Chromosome nondisjunction

Stoler, S., Keith, K.C., Curnick, K.E., and Fitzgerald-Hayes, M. (1995) A mutation in CSE4, an essential gene encoding a novel chromatin-associated protein in yeast, causes chromosome nondisjunction and cell cycle arrest at mitosis. Gene Dev. 9, 573-586. 

Positive results from the in vitro micronucleus test indicate that the test substance induces chromosome damage and/or damage to the cell division apparams, in cultured mammahan somatic cells. Immunochemical labehng (FISH fluorescence in sim hybridization) of kinetochores, or hybridization with general or chromosome specific centromeric/telomeric probes can provide useful information on the mechanism of micronucleus formation. Use of cytokinesis block facilitates the acquisition of the additional mechanistic information (e.g., chromosome nondisjunction) that can be obtained by FISH techniques. The micronucleus assay has a number of advantages over metaphase analysis performed to measure chromosome aberrations (see OECD TG 487 draft). 

Clearly, this complex process must be controlled by the cell such that there are checkpoint controls, which make sure that there are two centrosomes and two half spindles, that the correct chromatids associate with the correct half-spindle and that separation does not occur until all of the chromatids are in the correct place. Failure of any part of this system could lead to the wrong number of chromosomes in one daughter cell. This uneven segregation is known as chromosomal nondisjunction. A number of chemicals, including some drugs, will interfere with this process. Thus, spindle formation can be disrupted, so the chromosomes may segregate in a random fashion. 

The unequal partition of chromosomes or nondisjunction is a serious effect if the affected daughter cells survive. Down syndrome or Trisomy 21 is the result of chromosome nondisjunction in humans, those affected having 47 chromosomes instead of 46. This unequal partitioning of chromosomes can occur at mitosis in germ cells or during meiosis in the production of sperm or ova. 

Tates, A.D. Microtus oeconomus (Rodentia), a useful mammal for studying the induction of sex-chromosome nondisjunction and diploid gametes in male germ cells. Environ. Health Perspect. 31 151-159, 1979. 

Two organic mercury compounds (methylmercury chloride at 0.08-0.4 g Hg/mL and methoxyethyl mercury chloride at 0.04-0.23 g Hg/mL) induced weak but dose-related mutagenic responses in Chinese hamster V-79 cells near the cytotoxic threshold (Fiskesjo 1979). Methylmercury was neither mutagenic nor caused recombination in Saccharomyces cerevisiae, but it did produce a slight increase in the frequency of chromosomal nondisjunction (Nakai and Machida 1973). Both methylmercury and phenylmercuric acetate induced primary DNA damage in the B. subtilis rec-assay (Kanematsu et al. 

Chromosomal aberrations Gene mutation Dominant lethal mutation Micronucleus formation Micronucleus formation Micronucleus formation Chromosomal aberrations Sister chromatid exchange Micronucleus formation Chromosomal aberrations Sister chromatid exchange DNA-protein cross-links Nondisjunction of Y chromosome in sperm DNA damage (single-strand breaks)... 

Drosophila melanogaster Chromosome loss or nondisjunction - Ramel and Magnusson 1979... 

Some chromosomal conditions are caused by changes in the number of chromosomes. These changes are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in reproductive cells with an abnormal number of chromosomes. For example, a reproductive cell may accidentally gain or lose one copy of a chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra or missing chromosome in each of the body s cells. 

Aneuploidy, which indicates a deviation from the euploid number of chromosomes, is the term used to describe the loss or gain of specific chromosomes. Two major types of aneuploidy are observed trisomy (three copies of a specific chromosome) and monosomy (one copy of a specific chromosome). Monosomies and trisomies are usually caused by nondisjunction (the failure of the two members of the chromosome pair to disjoin or separate) during meiosis (Fig II-3-2). All autosomal monosomies are lethal, but trisomies of three different autosomes (13,18, and 21) are compatible with survival to term in at least some cases. This difference illustrates the fact that the body tolerates extra genetic material more successfiiUy than a loss of genetic material. 

