Study of oxidative DNA damage in TK6 human lymphoblastoid cells by use of the thymidine kinase gene-mutation assay and the in vitro modified comet assay: Determination of No-Observed-Genotoxic-Effect-Levels

Platel, Anne; Nesslany, Fabrice; Gervais, Véronique; Claude, Nancy; Marzin, Daniel

doi:10.1016/j.mrgentox.2011.09.003

Cited by 24 publications

(16 citation statements)

References 51 publications

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“…, 2011; Platel et al. , 2011). The potential for threshold-like behavior in the micronuclei response curves was evaluated using a model that can test whether a threshold model is more likely than a linear model (Lutz and Lutz, 2009).…”

Section: Resultsmentioning

confidence: 99%

Profiling Dose-Dependent Activation of p53-Mediated Signaling Pathways by Chemicals with Distinct Mechanisms of DNA Damage

Clewell

Sun

Adeleye

et al. 2014

Toxicological Sciences

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As part of a larger effort to provide proof-of-concept in vitro-only risk assessments, we have developed a suite of high-throughput assays for key readouts in the p53 DNA damage response toxicity pathway: double-strand break DNA damage (p-H2AX), permanent chromosomal damage (micronuclei), p53 activation, p53 transcriptional activity, and cell fate (cell cycle arrest, apoptosis, micronuclei). Dose-response studies were performed with these protein and cell fate assays, together with whole genome transcriptomics, for three prototype chemicals: etoposide, quercetin, and methyl methanesulfonate. Data were collected in a human cell line expressing wild-type p53 (HT1080) and results were confirmed in a second p53 competent cell line (HCT 116). At chemical concentrations causing similar increases in p53 protein expression, p53-mediated protein expression and cellular processes showed substantial chemical-specific differences. These chemical-specific differences in the p53 transcriptional response appear to be determined by augmentation of the p53 response by co-regulators. More importantly, dose-response data for each of the chemicals indicate that the p53 transcriptional response does not prevent micronuclei induction at low concentrations. In fact, the no observed effect levels and benchmark doses for micronuclei induction were less than or equal to those for p53-mediated gene transcription regardless of the test chemical, indicating that p53's post-translational responses may be more important than transcriptional activation in the response to low dose DNA damage. This effort demonstrates the process of defining key assays required for a pathway-based, in vitro-only risk assessment, using the p53-mediated DNA damage response pathway as a prototype.

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Section: Resultsmentioning

confidence: 99%

Profiling Dose-Dependent Activation of p53-Mediated Signaling Pathways by Chemicals with Distinct Mechanisms of DNA Damage

Clewell

Sun

Adeleye

et al. 2014

Toxicological Sciences

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“…A threshold is suggested in vivo even in the genotoxicity, especially for chromosomal aberration including micronucleus tests [14][15][16][17] . Because the existence of threshold would be experimentally determined with genotoxicity data, the overall understanding of genotoxicity and carcinogenicity could be crucial for the assessment of carcinogenicity.…”

Section: Current Issues Test Methodsmentioning

confidence: 99%

“…Liver tumors induced by some non-genotoxic chemicals are thought to be quantitatively far irrelevant to human risk based on the MOA simply related to transcription factors such as constitutive androstane receptor (CAR), pregnane X receptor (PXR) and peroxisome proliferator-activated receptor-α (PPARα) 101,102) . Possible secondary genotoxicity such as oxidative DNA damage may have a threshold because possible primary events such as inflammation and cytotoxicity followed by oxidative stress would have a threshold 14,103,104) . Taken together, it is very important to define what tumor is based on the rodentspecific carcinogenesis mechanisms qualitatively or quantitatively.…”

Section: Proposed Assessment Strategymentioning

confidence: 99%

“…Recently, non-threshold approaches such as threshold of toxicological concern (TTC) [3][4][5][6][7][8][9][10][11] and margin of exposure (MOE) [11][12][13] have also been introduced for both intended and unintended chemicals. Although genotoxicity is assumed in general to have no threshold, it remains unknown whether genotoxicity of some chemicals may have any no-observed-genotoxic-effect-level (NOGEL) [14][15][16][17] . Another current major issue on rodent carcinogenicity is how to extrapolate rodent data to human risk assessments, since such extrapolation is not fully supported scientifically in most cases.…”

Section: Introductionmentioning

confidence: 99%

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Carcinogenicity Assessment for Risk Factors in Food:

Nishikawa

2013

Food Safety

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In the current carcinogenicity assessment, the threshold is a major issue for genotoxic carcinogens. Carcinogenicity is usually assessed in combination with genotoxicity data. The current assessment methodology is based on the hypothesis that non-genotoxic carcinogens have thresholds but genotoxic carcinogens do not. However, it remains unclear in most cases as to how much the detected genotoxic potential is actually associated with the carcinogenicity at an organ level. To clarify this critical issue, in vivo genotoxicity has been investigated in transgenic rodents carrying reporter genes, which can simultaneously detect both genotoxicity and carcinogenicity on each organ basis. Studies of a number of genotoxic carcinogens have revealed good correlations between in vivo genotoxicity and carcinogenicity. However, some discordant results have been also found in some cases. Besides experimentally observed values of genotoxicity, MOA or statistics might be taken into account for biological or practical threshold. Then, statistical or mathematical evaluation can provide values of BMDL or MOE even for strictly defined genotoxic carcinogens. Another major issue is concerning extrapolation of animal data for human risk. For this purpose, WOE approaches based on MOA may be extremely useful. Experiments using transgenic rodents such as p53, nrf2 or CAR knockout mice might be helpful to elucidate the mechanisms of carcinogenicity. The other issues concern the development of screening or alternative methods. In the future, in silico and in vitro approaches will be powerful tools for screening genotoxic and carcinogenic potentials of a number of chemicals/agents.

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“…A recent study of several mutational endpoints in human TK6 lymphoblastoid cells revealed a clear noobserved genotoxic effect level (NOGEL) following exposures to a range of concentrations of agents known to induce oxidative stress. 33 Finally, as indicated in Chapters 2.1 and 2.2, indirect mutagenicity (especially that due to oxidative DNA damage) that is generated by many exogenous chemicals can be intimately associated with the direct, DNA reactive mutagenicity of these same agents. Metabolism is the critical link, especially phase II detoxification.…”

Section: Metabolic Inactivation Of Genotoxic Compoundsmentioning

confidence: 99%

Introduction and Conclusion: The Rationale for Thresholds for Genotoxic Carcinogens

Greim¹,

Albertini²

2012

Issues in Toxicology

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Study of oxidative DNA damage in TK6 human lymphoblastoid cells by use of the thymidine kinase gene-mutation assay and the in vitro modified comet assay: Determination of No-Observed-Genotoxic-Effect-Levels

Cited by 24 publications

References 51 publications

Profiling Dose-Dependent Activation of p53-Mediated Signaling Pathways by Chemicals with Distinct Mechanisms of DNA Damage

Profiling Dose-Dependent Activation of p53-Mediated Signaling Pathways by Chemicals with Distinct Mechanisms of DNA Damage

Carcinogenicity Assessment for Risk Factors in Food:

Introduction and Conclusion: The Rationale for Thresholds for Genotoxic Carcinogens

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