Benchmark Dose Analysis of DNA Damage Biomarker Responses Provides Compound Potency and Adverse Outcome Pathway Information for the Topoisomerase II Inhibitor Class of Compounds.
adverse outcome pathway
dose response
genotoxicity
mode of action
quantitative
Journal
Environmental and molecular mutagenesis
ISSN: 1098-2280
Titre abrégé: Environ Mol Mutagen
Pays: United States
ID NLM: 8800109
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
08
09
2019
revised:
11
01
2020
accepted:
21
01
2020
pubmed:
27
1
2020
medline:
30
10
2020
entrez:
27
1
2020
Statut:
ppublish
Résumé
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.
Substances chimiques
Mutagens
0
Topoisomerase II Inhibitors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
396-407Subventions
Organisme : Research and Development
Pays : International
Informations de copyright
© 2020 Wiley Periodicals, Inc.
Références
Aldred KJ, Kerns RJ, Osheroff N. 2014. Mechanism of quinolone action and resistance. Biochemistry 53(10):1565-1574.
Bal-Price A, Meek MEB. 2017. Adverse outcome pathways: Application to enhance mechanistic understanding of neurotoxicity. Pharmacol Ther 179:84-95.
Barber C, Hanser T, Judson P, Williams R. 2017. Distinguishing between expert and statistical systems for applications under ICHM7. Regul Toxicol Pharmacol 84:124-130.
Bemis JC, Wills JW, Bryce SM, Torous DK, Dertinger SD, Slob W. 2016. Comparison of in vitro and in vivo clastogenic potency based on benchmark dose analysis of flow cytometric micronucleus data. Mutagenesis 31(3):277-285.
Berger JM. 1998. Type II DNA topoisomerases. Curr Opin Struct Biol 8(1):26-32.
Bernacki DT, Bryce SM, Bemis JC, Kirkland D, Dertinger SD. 2016. γH2AX and p53 responses in TK6 cells discriminate promutagens and nongenotoxicant in the presence of rat liver S9. Environ Mol Mutagen 57:546-558.
Boehden GS, Akyüz N, Roemer K, Wiesmüller L. 2003. p53 mutated in the transactivation domain retains regulatory functions in homology-directed double-strand break repair. Oncogene 22(26):4111-4117.
Boehden GS, Restle A, Marschalek R, Stocking C, Wiesmüller L. 2004. Recombination at chromosomal sequences involved in leukaemogenic rearrangements is differentially regulated by p53. Carcinogenesis 25(8):1305-1313.
Boehden GS, Baumann C, Siehler S, Wiesmüller L. 2005. Wild-type p53 stimulates homologous recombination upon sequence-specific binding to the ribosomal gene cluster repeat. Oncogene 24(26):4183-4192.
Bryce SM, Bemis JC, Mereness JA, Spellman RA, Moss J, Dickinson D, Schuler MJ, Dertinger SD. 2014. Interpreting in vitro micronucleus positive results: Simple biomarker matrix discriminates clastogens, aneugens, and misleading positive agents. Environ Mol Mutagen 55:542-555.
Bryce SM, Bernacki DT, Bemis JC, Dertinger SD. 2016. Genotoxic mode of action predictions from a multiplexed flow cytometric assay and a machine learning approach. Environ Mol Mutagen 57:171-189.
Bryce SM, Bernacki DT, Bemis JC, Spellman RA, Engel ME, Schuler M, Lorge E, Heikkinen PT, Hemmann U, Thybaud V, et al. 2017. Interlaboratory evaluation of a multiplexed high information content in vitro genotoxicity assay. Environ Mol Mutagen 58:146-161.
Bryce SM, Bernacki DT, Smith-Roe SL, Witt KL, Bemis JC, Dertinger SD. 2018. Investigating the generalizability of the MultiFlow® DNA damage assay and several machine learning models with a set of 103 diverse test chemicals. Toxicol Sci 162:146-166.
Chow KC, Macdonald TL, Ross WE. 1988. DNA binding by epipodophyllotoxins and N-acyl anthracyclines: Implications for mechanism of topoisomerase II inhibition. Mol Pharmacol 34(4):467-473.
