Chromosome nondisjunction during bipolar mitoses of binucleated intermediates promote aneuploidy formation along with multipolar mitoses rather than chromosome loss in micronuclei induced by asbestos

Our plain-English summary of Chromosome nondisjunction during bipolar mitoses of binucleated intermediates promote aneuploidy formation along with multipolar mitoses rather than chromosome loss in micronuclei induced by asbestos, by T. Zhang, L. Lv, Y. Huang, et al (Oncotarget, 2017).

The study

• Authors: T. Zhang, L. Lv, Y. Huang, X. Ren, Q. Shi
• Journal: Oncotarget
• Published: 2017;8(7):11030-11041
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Asbestos is a well-known occupational carcinogen that can cause aneuploidy during the early stages of neoplastic development. To explore the origins of asbestos-induced aneuploidy, we performed long-term live-cell imaging followed by fluorescence in situ hybridization of chromosomes 8 and 12 in human bronchial epithelial (HBEC) and mesothelial (MeT5A) cells. We demonstrate that asbestos induces aneuploidy via binucleated intermediates resulting from cytokinesis failure. On the one hand, asbestos increases chromosome nondisjunction during bipolar divisions of binucleated intermediates and produces near-tetraploidy. On the other hand, asbestos increases multipolar divisions of binucleated intermediates to produce aneuploidy. Surprisingly, chromosomes in asbestos-induced micronucleated cells are not truly lost by the cells, and do not contribute to aneuploid cell formation in either cell type. These results clarify the cellular source of asbestos-induced aneuploidy. In particular, they show the asbestos-induced disruption of bipolar chromosomal segregation in tetraploid cells, thereby demonstrating the causality between binucleated intermediates and aneuploidy evolution, rather than chromosome loss in micronuclei.

