA sequencing versus standard prenatal diagnosis. N Engl J Med 370:799-808.

Canick JA, Lambert-Messerlian GM, Palomaki GE, Neveus LM, Malone FD, Ball RH, Nyberg DA, Comstock CH, Bukowski R, Saade GR, Berkowits RL, Dar P, Dugoff L, Craigo, SD, Timor-Trisch IE, Carr, SR, Wolfe HM, D’Alton ME. 2006. First and Second Trimester Evaluation of Risk (FASTER) Trial Research Consortium. Comparison of serum markers in first-trimester down syndrome screening. Obstet Gynecol 108:1192-1199.

Crandall BF, Lebherz TB. 1976. Prenatal genetic diagnosis in 350 amniocenteses. Obstet Gynecol, 48:158-162.

Dacus JV, Wilroy RS, Summitt RL, Garbaciak JA, Abdella TN, Spinnato JA, Luthardt FW, Flinn GS, Lewis BA. 1985. Genetic amniocentesis: a twelve years’s experience. Am J Med Genet, 20:443-452.

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.

Farkas LG, Katic MJ, Forrest CR. 2002. Age-related changes in anthropometric measurements in the craniofacial regions and in height in Down’s syndrome. J Craniofac Surg 13:614-622.

Fink GB, Madaus WK, Walker GF. 1975. A quantitative study of the face in Down’s syndrome. Am J Orthod, 67:540-553.

Fragouli E, Alfarawati S, Spath K, Jaroudi S, Saras J, Enciso M, Wells D. 2013. The origin and impact of embryonic aneuploidy. Hum Genet 132:1001–1013.

Fragouli E, Alfarawati S, Spath K, Wells D. 2014. Morphological and cytogenetic assessment of cleavage and blastocyst stage embryos. Mol Hum Reprod 20:117–126.

Gil MM, Accurti V, Santacruz B, Plana MN, Nicolaides KH. 2017. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. Epub: April 11, 2017. doi: 10.1002/uog.17484.

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.

Hogge WA, Schonberg SA, Golbus MS. 1985. Prenatal diagnosis by chorionic villus sampling: lessons of the first 600 cases. Prenat Diagn 5:393-400.

Jenkins TM, Wapner RJ. 1999. First trimester prenatal diagnosis: chorionic villus sampling. Semin Perinatol 23:403-413.

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 F, Massarotti A, Yauk CL, Pacchierotti F, Russo A. 2016. The adverse outcome pathway (AOP) for chemical binding to tubulin in oocytes leading to aneuploid offspring. Environ Mol Mutagen 57:87-113.

Rao R, Platt LD. 2016. Ultrasound screening: status of markers and efficacy of screening for structural abnormalities. Seminal Perinatol 40:67-78.

Rink BD, Norton ME. 2016. Screening for fetal aneuploidy. Semin Perinatol 40:35-43.

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.

Sehnert AJ, Rhees B, Comstock D, de Feo E, Heilek G, Burke J, Rava RP. 2011. Optimal detection of fetal chromosomal abnormalities by massively parallel DNA sequencing of cell-free DNA from maternal blood. Clin Chem 57:1042-1049.

Valderramos SG, Rao RR, Scibetta EW, Silverman NS, Han CS, Platt LD. 2016. Cell-free DNA screening in clinical practice: abnormal autosomal aneuploidy and microdeletion results. Am J Obstet Gynecol 215:626.e1-626.e10.

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. 2015a. 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.

Yauk CL, Lambert IB, Meek ME, Douglas GR. Marchetti F. 2015b. Development of the adverse outcome pathway “alkylation of DNA in male premeiotic germ cells leading to heritable mutations” using the OECD’s users’ handbook supplement. Environ Mol Mutagen 56:724-750.

Yauk C, Lamber I, Marchetti F, Douglas G. 2016. Adverse Outcome Pathway on alkylation of DNA in male pre-meiotic germ cells leading to heritable mutations. OECD Series on Adverse Outcome Pathways, No. 3, OECD publishing. http://dx.doi.org/10.1787/5jlsvvxn1zjc-en.