The detection and evaluation of aneugenic chemicals

Parry, James M.; Parry, Elizabeth M.; Boumer, R; Doherty, Ann; Ellard, Sian; O’Donovan, Joye; Hoebee, Barbara; Stoppelaar, Joyce M. de; Mohn, G.R.; Önfelt, Agneta; Renglin, A; Schultz, Niklas; Soderpalm-Bemdes, C; Jensen, Klaus Gjervig; Kirsch‐Volders, Micheline; Elhajouji, Azeddine; Hummelen, Paul Van; Degrassi, Francesca; Antoccia, Antonio; Cimini, Daniela; Izzo, Massimo; Tanzarella, Caterina; Adler, I.‐D.; Kliesch, U.; Schriever‐Schwemmer, G.; Gasser, P.; Crebelli, Riccardo; Carere, A.; Andreoli, Cristina; Benigni, Roberto; Leopardi, Paola; Marcon, Francesca; Zinjo, Z; Natarajan, A.T.; Boei, J. J. W. A.; Kappas, A.; Voutsinas, Gerassimos E.; Zarani, Flora E.; Patrinelli, A; Pachierotti, Francesca; Tiveron, Cecilia; Hess, Pablo

doi:10.1016/0027-5107(95)00242-1

Cited by 77 publications

(30 citation statements)

References 71 publications

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“…Our finding that HU was positive in the TK mutation assay but negative in the MN test is unusual in light of the fact that the MN test is more effective for detecting clastogens because it detects genotoxins regardless of whether they interact with DNA [Parry et al, 1996]. The explanation may relate to the protocol.…”

Section: Discussioncontrasting

confidence: 52%

Comparison of in vitro micronucleus and gene mutation assay results for p53‐competent versus p53‐deficient human lymphoblastoid cells

Honma

Hayashi²

2010

Environ and Mol Mutagen

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The high frequency of false or irrelevant positive results in in vitro mammalian cell genotoxicity tests is a critical concern for regulators. Here, we tested whether such results may be due to the mammalian cells used in the tests being deficient in p53, which is involved in the maintenance of genomic stability. We compared the in vitro responses of two human lymphoblastoid cell lines derived from the same progenitor cell-p53-competent (TK6) and p53-deficient (WTK-1) cells-in a micronucleus (MN) test and a thymidine kinase gene (TK) mutation assay. We tested 14 chemicals including three mutagens and 11 clastogens and spindle poisons. The three mutagens evoked clear positive responses in both assays in both cell lines. The responses to the clastogens and spindle poisons, on the other hand, depended on the assay endpoint and/or the cell line. Most of clastogens and spindle poisons were positive in the MN test in both cell lines. In the TK mutation assay, on the other hand, WTK-1 cells but not TK6 cells detected spindle poisons, which may have been due to the disturbance of the spindle checkpoint and lack of apoptosis in the p53-deficient cells. Some chemicals that induced chromosome aberrations in rodent cells were negative in both TK6 and WTK-1 cells, indicating that a species-specific factor rather than p53 status was associated with the response. In conclusion, the p53 status did not seriously influence the MN test results but it did influence the TK mutation assay results.

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Section: Discussioncontrasting

confidence: 52%

Comparison of in vitro micronucleus and gene mutation assay results for p53‐competent versus p53‐deficient human lymphoblastoid cells

Honma

Hayashi²

2010

Environ and Mol Mutagen

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“…et al, 1995). The development of appropriate methods for the detection and assessment of aneugenic chemicals has been a major thrust of a number of research programmes of the European Union (reviewed by Parry and Sors, 1993;Parry et al, 1996). These projects have progressed since that time to develop and to apply a range of methodologies capable of detecting and assessing the significance of aneugenic activity to both somatic and germ cells by the use of both in vitro and in vivo tests.…”

Section: Introductionmentioning

confidence: 99%

Detection and characterization of mechanisms of action of aneugenic chemicals

Parry

Parry²,

Corso³

et al. 2002

Mutagenesis

148

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A comprehensive evaluation of the genotoxic potential of chemicals requires the assessment of the ability to induce gene mutations and structural chromosome (clastogenic activity) and numerical chromosome (aneugenic activity) aberrations. Aneuploidy is a major cause of human reproductive failure and an important contributor to cancer and it is therefore important that any increase in its frequency due to chemical exposures should be recognized and controlled. The in vitro binucleate cell micronucleus assay provides a powerful tool to determine the ability of a chemical to induce chromosome damage. The application of an anti-kinetochore antibody to micronuclei allows their classification into kinetochore-positive and kinetochorenegative, indicating their origin by aneugenic or clastogenic mechanisms, respectively. The availability of chromosomespecific centromere probes allows the analysis of the segregation of chromosomes into the daughter nuclei of binucleate cells to evaluate chromosome non-disjunction. Quantitative relationships between the two major causes of aneuploidy, chromosome loss and non-disjunction, can be determined. The mechanisms leading to chromosome loss and non-disjunction can be investigated by the analysis of morphological and structural changes in the cell division apparatus by the application of specific stains and antibodies for various cell division components. We illustrate such analyses by the demonstration of the interaction of the monomer bisphenol-A with the centrosome of the mitotic spindle and the folic acid antagonist pyrimethamine with the centromeres of chromosomes. Both types of modifications lead to the induction of aneuploidy in exposed cells. Our studies also implicate the products of the p53 and XPD genes in the regulation of the fidelity of chromosome segregation at mitosis.

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“…Little further insight into quantifying the portion of micronuclei caused by failure of the mitotic spindle can be gained using in situ hybridization with whole centromere DNA probes in cytochalasin-induced binucleated cells. Improvements in the micronucleus assay in vitro, particularly a method for chromosome painting in micronuclei, developed more recently are expected to elucidate the interrelationship between micronucleus formation and mutagenesis and to evaluate the relative hazards of low dose response to aneugenic chemicals (Parry et al, 1996). This will lead to a better understanding and interpretation of results obtained by examination of in vivo exposed humans.…”

Section: Discussionmentioning

confidence: 98%