{"doi":"10.1093/narmme/ugae006","title":"Frequencies and spectra of aflatoxin B1-induced mutations in liver genomes of NEIL1-deficient mice as revealed by duplex sequencing","abstract":"Abstract Increased risk for the development of hepatocellular carcinoma (HCC) is driven by a number of etiological factors including hepatitis viral infection and dietary exposures to foods contaminated with aflatoxin-producing molds. Intracellular metabolic activation of aflatoxin B1 (AFB1) to a reactive epoxide generates highly mutagenic AFB1-Fapy-dG adducts. Previously, we demonstrated that repair of AFB1-Fapy-dG adducts can be initiated by the DNA glycosylase NEIL1 and that male Neil1−/− mice were significantly more susceptible to AFB1-induced HCC relative to wild-type mice. To investigate the mechanisms underlying this enhanced carcinogenesis, WT and Neil1−/− mice were challenged with a single, 4 mg/kg dose of AFB1 and frequencies and spectra of mutations were analyzed in liver DNAs 2.5 months post-injection using duplex sequencing. The analyses of DNAs from AFB1-challenged mice revealed highly elevated mutation frequencies in the nuclear genomes of both males and females, but not the mitochondrial genomes. In both WT and Neil1−/− mice, mutation spectra were highly similar to the AFB1-specific COSMIC signature SBS24. Relative to wild-type, the NEIL1 deficiency increased AFB1-induced mutagenesis with concomitant elevated HCCs in male Neil1−/− mice. Our data establish a critical role of NEIL1 in limiting AFB1-induced mutagenesis and ultimately carcinogenesis.","journal":"NAR Molecular Medicine","year":2024,"id":453058,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1110907,"name":"Michael M. Luzadder","orcid":"0000-0001-7227-6207","position":1,"is_corresponding":false},{"id":490387,"name":"Vladimir L. Vartanian","orcid":"0000-0003-1290-953X","position":2,"is_corresponding":false},{"id":874233,"name":"Sean P. M. Rice","orcid":"0000-0001-7712-4667","position":3,"is_corresponding":false},{"id":676768,"name":"Megan Nguyen","orcid":"0000-0002-2413-1406","position":4,"is_corresponding":false},{"id":1275612,"name":"Mónica Sánchez-Contreras","orcid":"0000-0002-3092-2781","position":5,"is_corresponding":false},{"id":1060585,"name":"Phu Van","orcid":"0000-0001-8605-316X","position":6,"is_corresponding":false},{"id":484209,"name":"Scott R. Kennedy","orcid":"0000-0002-4444-1145","position":7,"is_corresponding":false},{"id":827017,"name":"Amanda K. McCullough","orcid":"0000-0002-9500-4973","position":8,"is_corresponding":false},{"id":490390,"name":"R. Stephen Lloyd","orcid":"0000-0001-7273-372X","position":9,"is_corresponding":false},{"id":827016,"name":"Irina G. Minko","orcid":"0000-0002-0012-2265","position":0,"is_corresponding":true}],"reference_count":106,"raw_metadata":null,"created_at":"2026-07-19T02:02:58.784290Z","pmid":"38779538","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}