In plain English

This was a laboratory study of two lines of human cells grown in dishes: bronchial lining cells (HBEC) and mesothelial cells (MeT5A). The authors added chrysotile asbestos (2 μg/cm2) and filmed the cells dividing. They then stained chromosomes 8 and 12 to count the copies in each daughter cell. Daughter cells with an abnormal chromosome count (aneuploid) made up 2.89% (48/1661) of treated HBEC cells, against 0.00% of untreated cells. They made up 4.54% (37/815) of treated MeT5A cells, against 1.17% of untreated cells. Chrysotile often stopped dividing cells from fully splitting, which left cells with two nuclei. Most aneuploid cells came from later divisions of these two-nucleus cells. Some split into three or more cells. Others split into two cells that shared their chromosomes unevenly. Chromosome 8 or 12 trapped in small extra nuclei (micronuclei) was seen in 0.60% (10/1661) of treated HBEC and 0.61% (5/815) of treated MeT5A daughter cells, and none of those cells were aneuploid. The authors concluded that chromosome loss into micronuclei does not substantially contribute to asbestos-induced aneuploidy. Only chromosomes 8 and 12 were counted.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell culture experiment: long-term live-cell video imaging of dividing cells, followed by fluorescence in situ hybridization (FISH) to count copies of chromosomes 8 and 12 in each daughter cell
• Who was studied: Two immortalized human cell lines: HBEC bronchial epithelial cells and MeT5A mesothelial cells. For the main aneuploidy count, 1661 treated and 850 untreated HBEC daughter cells, and 815 treated and 683 untreated MeT5A daughter cells, were analyzed. No people or animals were studied.
• Exposure: Chrysotile A Rhodesian asbestos (UICC standard), added at 2 μg/cm2 during live-cell imaging. A separate binucleation test used chrysotile or crocidolite at 0, 2, 5 and 10 μg/cm2. Cells with two nuclei produced by the drug cytochalasin B (1 μg/ml) served as a comparison.
• Main results:
  • Aneuploid daughter cells: 2.89% (48/1661) of chrysotile-treated HBEC cells versus 0.00% of untreated HBEC cells, and 4.54% (37/815) of chrysotile-treated MeT5A cells versus 1.17% of untreated MeT5A cells. Both differences had p less than 0.001.
  • Divisions of single-nucleus cells that ended with a two-nucleus cell (binucleation) were more frequent with chrysotile treatment. For HBEC cells the figures were 28.63 plus or minus 6.69% treated versus 0.92 plus or minus 0.61% untreated. For MeT5A cells they were 29.99 plus or minus 2.37% treated versus 7.19 plus or minus 3.80% untreated. Both differences had p less than 0.001.
  • Origins of the 48 aneuploid HBEC cells: 46% (22/48) came from two-way (bipolar) divisions of binucleated cells, 50% (24/48) from multi-way (multipolar) divisions of binucleated cells, and 4% (2/48) from multipolar divisions of mononucleated cells.
  • Origins of the 37 aneuploid MeT5A cells: 16% (6/37) came from bipolar divisions of binucleated cells, 54% (20/37) from multipolar divisions of binucleated cells, 19% (7/37) from bipolar divisions of mononucleated cells, and 11% (4/37) from multipolar divisions of mononucleated cells.
  • Among treated cells, aneuploidy in daughter cells of binucleated cells was 9.94% (46/462) for HBEC and 15.85% (26/164) for MeT5A. In daughter cells of mononucleated cells it was 0.17% (2/1199) for HBEC and 1.69% (11/651) for MeT5A.
  • Uneven sharing of chromosomes (nondisjunction) occurred in 11.87% (26/219) of bipolar divisions of chrysotile-induced binucleated HBEC cells, versus 1.38% (2/145) in cytochalasin B-induced binucleated HBEC cells (p less than 0.001). For MeT5A cells the article gives 19.16% (10/51), also printed as 19.61%, versus 5.08% (3/59) in cytochalasin B-induced cells (p less than 0.05).
  • In cytochalasin B-induced binucleated cells, all aneuploid daughter cells came from multipolar mitosis (HBEC 22/22; MeT5A 87/87).
  • After chrysotile treatment, only 0.60% (10/1661) of HBEC and 0.61% (5/815) of MeT5A daughter cells had chromosome 8 or 12 inside a micronucleus.
  • All cells with chromosome 8 or 12 in a micronucleus fell into two types, and neither type was aneuploid.
• The authors' conclusion: The authors concluded that asbestos can directly cause uneven chromosome sharing during bipolar divisions of binucleated cells, and that this is a pathway to aneuploidy as important as multipolar division. They also concluded that, contrary to the conventional assumption, chromosome loss into micronuclei caused by asbestos does not substantially contribute to aneuploidy.

Topics

Medical terms in this study, explained in our Lexicon: Micronuclei, Fluorescence In Situ Hybridization (FISH).

Related studies

• Multipolar mitosis and aneuploidy after chrysotile treatment: a consequence of abscission failure and cytokinesis regression — B.A. Cortez, P. Rezende-Teixeira, et al. (2016)
• The fate of chrysotile-induced multipolar mitosis and aneuploid population in cultured lung cancer cells — A. Cortez Bde, G. Quassollo, et al. (2011)
• Induction of micronuclei, hyperdiploidy and chromosomal breakage affecting the centric/pericentric regions of chromosomes 1 and 9 in human amniotic fluid cells after treatment with asbestos and ceramic fibers — E. Dopp, M. Schuler, et al. (1997)
• Recurring loss involving chromosomes 1, 3, and 22 in malignant mesothelioma: possible sites of tumor suppressor genes — W.L. Flejter, F.P. Li, et al. (1989)
• Mitotic disturbances and micronucleus induction in Syrian hamster embryo fibroblast cells caused by asbestos fibers — E. Dopp, J. Saedler, et al. (1995)
• Chromosome 3 and 12p rearranged in a well-differentiated peritoneal mesothelioma — H.J. Decker, F.P. Li, et al. (1990)

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