Non-linear dose–response of DNA-reactive genotoxins: Recommendations for data analysis

Johnson, George E.; Doak, Shareen H.; Griffiths, Sioned M.; Quick, Emma; Skibinski, D. O. F.; Zaïr, Zoulikha M.; Jenkins, Gareth

doi:10.1016/j.mrgentox.2009.05.009

Cited by 67 publications

(40 citation statements)

References 19 publications

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“…All these datasets were statistically evaluated with a methodology that directly compared goodness-of-fit of a linear dose-response model to that of a non-linear/bilinear dose-response model [27, 29, 59]. These studies demonstrated non-linear/bilinear dose-response curves for genotoxic effects with the S N 2 alkylating agents EMS and MMS [3, 56-58] and with the S N 1 alkylating nitrosoureas, ENU and MNU [3, 56-58, 60, 61]. …”

Section: Alkylating Agentsmentioning

confidence: 99%

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Klapacz

Pottenger

Engelward

et al. 2016

Mutation Research/Reviews in Mutation Research

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From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations.

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Section: Alkylating Agentsmentioning

confidence: 99%

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Klapacz

Pottenger

Engelward

et al. 2016

Mutation Research/Reviews in Mutation Research

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“…This situation highlights the need for in vitro assays that can comprehensively evaluate the low end of the dose-response curve. Indeed, Johnson and colleagues [12] expressed the need for in vitro assays that allow for large numbers of individual cells to be analyzed, include many replicates, and utilize closely-spaced dose levels. However, the desire for thorough dose-response data is problematic unless the assay is very efficient, with data acquisition occurring via an automated process.…”

Section: Introductionmentioning

confidence: 99%

Miniaturized flow cytometric in vitro micronucleus assay represents an efficient tool for comprehensively characterizing genotoxicity dose–response relationships

Bryce

Avlasevich

Bemis

et al. 2010

Mutation Research/Genetic Toxicology and Environmental Mutagene

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This laboratory has developed a flow cytometric approach for scoring in vitro micronuclei (In Vitro MicroFlow ® ) whose characteristics are expected to benefit studies designed to comprehensively investigate genotoxicity dose-response relationships. In particular, new experimental designs become possible when automated scoring is combined with treatment, processing and sampling that all occur in microtiter plates. To test this premise, experiments described herein investigated micronucleus (MN) formation in TK6 cells treated with genotoxic agents applied at 22 closely-spaced concentrations in quadruplicate, with 10,000 cells analyzed per replicate. The genotoxicants colchicine, vinblastine sulfate, ethyl methanesulfonate, methyl methanesulfonate, ethyl nitrosourea, methyl nitrosourea, and bleomycin were applied continuously for 24 -30 hrs. Following treatment, all cell processing, sampling and data acquisition steps were accomplished in the same 96-well plate. Data acquisition occurred in a walk-away mode via the use of a high throughput sampling device. The resulting flow cytometric MN values were evaluated with a statistical model that indicated non-linear relationships describe the data better than linear fits. The one exception was bleomycin, where MN induction was consistently best described by a linear dose-response relationship. Collectively, these results suggest that flow cytometry represents a practical and efficient approach for thoroughly examining the doseresponse relationship, and clearly benefits studies that seek to characterize no observable genotoxic effect levels, lowest observable genotoxic effect levels, and/or benchmark doses.

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“…5) confirm apoptotic death. High radioresistance and active postradiation repair of irradiation induced DNA breaks show that there is a genotoxic threshold underlying nonlinear dose response effect (Johnson et al, 2009). A genotoxic threshold was observed for genotoxic alkylating agents in proliferating cells (Jen kins et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of radioresistance in terminally differentiated cells of mature retina

et al. 2012

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Abstract⎯Retinopathy of animals is induced by many DNA damaging agents. This fact shows that DNA lesions may initiate retinal degeneration. The aim of our work was to study the effects of gamma and proton irradiation and single administration of methylnitrosourea (MNU) on mice retina. We assessed morpholog ical changes, DNA damage and repair, as well as expression of proteins (p53, ATM, PARP, FasR, and caspase 3) participating in apoptosis in retina. 14 Gy was the equitoxic dose for induction of DNA single strand breaks by both gamma and proton irradiation. However, protons were twice as effective as γ rays in induction of DNA double strand breaks. All breaks have been repaired for ≤10 h. Irradiation resulted in increased expression of p53 and ATM. Seven days after irradiation, no signs of cell death and retinal degen eration were observed. Proton irradiation with 25 Gy resulted in destructive changes in retina localized mainly in the photoreceptor layer. These changes were accompanied by enhanced expression of proapoptotic proteins. A single systemic administration of MNU (70 mg/kg) increased intracellular levels of p53, PARP, FasR, and Caspase 3 followed by destructive changes in retina with sings of apoptosis in photoreceptors. Sim ilarly to irradiation, a halved MNU dose did not exhibit a cytotoxic effect on retina. A high level of sponta neous DNA damage at apurine and apyrimidine sites were observed in mouse retina. The results show that there is a genotoxic threshold in initiation of retinal cell death in vivo. It is suggested that topoisomerase 2 translates primary DNA damage into a cytotoxic effect in retina.

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Non-linear dose–response of DNA-reactive genotoxins: Recommendations for data analysis

Cited by 67 publications

References 19 publications

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Miniaturized flow cytometric in vitro micronucleus assay represents an efficient tool for comprehensively characterizing genotoxicity dose–response relationships

Mechanisms of radioresistance in terminally differentiated cells of mature retina

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