Benchmark Dose Analysis of DNA Damage Biomarker Responses Provides Compound Potency and Adverse Outcome Pathway Information for the Topoisomerase II Inhibitor Class of Compounds

Wheeldon, Ryan P.; Bernacki, Derek T.; Dertinger, Stephen D.; Bryce, Steven M.; Bemis, Jeffrey C.; Johnson, George E.

doi:10.1002/em.22360

Title: Benchmark Dose Analysis of DNA Damage Biomarker Responses Provides Compound Potency and Adverse Outcome Pathway Information for the Topoisomerase II Inhibitor Class of Compounds

Journal Article · 10 February 2020 · Environmental and Molecular Mutagenesis

DOI: https://doi.org/10.1002/em.22360 · OSTI ID:1598725

^[1]; Bernacki, Derek T. ^[2]; Dertinger, Stephen D. ^[2]; Bryce, Steven M. ^[2]; Bemis, Jeffrey C. ^[2];

^[1]

Institute of Life Science, Swansea University Medical School, Swansea University Wales United Kingdom
Litron Laboratories Rochester New York

Genetic toxicology data have traditionally been utilized for hazard identification to provide a binary call for a compound's risk. Recent advances in the scientific field, especially with the development of high‐throughput methods to quantify DNA damage, have influenced a change of approach in genotoxicity assessment. The in vitro MultiFlow® DNA Damage Assay is one such method which multiplexes γH2AX, p53, phospho‐histone H3 biomarkers into a single‐flow cytometric analysis (Bryce et al., [2016]: Environ Mol Mutagen 57:546–558). This assay was used to study human TK6 cells exposed to each of eight topoisomerase II poisons for 4 and 24 hr. Using PROAST v65.5, the Benchmark Dose approach was applied to the resulting flow cytometric datasets. With “compound” serving as covariate, all eight compounds were combined into a single analysis, per time point and endpoint. The resulting 90% confidence intervals, plotted in Log scale, were considered as the potency rank for the eight compounds. The in vitro MultiFlow data showed a maximum confidence interval span of 1Log, which indicates data of good quality. Patterns observed in the compound potency rank were scrutinized by using the expert rule‐based software program Derek Nexus, developed by Lhasa Limited. Compound sub‐classification and structural alerts were considered contributory to the potencies observed for the topoisomerase II poisons studied herein. The Topo II poison Adverse Outcome Pathway was evaluated with MultiFlow endpoints serving as Key Events. The step‐wise approach described herein can be considered as a foundation for risk assessment of compounds within a specific mode of action of interest. Environ. Mol. Mutagen. 2020. © 2020 Wiley Periodicals, Inc.

View Accepted Manuscript (Publisher)

Cite

Export

Save

Sponsoring Organization:: USDOE

OSTI ID:: 1598725

Journal Information:: Environmental and Molecular Mutagenesis, Journal Name: Environmental and Molecular Mutagenesis Vol. 61 Journal Issue: 4; ISSN 0893-6692

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 5 works

Citation information provided by
Web of Science

References (51)