Clayton AL, Rose S, Barratt MJ, Mahadevan LC. 2000. Phosphoacetylation of histone H3 on c-fos- and c-Jun-associated nucleosomes upon gene activation. EMBO J. 19(14):3714-3726.
Crump KS. 1984. A new method for determining allowable daily intakes. Fundam Appl Toxicol 4(5):854-871.
de la Barre AE, Gerson V, Gout S, Creaven M, Allis CD, Dimitrov S. 2000. Core histone N-termini play an essential role in mitotic chromosome condensation. EMBO J. 19(3):379-391.
Dearfield KL, Gollapudi BB, Bemis JC, Benz RD, Douglas GR, Elespuru RK, Johnson GE, Kirkland DJ, LeBaron MJ, Li AP, et al. 2017. Next generation testing strategy for assessment of genomic damage: A conceptual framework and considerations. Environ Mol Mutagen 58(5):264-283.
Dertinger SD, Kraynak AR, Wheeldon RP, Bernacki DT, Bryce SM, Hall N, Bemis JC, Galloway SM, Escobar PA, Johnson GE, 2019 “Predictions of genotoxic potential, mode of action, molecular targets, and potency via a tiered multiflow assay data analysis strategy.” Environ Mol Mutagen. 2019 Jul;60(6):513-533.
Deweese JE, Osheroff N. 2009. The DNA cleavage reaction of topoisomerase II: Wolf in sheep's clothing. Nucleic Acids Res. 37:738-748.
Ellis-Hutchings R, Giuliani J, Hayashi M, Masumori S, McClymont EL, Murphy S, Wiench K. 2018. 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). Regul Toxicol Pharmacol 92:173-181.
Frank KM, Sharpless NE, Gao Y, Sekiguchi JM, Ferguson DO, Zhu C, Manis JP, Horner J, DePinho RA, Alt FW. 2000. DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol Cell 5(6):993-1002.
Gao Y, Sun Y, Frank KM, Dikkes P, Fujiwara Y, Seidl KJ, Sekiguchi JM, et al. 1998. A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95(7):891-902.
Gao Y, Ferguson DO, Xie W, Manis JP, Sekiguchi J, Frank KM, Chaudhuri J, et al. 2000. Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. 404(6780):897-900.
Gollapudi BB, Johnson GE, Hernández LG, et al. 2013. Quantitative approaches for assessing dose-response relationships in genetic toxicology studies. Environ Mol Mutagen 54:8-18.
ICHM7(R1). Step 4. 2017. Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH).
Jadhav AK, Karuppayil SM. 2017. Molecular docking studies on thirteen fluoroquinolines with human topoisomerase II a and b. In Silico Pharmacol 5(1):4.
Kaszás E, Cande WZ. 2000. 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. J Cell Sci 113(18):3217-3226.
Larsen AK, Escargueil AE, Skladanowski A. 2003. Catalytic topoisomerase II inhibitors in cancer therapy. Pharmacol Ther 99(2):167-181.
Lee S, Elenbaas B, Levine A, Griffith J. 1995. p53 and its 14 kDa C-terminal domain recognize primary DNA damage in the form of insertion/deletion mismatches. Cell 81(7):1013-1020.
Liu Y, Kulesz-Martin M. 2001. p53 protein at the hub of cellular DNA damage response pathways through sequence-specific and non-sequence-specific DNA binding. Carcinogenesis 22(6):851-860.
Long BH. 1992. Mechanisms of action of Teniposide (VM-26) and comparison with Etoposide (VP-16). Semin Oncol 19(2):3-19.
MacGregor JT, Frötschl R, White PA, Crump KS, Eastmond DA, Fukushima S, Guérard M, Hayashi M, Soeteman-Hernández LG, Kasamatsu T, et al. 2015a. IWGT report on quantitative approaches to genotoxicity risk assessment I. methods and metrics for defining exposure-response relationships and points of departure (PoDs). Mutat Res 783:55-65.
MacGregor JT, Frötschl R, White PA, et al. 2015b. 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. Mutat Res 783:66-78.
Marchant CA, Briggs KA, Long A. 2008. In silico tools for sharing data and knowledge on toxicity and metabolism: derek for windows, meteor, and vitic. Toxicol Mech Methods 18(2-3):177-187.
