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 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
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
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., 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.
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.