The DNA cleavage reaction of topoisomerase II: wolf in sheep's clothing Deweese, J. E.; Osheroff, N. Nucleic Acids Research, Vol. 37, Issue 3 https://doi.org/10.1093/nar/gkn937	journal	November 2008
DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways. Nelson, W. G.; Kastan, M. B. Molecular and Cellular Biology, Vol. 14, Issue 3 https://doi.org/10.1128/MCB.14.3.1815	journal	March 1994
The role of ethyl acrylate induced GSH depletion in the rodent forestomach and its impact on MTD and in vivo genotoxicity in developing an adverse outcome pathway (AOP) Ellis-Hutchings, R.; Giuliani, J.; Hayashi, M. Regulatory Toxicology and Pharmacology, Vol. 92 https://doi.org/10.1016/j.yrtph.2017.11.012	journal	February 2018
DNA Ligase IV Deficiency in Mice Leads to Defective Neurogenesis and Embryonic Lethality via the p53 Pathway Frank, Karen M.; Sharpless, Norman E.; Gao, Yijie Molecular Cell, Vol. 5, Issue 6 https://doi.org/10.1016/S1097-2765(00)80264-6	journal	June 2000
Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development Gao, Yijie; Ferguson, David O.; Xie, Wei Nature, Vol. 404, Issue 6780 https://doi.org/10.1038/35009138	journal	April 2000
γH2AX and p53 responses in TK6 cells discriminate promutagens and nongenotoxicants in the presence of rat liver S9: γH2AX and p53 Responses in TK6 Cells Bernacki, Derek T.; Bryce, Steven M.; Bemis, Jeffrey C. Environmental and Molecular Mutagenesis, Vol. 57, Issue 7 https://doi.org/10.1002/em.22028	journal	July 2016
p53 mutated in the transactivation domain retains regulatory functions in homology-directed double-strand break repair Boehden, Gisa S.; Akyüz, Nuray; Roemer, Klaus Oncogene, Vol. 22, Issue 26 https://doi.org/10.1038/sj.onc.1206632	journal	June 2003
Stabilization of Eukaryotic Topoisomerase II-DNA Cleavage Complexes Wilstermann, Amy; Osheroff, Neil Current Topics in Medicinal Chemistry, Vol. 3, Issue 3 https://doi.org/10.2174/1568026033452519	journal	January 2003
Predictions of genotoxic potential, mode of action, molecular targets, and potency via a tiered multiflow® assay data analysis strategy: Tiered Data Analysis Strategy Dertinger, Stephen D.; Kraynak, Andrew R.; Wheeldon, Ryan P. Environmental and Molecular Mutagenesis, Vol. 60, Issue 6 https://doi.org/10.1002/em.22274	journal	February 2019
DNA topoisomerase II, genotoxicity, and cancer McClendon, A. Kathleen; Osheroff, Neil Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 623, Issue 1-2 https://doi.org/10.1016/j.mrfmmm.2007.06.009	journal	October 2007
Distinguishing between expert and statistical systems for application under ICH M7 Barber, Chris; Hanser, Thierry; Judson, Philip Regulatory Toxicology and Pharmacology, Vol. 84 https://doi.org/10.1016/j.yrtph.2016.12.012	journal	March 2017
A new method for determining allowable daily intakes*1 Crump, K. Fundamental and Applied Toxicology, Vol. 4, Issue 5 https://doi.org/10.1016/0272-0590(84)90107-6	journal	October 1984
Phosphorylation of histone H3 is correlated with changes in the maintenance of sister chromatid cohesion during meiosis in maize, rather than the condensation of the chromatin Kaszas, E.; Cande, W. Z. Journal of Cell Science, Vol. 113, Issue 18 https://doi.org/10.1242/jcs.113.18.3217	journal	September 2000
p53 protein at the hub of cellular DNA damage response pathways through sequence-specific and non-sequence-specific DNA binding Liu, Y. Carcinogenesis, Vol. 22, Issue 6 https://doi.org/10.1093/carcin/22.6.851	journal	June 2001
Quantitative approaches for assessing dose-response relationships in genetic toxicology studies Gollapudi, B. B.; Johnson, G. E.; Hernandez, L. G. Environmental and Molecular Mutagenesis, Vol. 54, Issue 1 https://doi.org/10.1002/em.21727	journal	September 2012
In Silico Tools for Sharing Data and Knowledge on Toxicity and Metabolism: Derek for Windows, Meteor, and Vitic Marchant, Carol A.; Briggs, Katharine A.; Long, Anthony Toxicology Mechanisms and Methods, Vol. 18, Issue 2-3 https://doi.org/10.1080/15376510701857320	journal	January 2008
Type II DNA topoisomerases Berger, James M. Current Opinion in Structural Biology, Vol. 8, Issue 1 https://doi.org/10.1016/S0959-440X(98)80006-7	journal	February 1998
Application of the adverse outcome pathway framework to genotoxic modes of action Sasaki, Jennifer C.; Allemang, Ashley; Bryce, Steven M. Environmental and Molecular Mutagenesis, Vol. 61, Issue 1 https://doi.org/10.1002/em.22339	journal	October 2019
IWGT report on quantitative approaches to genotoxicity risk assessment I. Methods and metrics for defining exposure–response relationships and points of departure (PoDs) MacGregor, James T.; Frötschl, Roland; White, Paul A. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, Vol. 783 https://doi.org/10.1016/j.mrgentox.2014.09.011	journal	May 2015
