In vitro and in vivo extrapolations of genotoxin exposures: consideration of factors which influence dose–response thresholds

Parry, James M.; Jenkins, Gareth; Haddad, Farhang; Bourner, R; Parry, Elizabeth M.

doi:10.1016/s1383-5718(99)00166-7

Cited by 46 publications

(24 citation statements)

References 20 publications

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“…An interaction of these agents with many tubulin molecules is required for the appreciable manifestation of the aneugenic effect. The threshold existence in this case is theoretically expected and well confirmed by experimental data [38,39].…”

Section: Aneugens and Mechanisms Underlying The Induction Of Genomic supporting

confidence: 83%

“…This effect was shown for the MN induction in mouse bone marrow by carbendazim, Note: BC, binuclear cells with blocked cytokinesis; CL, cultured human lymphocytes; NL, noncultured human lymphocytes; MN, micronuclei; kinetochore +/-MN, micronuclei carrying (+) and lacking (-) kinetochore; cen + MN, centromere-positive micronuclei. The methods of aneugenic effect detection: FISH with centromeric probes on chromosomes presented in column 3 [7,14,15,38,50,54,58,71,72]; metaphase analysis [39,68,72,74]; immunocytochemical kinetochore staining [17,69,70]; fluorescent spindle staining [73].…”

Section: Aneugens and Mechanisms Underlying The Induction Of Genomic mentioning

confidence: 99%

“…Note that conventional cytogenetic analysis is poorly suitable for detecting AE induced by various carcinogenic agents. As mentioned above, these studies are hindered by the dose threshold, i.e., when the agent concentration is lower than the threshold, cells do not respond to the aneugenic treatment [14,36,39,44]. Furthermore, in some cases the aneugenic effect observed in vitro, may not be detected in vivo [37].…”

Section: Carcinogenicity and Chromosome Specificity Of The Aneugenic mentioning

confidence: 99%

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Interphase cytogenetics in estimation of genomic mutations in somatic cells

2005

Russ J Genet

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Section: Aneugens and Mechanisms Underlying The Induction Of Genomic supporting

confidence: 83%

Section: Aneugens and Mechanisms Underlying The Induction Of Genomic mentioning

confidence: 99%

Section: Carcinogenicity and Chromosome Specificity Of The Aneugenic mentioning

confidence: 99%

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Interphase cytogenetics in estimation of genomic mutations in somatic cells

2005

Russ J Genet

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“…Aneugenic compounds, such as colchicine, nocodazole, vinblastine, and griseofulvin (5)(6)(7), that inhibit tubulin polymerization are prime examples. As the spindle apparatus consists of many tubulin monomers, its inactivation would require multiple targets to be damaged before a significant adverse effect occurs; thus, chromosome segregation is only altered at the concentration that prevents the formation of sufficient microtubules.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Influences for Mutation Induction Curves after Exposure to DNA-Reactive Carcinogens

et al. 2007

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A mechanistic understanding of carcinogenic genotoxicity is necessary to determine consequences of chemical exposure on human populations and improve health risk assessments. Currently, linear dose-responses are assumed for DNA reactive compounds, ignoring cytoprotective processes that may limit permanent damage. To investigate the biological significance of low-dose exposures, human lymphoblastoid cells were treated with alkylating agents that have different mechanisms of action and DNA targets: methylmethane sulfonate (MMS), methylnitrosourea (MNU), ethylmethane sulfonate (EMS), and ethylnitrosourea (ENU). Chromosomal damage and point mutations were quantified with the micronucleus and hypoxanthine phosphoribosyltransferase forward mutation assays. MNU and ENU showed linear dose-responses, whereas MMS and EMS had nonlinear curves containing a range of nonmutagenic low doses. The lowest observed effect level for induction of chromosomal aberrations was 0.85 Mg/mL MMS and 1.40 Mg/mL EMS; point mutations required 1.25 Mg/mL MMS and 1.40 Mg/mL EMS before a mutagenic effect was detected. This nonlinearity could be due to homeostatic maintenance by DNA repair, which is efficient at low doses of compounds that primarily alkylate N 7 -G and rarely attack O atoms. A pragmatic threshold for carcinogenicity may therefore exist for such genotoxins. [Cancer Res 2007;67(8):3904-11]

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“…Parry et al 73 have provided persuasive evidence for an uneven distribution of mutations in three sequences of the p53 tumor suppressor gene in mice exposed to three different DNA-reactive carcinogens. Negative selection occurred for more than 80% of mutations in coding exons.…”

Section: Mutagenesismentioning

confidence: 99%