title: Aflatoxin B1 induces persistent epigenomic effects in primary human hepatocytes associated with hepatocellular carcinoma.
abstract: Chronic exposure to aflatoxin B1 (AFB1) has, in certain regions in the world, been strongly associated with hepatocellular carcinoma (HCC) development. AFB1 is a very potent hepatotoxic and carcinogenic mycotoxin which is frequently reported as a food contaminant. Epigenetic modifications provoked by environmental exposures, such as AFB1, may create a persistent epigenetic footprint. Deregulation of epigenetic mechanisms has actually been reported in HCC patients following AFB1 exposure; however, no attempts have yet been made to investigate early effects on the epigenome level which may be persistent on longer term, thereby possibly initiating carcinogenic events. In this study, we aim to identify methyl DNA-mRNA-interactions representative for a persistent epigenetic footprint associated with the early onset of AFB1-induced HCC. For this, primary human hepatocytes were exposed to 0.3μM of AFB1 for 5 days. Persistent epigenetic effects were measured 3 days after terminating the carcinogenic exposure. Whole genome DNA methylation changes and whole genome transcriptomic analysis were analyzed applying microarray technologies, and cross-omics interactions were evaluated. Upon combining transcriptomics data with results on DNA methylation, a range of persistent hyper- and hypo-methylated genes was identified which also appeared affected on the transcriptome level. For six of the hypo-methylated and up-regulated genes, namely TXNRD1, PCNA, CCNK, DIAPH3, RAB27A and HIST1H2BF, a clear role in carcinogenic events could be identified. This study is the first to report on a carcinogen-induced persistent impact on the epigenetic footprint in relation with the transcriptome which could be indicative for the early onset of AFB1-related development of HCC.
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands; Netherlands Toxicogenomics Centre (NTC), 6229 ER Maastricht, The Netherlands. Electronic address: linda.rieswijk@maastrichtuniversity.nl.
authors.forename: Linda
authors.initials: L
authors.lastname: Rieswijk
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Sandra M H
authors.initials: SM
authors.lastname: Claessen
authors.affiliation: Central Diagnostic Laboratory, Maastricht University Medical Centre, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
authors.forename: Otto
authors.initials: O
authors.lastname: Bekers
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: van Herwijnen
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Daniël H J
authors.initials: DH
authors.lastname: Theunissen
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands; Netherlands Toxicogenomics Centre (NTC), 6229 ER Maastricht, The Netherlands.
authors.forename: Danyel G J
authors.initials: DG
authors.lastname: Jennen
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Theo M C M
authors.initials: TM
authors.lastname: de Kok
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands; Netherlands Toxicogenomics Centre (NTC), 6229 ER Maastricht, The Netherlands.
authors.forename: Jos C S
authors.initials: JC
authors.lastname: Kleinjans
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Simone G J
authors.initials: SG
authors.lastname: van Breda
mesh_terms: D016604:Aflatoxin B1 / Q000633:toxicity*; D063646:Carcinogenesis / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic; D057890:Epigenomics; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D002273:Carcinogens; D012333:RNA, Messenger; D016604:Aflatoxin B1
keywords: Aflatoxin B1; Epigenomics; Hepatocellular carcinoma; Persistence; Wash-out