An appraisal of critical effect sizes for the benchmark dose approach to assess dose–response relationships in genetic toxicology Zeller, Andreas; Duran-Pacheco, Gonzalo; Guérard, Melanie Archives of Toxicology, Vol. 91, Issue 12 https://doi.org/10.1007/s00204-017-2037-3	journal	August 2017
ATR-p53 Restricts Homologous Recombination in Response to Replicative Stress but Does Not Limit DNA Interstrand Crosslink Repair in Lung Cancer Cells Sirbu, Bianca M.; Lachmayer, Sarah J.; Wülfing, Verena PLoS ONE, Vol. 6, Issue 8 https://doi.org/10.1371/journal.pone.0023053	journal	August 2011
Phosphoacetylation of histone H3 on c- fos - and c- jun -associated nucleosomes upon gene activation Clayton, Alison L.; Rose, Sally; Barratt, Michael J. The EMBO Journal, Vol. 19, Issue 14 https://doi.org/10.1093/emboj/19.14.3714	journal	July 2000
p53 and its 14 kDa C-terminal domain recognize primary DNA damage in the form of insertion/deletion mismatches Lee, Suman; Elenbaas, Brian; Levine, Arnold Cell, Vol. 81, Issue 7 https://doi.org/10.1016/S0092-8674(05)80006-6	journal	June 1995
Recombination at chromosomal sequences involved in leukaemogenic rearrangements is differentially regulated by p53 Boehden, G. S. Carcinogenesis, Vol. 25, Issue 8 https://doi.org/10.1093/carcin/bgh092	journal	March 2004
Histone H3 phosphorylation is required for the initiation, but not maintenance, of mammalian chromosome condensation Van Hooser, A.; Goodrich, D. W.; Allis, C. D. Journal of Cell Science, Vol. 111, Issue 23 https://doi.org/10.1242/jcs.111.23.3497	journal	December 1998
Global phosphoproteomic effects of natural tyrosine kinase inhibitor, genistein, on signaling pathways Yan, Guang-Rong; Xiao, Chuan-Le; He, Gui-Wei PROTEOMICS https://doi.org/10.1002/pmic.200900662	journal	January 2010
Adverse outcome pathways: Application to enhance mechanistic understanding of neurotoxicity Bal-Price, Anna; Meek, M. E. (Bette) Pharmacology & Therapeutics, Vol. 179 https://doi.org/10.1016/j.pharmthera.2017.05.006	journal	November 2017
Genotoxic mode of action predictions from a multiplexed flow cytometric assay and a machine learning approach: Genotoxic Mode of Action Predictions Bryce, Steven M.; Bernacki, Derek T.; Bemis, Jeffrey C. Environmental and Molecular Mutagenesis, Vol. 57, Issue 3 https://doi.org/10.1002/em.21996	journal	January 2016
Shape and steepness of toxicological dose–response relationships of continuous endpoints Slob, Wout; Setzer, R. Woodrow Critical Reviews in Toxicology, Vol. 44, Issue 3 https://doi.org/10.3109/10408444.2013.853726	journal	November 2013
Investigating the Generalizability of the MultiFlow ® DNA Damage Assay and Several Companion Machine Learning Models With a Set of 103 Diverse Test Chemicals Bryce, Steven M.; Bernacki, Derek T.; Smith-Roe, Stephanie L. Toxicological Sciences, Vol. 162, Issue 1 https://doi.org/10.1093/toxsci/kfx235	journal	November 2017
The interaction of p53 with replication protein A mediates suppression of homologous recombination Romanova, Larisa Y.; Willers, Henning; Blagosklonny, Mikhail V. Oncogene, Vol. 23, Issue 56 https://doi.org/10.1038/sj.onc.1207982	journal	October 2004
A high-throughput fluorescence anisotropy-based assay for human topoisomerase II β-catalyzed ATP-dependent supercoiled DNA relaxation Shapiro, Adam B.; Austin, Caroline A. Analytical Biochemistry, Vol. 448 https://doi.org/10.1016/j.ab.2013.11.029	journal	March 2014
IWGT report on quantitative approaches to genotoxicity risk assessment II. Use of point-of-departure (PoD) metrics in defining acceptable exposure limits and assessing human risk MacGregor, James T.; Frötschl, Roland; White, Paul A. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, Vol. 783 https://doi.org/10.1016/j.mrgentox.2014.10.008	journal	May 2015
A general theory of effect size, and its consequences for defining the benchmark response (BMR) for continuous endpoints Slob, Wout Critical Reviews in Toxicology, Vol. 47, Issue 4 https://doi.org/10.1080/10408444.2016.1241756	journal	November 2016
Mechanism of Quinolone Action and Resistance Aldred, Katie J.; Kerns, Robert J.; Osheroff, Neil Biochemistry, Vol. 53, Issue 10 https://doi.org/10.1021/bi5000564	journal	March 2014
Wild-type p53 stimulates homologous recombination upon sequence-specific binding to the ribosomal gene cluster repeat Boehden, Gisa S.; Baumann, Cindy; Siehler, Simone Oncogene, Vol. 24, Issue 26 https://doi.org/10.1038/sj.onc.1208592	journal	March 2005
