{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T14:39:27Z","timestamp":1789655967159,"version":"4.0.1"},"reference-count":46,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T00:00:00Z","timestamp":1746662400000},"content-version":"vor","delay-in-days":37,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["ES\u2010031086"],"award-info":[{"award-number":["ES\u2010031086"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Environ and Mol Mutagen"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer\u2010associated mortality, correlating with obesity, alcohol consumption, hepatitis B and C infections, and dietary exposure to aflatoxin B<jats:sub>1<\/jats:sub> (AFB<jats:sub>1<\/jats:sub>). The etiology of AFB<jats:sub>1<\/jats:sub>\u2010induced HCC involves the formation of highly mutagenic guanine lesions that can be repaired by a branch of the base excision repair pathway initiated by the DNA glycosylase, NEIL1. In a murine model, NEIL1 deficiency results in increased AFB<jats:sub>1<\/jats:sub>\u2010induced mutagenesis and carcinogenesis. Previous analyses identified several defective NEIL1 variants in human populations, including the temperature\u2010sensitive A51V and glycosylase\u2010deficient G83D variants. Herein, we report AFB<jats:sub>1<\/jats:sub>\u2010induced mutagenesis in mice expressing the A51V and G83D NEIL1 variants. Cohorts of 6\u2010day\u2010old <jats:italic>Neil1<\/jats:italic><jats:sup><jats:italic>A51V<\/jats:italic><\/jats:sup> and <jats:italic>Neil1<\/jats:italic><jats:sup><jats:italic>G83D<\/jats:italic><\/jats:sup> homozygous mice were injected with a single dose of AFB<jats:sub>1<\/jats:sub>, and frequencies and spectra of mutations were assessed in liver genomes 2.5\u2009months post\u2010exposure using duplex sequencing. Comparisons of these data with previously generated data on AFB<jats:sub>1<\/jats:sub>\u2010induced mutagenesis in wild\u2010type (WT) and <jats:italic>Neil1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice revealed that although mutation frequencies in <jats:italic>Neil1<\/jats:italic><jats:sup><jats:italic>A51V<\/jats:italic><\/jats:sup> and <jats:italic>Neil1<\/jats:italic><jats:sup><jats:italic>G83D<\/jats:italic><\/jats:sup> animals were comparable to those measured in WT, elevated proportions of base substitutions at A\/T sites were consistent with NEIL1 deficiency in both of these models. These findings suggest that individuals carrying these NEIL1 variants could be at an elevated risk for the development of AFB<jats:sub>1<\/jats:sub>\u2010induced HCC.<\/jats:p>","DOI":"10.1002\/em.70014","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T14:58:13Z","timestamp":1747666693000},"page":"144-154","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Aflatoxin <scp>B<sub>1<\/sub><\/scp>\u2010Induced Hepatic Mutagenesis in Mice Expressing Gene\u2010Edited <i>Neil1<\/i>"],"prefix":"10.1002","volume":"66","author":[{"given":"Irina G.","family":"Minko","sequence":"first","affiliation":[{"name":"Oregon Institute of Occupational Health Sciences Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir L.","family":"Vartanian","sequence":"additional","affiliation":[{"name":"Oregon Institute of Occupational Health Sciences Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael M.","family":"Luzadder","sequence":"additional","affiliation":[{"name":"Oregon Institute of Occupational Health Sciences Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingming","family":"Wang","sequence":"additional","affiliation":[{"name":"Transgenic Mouse Models Shared Resource Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lev M.","family":"Fedorov","sequence":"additional","affiliation":[{"name":"Transgenic Mouse Models Shared Resource Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda K.","family":"McCullough","sequence":"additional","affiliation":[{"name":"Oregon Institute of Occupational Health Sciences Oregon Health and Science University  Portland Oregon USA"},{"name":"Department of Molecular and Medical Genetics Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Stephen","family":"Lloyd","sequence":"additional","affiliation":[{"name":"Oregon Institute of Occupational Health Sciences Oregon Health and Science University  Portland Oregon USA"},{"name":"Department of Molecular and Medical Genetics Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgh098"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1111191"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010020\u20101943\u20103"},{"issue":"3","key":"e_1_2_9_5_1","first-page":"694","article-title":"Metabolism of Aflatoxin B1 and Identification of the Major Aflatoxin B1\u2010DNA Adducts Formed in Cultured Human Bronchus and Colon","volume":"39","author":"Autrup H.","year":"1979","journal-title":"Cancer Research"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph17041215"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-018-0539-0"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00503a018"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja063781y"},{"issue":"15","key":"e_1_2_9_10_1","first-page":"E3101","article-title":"Mutational Spectra of Aflatoxin B1 In\u00a0Vivo Establish Biomarkers of Exposure for Human Hepatocellular Carcinoma","volume":"114","author":"Chawanthayatham S.","year":"2017","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky354"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.75.4.1745"},{"issue":"1","key":"e_1_2_9_13_1","first-page":"197","article-title":"Temporal Patterns of Covalent DNA Adducts in Rat Liver After Single and Multiple Doses of Aflatoxin B1","volume":"41","author":"Croy R. 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