{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,23]],"date-time":"2025-08-23T05:20:27Z","timestamp":1755926427776},"reference-count":68,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T00:00:00Z","timestamp":1583280000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Environ and Mol Mutagen"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Genome instability is a hallmark of most human cancers and is exacerbated following replication stress. However, the effects that drugs\/xenobiotics have in promoting genome instability including chromosomal structural rearrangements in normal cells are not currently assessed in the genetic toxicology battery. Here, we show that drug\u2010induced replication stress leads to increased genome instability in vitro using proliferating primary human cells as well as in vivo in rat bone marrow (BM) and duodenum (DD). p53\u2010binding protein 1 (53BP1, biomarker of DNA damage repair) nuclear bodies were increased in a dose\u2010dependent manner in normal proliferating human mammary epithelial fibroblasts following treatment with compounds traditionally classified as either genotoxic (hydralazine) and nongenotoxic (low\u2010dose aphidicolin, duvelisib, idelalisib, and amiodarone). Comparatively, no increases in 53BP1 nuclear bodies were observed in nonproliferating cells. Negative control compounds (mannitol, alosteron, diclofenac, and zonisamide) not associated with cancer risk did not induce 53BP1 nuclear bodies in any cell type. Finally, we studied the in vivo genomic consequences of drug\u2010induced replication stress in rats treated with 10 mg\/kg of cyclophosphamide for up to 14\u2009days followed by polymerase chain reaction\u2010free whole genome sequencing (30X coverage) of BM and DD cells. Cyclophosphamide induced chromosomal structural rearrangements at an average of 90 genes, including 40 interchromosomal\/intrachromosomal translocations, within 2\u2009days of treatment. Collectively, these data demonstrate that this drug\u2010induced genome instability test (DiGIT) can reveal potential adverse effects of drugs not otherwise informed by standard genetic toxicology testing batteries. These efforts are aligned with the food and drug administration's (FDA's) predictive toxicology roadmap initiative.<\/jats:p>","DOI":"10.1002\/em.22364","type":"journal-article","created":{"date-parts":[[2020,2,20]],"date-time":"2020-02-20T16:20:15Z","timestamp":1582215615000},"page":"770-785","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Biomarkers of genome instability in normal mammalian genomes following drug\u2010induced replication stress"],"prefix":"10.1002","volume":"61","author":[{"given":"Sheroy","family":"Minocherhomji","sequence":"first","affiliation":[{"name":"Translational Safety and Bioanalytical Sciences Amgen Research, Amgen Inc.  Thousand Oaks California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Genome Analysis Unit Amgen Research, Amgen Inc.  Thousand Oaks California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yudong D.","family":"He","sequence":"additional","affiliation":[{"name":"Genome Analysis Unit Amgen Research, Amgen Inc.  Thousand Oaks California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark R.","family":"Fielden","sequence":"additional","affiliation":[{"name":"Translational Safety and Bioanalytical Sciences Amgen Research, Amgen Inc.  Thousand Oaks California"},{"name":"Expansion Therapeutics  San Diego California"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,3,4]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2015.04.004"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03482"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000110"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinternmed.2007.107"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.10.037"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100244"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2011.02.009"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.023"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V128.22.2979.2979"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2015.07.009"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.22087"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-03-633156"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw339"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2682"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.4161\/fly.19695"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.20616"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature21406"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.04.027"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature20099"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-421-6_7"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt301"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2017.11.005"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.066"},{"key":"e_1_2_9_25_1","doi-asserted-by":"crossref","unstructured":"FreedD PanR AldanaR.2018.TNscope: accurate detection of somatic mutations with haplotype\u2010based variant candidate detection and machine learning filtering. bioRxiv:250647.","DOI":"10.1101\/250647"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature25154"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1119396109"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00272988"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03485"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgy031"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a012740"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2015.10.006"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2008.03.008"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-1461"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1161(95)00038-0"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/gix098"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2007.1.453"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2201"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-012414-040424"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2014.05.004"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature16139"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2016.07.003"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.116"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.17226\/25801"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.24745"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(80)90601-4"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1110(94)90015-9"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780380815"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.2131\/jts.35.149"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.10.5858"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7871"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0712168105"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.22342"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1208715109"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/0163-7258(88)90004-6"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.1509912"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V124.21.3091.3091"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.27881"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0963-7"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1015"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4609"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.177121.114"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(91)90195-B"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2773"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208710"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2897"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.399"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2013.09.003"}],"container-title":["Environmental and Molecular Mutagenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fem.22364","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/em.22364","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/em.22364","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/em.22364","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,3]],"date-time":"2023-09-03T19:50:24Z","timestamp":1693770624000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/em.22364"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,4]]},"references-count":68,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2020,10]]}},"alternative-id":["10.1002\/em.22364"],"URL":"https:\/\/doi.org\/10.1002\/em.22364","archive":["Portico"],"relation":{},"ISSN":["0893-6692","1098-2280"],"issn-type":[{"value":"0893-6692","type":"print"},{"value":"1098-2280","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,4]]},"assertion":[{"value":"2019-11-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-02-16","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}