Core histone N-termini play an essential role in mitotic chromosome condensation de la Barre, A. -E. The EMBO Journal, Vol. 19, Issue 3 https://doi.org/10.1093/emboj/19.3.379	journal	February 2000
Dose-Response Modeling of Continuous Endpoints Slob, W. Toxicological Sciences, Vol. 66, Issue 2 https://doi.org/10.1093/toxsci/66.2.298	journal	April 2002
Apoptosis Induced by DNA Topoisomerase I and II Inhibitors in Human Leukemic HL-60 Cells Solary, Eric; Bertrand, Richard; Pommier, Yves Leukemia & Lymphoma, Vol. 15, Issue 1-2 https://doi.org/10.3109/10428199409051674	journal	January 1994
Molecular docking studies on thirteen fluoroquinolines with human topoisomerase II a and b Jadhav, Ashwini Khanderao; Karuppayil, Sankunny Mohan In Silico Pharmacology, Vol. 5, Issue 1 https://doi.org/10.1007/s40203-017-0024-2	journal	June 2017
Phosphorylation of histone H3 correlates with transcriptionally active loci Nowak, S. J. Genes & Development, Vol. 14, Issue 23 https://doi.org/10.1101/gad.848800	journal	December 2000
A proposal for a novel rationale for critical effect size in dose–response analysis based on a multi-endpoint in vivo study with methyl methanesulfonate Zeller, Andreas; Tang, Leilei; Dertinger, Stephen D. Mutagenesis, Vol. 31, Issue 3 https://doi.org/10.1093/mutage/gev077	journal	November 2015
Stimulation of Topoisomerase II-Mediated DNA Damage via a Mechanism Involving Protein Thiolation ^† Wang, Huimin; Mao, Yong; Chen, Allan Y. Biochemistry, Vol. 40, Issue 11 https://doi.org/10.1021/bi002786j	journal	March 2001
Interpreting in vitro micronucleus positive results: Simple biomarker matrix discriminates clastogens, aneugens, and misleading positive agents: Interpreting In Vitro Micronucleus Positive Results Bryce, Steven M.; Bemis, Jeffrey C.; Mereness, Jared A. Environmental and Molecular Mutagenesis, Vol. 55, Issue 7 https://doi.org/10.1002/em.21868	journal	April 2014
Next generation testing strategy for assessment of genomic damage: A conceptual framework and considerations: Next Generation Testing Strategy for Assessment of Genomic Damage Dearfield, Kerry L.; Gollapudi, B. Bhaskar; Bemis, Jeffrey C. Environmental and Molecular Mutagenesis, Vol. 58, Issue 5 https://doi.org/10.1002/em.22045	journal	September 2016
A Critical Role for DNA End-Joining Proteins in Both Lymphogenesis and Neurogenesis Gao, Yijie; Sun, Yi; Frank, Karen M. Cell, Vol. 95, Issue 7 https://doi.org/10.1016/S0092-8674(00)81714-6	journal	December 1998
Comparison of in vitro and in vivo clastogenic potency based on benchmark dose analysis of flow cytometric micronucleus data Bemis, Jeffrey C.; Wills, John W.; Bryce, Steven M. Mutagenesis, Vol. 31, Issue 3 https://doi.org/10.1093/mutage/gev041	journal	June 2015
Empirical analysis of BMD metrics in genetic toxicology part I: in vitro analyses to provide robust potency rankings and support MOA determinations Wills, John W.; Johnson, George E.; Doak, Shareen H. Mutagenesis, Vol. 31, Issue 3 https://doi.org/10.1093/mutage/gev085	journal	December 2015
Estimating the carcinogenic potency of chemicals from the in vivo micronucleus test Soeteman-Hernández, Lya G.; Johnson, George E.; Slob, Wout Mutagenesis, Vol. 31, Issue 3 https://doi.org/10.1093/mutage/gev043	journal	July 2015
Interlaboratory evaluation of a multiplexed high information content in vitro genotoxicity assay: Multiplexed High Information Content Assay Bryce, Steven M.; Bernacki, Derek T.; Bemis, Jeffrey C. Environmental and Molecular Mutagenesis, Vol. 58, Issue 3 https://doi.org/10.1002/em.22083	journal	March 2017
Catalytic topoisomerase II inhibitors in cancer therapy Larsen, Annette K.; Escargueil, Alexandre E.; Skladanowski, Andrzej Pharmacology & Therapeutics, Vol. 99, Issue 2 https://doi.org/10.1016/S0163-7258(03)00058-5	journal	August 2003

Similar Records

CS1 is a novel topoisomerase IIα inhibitor with favorable drug resistance profiles

Journal Article · 2014 · Biochemical and Biophysical Research Communications · OSTI ID:22416790

Shen, Yan; Chen, Wang; Zhao, Baobing; +4 more

Comparison of genotoxicity of automotive exhaust particles from laboratory and environmental sources

Journal Article · 1984 · Environ. Mutagen.; (United States) · OSTI ID:6239247

Brooks, A L; Li, A P; Dutcher, J S; +5 more

Comparative potency approach based on H2AX assay for estimating the genotoxicity of polycyclic aromatic hydrocarbons

Journal Article · 2012 · Toxicology and Applied Pharmacology · OSTI ID:22215283

Zeman, F.; Beaudoin, R.; Péry, A.; +1 more

Title: Benchmark Dose Analysis of DNA Damage Biomarker Responses Provides Compound Potency and Adverse Outcome Pathway Information for the Topoisomerase II Inhibitor Class of Compounds

Citation Formats

References (51)

Similar Records

Related Subjects