The result of nondisjunction, loss of one chromosome, for example, may be incompatible with survival of the cell, so aneugens are often cytotoxic. This obviously only occurs in cells, which are actively dividing, therefore such compounds find use as anticancer drugs. Two examples are vincristine and vinblastine, two vinca alkaloids, derived from a plant. 

Toluene did not induce sex-linked recessive lethal mutations or translocations, but did induce sex-chromosome loss and nondisjunction in male Drosophila melanogaster and induced mitotic arrest (C-mitosis) in embryos of the grasshopper, Melanoplus sanguinipes. 

A specially constructed cross (1-41-5 x 1-34-8) of N. crassa has been used to determine the ability of agents to produce meiotic nondisjunction.11+7 The parental strains were heterozygous for four auxotrophic markers on chromosome 1 prototrophic disomies can be selected by plating ascospores on minimal medium. 

FIGURE 5-2 Diagram of a chromosome-loss test for the sex chromosomes when the male is the treated parent. The regular progeny are shown as classes (a) and (b). Class (c) is a presumptive loss of either the X or Y chromosome, but a portion of such a sex chromosome lacking marker mutants may still remain. Classes (d) and (e) represent loss of the and Bs marked regions, respectively, of the Y chromosome. Class (f) is a rare class and arises from nondisjunction of the X and Y chromosome in the parental male. Classes (g) and (h) are rare classes that arise from primary nondisjunction of the X chromosomes in the parental female. Reprinted with permission from Abrahamson and Lewis.5... 

Convenient methods378 exist in the mouse for detecting whole-chromosome aneuploidy, as determined by sex-chromosome loss and nondisjunction, ttiese methods are possible because XO female mice and XXY male mice are viable. 

Genetic markers are used that make it apparent from the phenotype of offspring whether they are aneuploids. Experiments can easily be designed to measure induction of sex-chromosome loss or nondisjunction in either sex. 

Some or all events leading to sex-chromosome loss or nondisjunction are either not inducible in or not recoverable from some of the germ cell stage.378 However, very few chemicals have been tested, and none in all germ cell stages. Sex-chromosome loss has been shown to be induced by triethylenemelamine in spermatids and spermatozoa, 55 by isopropyl methanesulfonate in primary oocytes within 6 wk of being ovulated,138 and by hycanthone methanesulfonate in primary oocytes within 1 wk of being ovulated.38 ... 

Several assays in mammals permit a determination of the incidence of micronuclei 393 of these, the only one sufficiently developed to be a standard assay is the in vivo mammalian bone marrow polychromatic-erythrocyte assay.155 Micronuclei are formed from chromosomes or chromosomal fragments that are not incorporated into daughter nuclei at the time of cell division. Ihus, this very rapid test serves as an in vivo somatic cell screening test for finding genotoxic chemicals that might break chromosomes or cause nondisjunction in germ cells. It has been applied to more than 150 chemicals.158... 

Aberrations in newborn persons consist of both numerical changes (due primarily to nondisjunction) and structural deletions and rearrangements (due to chromosomal breakage). There has been no unambiguous demonstration in human beings that mutagens can cause nondisjunction. An additional problem, insofar as monitoring is concerned, is that the trisomies and monosomies seen in newborn persons also cause increased risk of abortion, Therefore, only an unknown fraction survive to birth. 

Hie YFF test reflects nondisjunction of the Y chromosome. It is reasonable to assume that agents that are YFF-positive would also cause nondisjunction of autosomes. 

NONDISJUNCTION The failure of homologous chromosomes to separate at anaphase I of meiosis the failure of chromatids to separate at anaphase of mitosis or at anaphase II of meiosis. 

Foureman, P.A. A translocation X Y system for detecting meiotic nondisjunction and chromosome breakage in males of Drosophila melanogaster. Environ. Health Perspect. 31 53-58, 1979. 

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