McClendon AK, Osheroff N. 2007. DNA topoisomerase II, genotoxicity, and cancer. Mutation Res 623(1-2):83-97.
Nelson WG, Kastan MB. 1994. DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways. Mol Cell Biol 14(3):1815-1823.
Nowak SJ, Corces VG. 2000. Phosphorylation of histone H3 correlates with transcriptionally active loci. Genes Dev. 14(23):3003-3013.
Romanova LY, Willers H, Blagosklonny MV, Powell SN. 2004. The interaction of p53 with replication protein a mediates suppression of homologous recombination. Oncogene 23(56):9025-9033.
Sasaki JC, Allemang A, Bryce SM, Custer L, Dearfield KL, Dietz Y, Elhajouji A, Escobar PA, Fornace AJ Jr, Froetschl R, et al. 2019. Application of the adverse outcome pathway framework to genotoxic modes of action. Environ Mol Mutagen 61:114-134. https://doi.org/10.1002/em.22339.
Scientific Committee EFSA. 2017. Use of the benchmark dose approach in risk assessment. EFSA J 15(1):4658.
Shapiro AB, Austin CA. 2014. A high-throughput fluorescence anisotropy-based assay for human topoisomerase II β-catalyzed ATP-dependent supercoiled DNA relaxation. Anal Biochem 448((Supplement C)):23-29.
Sirbu BM, Lachmayer SJ, Wülfing V, Marten LM, Clarkson KE, Lee LW, Gheorghiu L, Zou L, Powell SN, Dahm-Daphi J, et al. 2011. ATR-p53 restricts homologous recombination in response to replicative stress but does not limit DNA interstrand crosslink repair in lung cancer cells. PLoS One 6(8):e23053.
Slob W. 2002. Dose-response modeling of continuous endpoints. Toxicol Sci 66(2):298-312.
Slob W. 2016. A general theory of effect size, and its consequences for defining the benchmark response (BMR) for continuous endpoints. Crit Rev Toxicol 47(4):342-351.
Slob W, Setzer RW. 2014. Shape and steepness of toxicological dose-response relationships of continuous endpoints. Crit Rev Toxicol 44(3):270-297.
Soeteman-Hernández LG, Fellows MD, Johnson GE, Slob W. 2015. Estimating the carcinogenic potency of chemicals from the in vivo micronucleus test. Mutagenesis 31(3):347-358.
Solary E, Bertrand R, Pommier Y. 1994. Apoptosis induced by DNA topoisomerase I and II inhibitors in human leukemic HL-60 cells. Leukemia Lymphoid 15:21-32.
Van Hooser A, Goodrich DW, Allis CD, Brinkley BR, Mancini MA, Liu LF. 1998. Histone H3 phosphorylation is required for the initiation, but not maintenance, of mammalian chromosome condensation. J Cell Sci 111(23):3497-3506.
Wang H, Mao Y, Chen AY, Zhou N, LaVoie EJ, Liu LF. 2001. Stimulation of topoisomerase II-mediated DNA damage via a mechanism involving protein Thiolation. Biochemistry 40(11):3316-3323.
Wills JW, Johnson GE, Doak SH, Soeteman-Hernández LG, Slob W, White PA. 2015. Empirical analysis of BMD metrics in genetic toxicology part I: in vitro analyses to provide robust potency rankings and support MOA determinations. Mutagenesis 31(3):255-263.
Wilstermann AM, Osheroff N. 2003. Stabilization of eukaryotic topoisomerase II-DNA cleavage complexes. Curr Top Med Chem. 3:1349-1364.
Yan GR, Xiao CL, He GW, Yin XF, Chen NP, Cao Y, He QY. 2010. Global phosphoproteomic effects of natural tyrosine kinase inhibitor, genistein, on signaling pathways. Proteomics 10(5):976-986.
Zeller A, Leilei T, Dertinger SD, Funk J, Duran-Pacheco G, Guerard M. 2015. 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. Mutagenesis 31(3):239-253.
Zeller A, Duran-Pacheco G, Guérard M. 2017. An appraisal of critical effect sizes for the benchmark dose response approach to assess dose-response relationships in genetic toxicology. Arch Toxicol 91(12):3799-3807.