title: MicroRNA Responses to the Genotoxic Carcinogens Aflatoxin B1 and Benzo[a]pyrene in Human HepaRG Cells.
abstract: Recent advances in toxicogenomics present an opportunity to develop new in vitro testing methodologies to identify human carcinogens. We have investigated microRNA expression responses to the treatment of human liver HepaRG cells with the human genotoxic carcinogens aflatoxin B1 (AFB1) and benzo[a]pyrene (B[a]P), and the structurally similar compounds aflatoxin B2 (AFB2) and benzo[e]pyrene (B[e]P) that exhibit minimal carcinogenic potential. We demonstrate that treatment of HepaRG cells with AFB1 or B[a]P resulted in specific changes in the expression of miRNAs as compared with their non-carcinogenic analogues, particularly in a marked over-expression of miR-410. An additional novel finding is the dose- and time-dependent inhibition of miR-122 in AFB1-treated HepaRG cells. Mechanistically, the AFB1-induced down-regulation of miR-122 was attributed to inhibition of the HNF4A/miR-122 regulatory pathway. These results demonstrate that HepaRG cells can be used to investigate miRNA responses to xenobiotic exposure, and illustrate the existence of early non-genotoxic events, in addition to a well-established genotoxic mode of action changes, in the mechanism of AFB1 and B[a]P carcinogenicity.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079.
authors.forename: April K
authors.initials: AK
authors.lastname: Marrone
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079.
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Tryndyak
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 igor.pogribny@fda.hhs.gov.
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
mesh_terms: D016604:Aflatoxin B1 / Q000633:toxicity*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D051557:Hepatocyte Nuclear Factor 4 / Q000032:analysis / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced*; D035683:MicroRNAs / Q000032:analysis / Q000502:physiology*
chemical_list: D002273:Carcinogens; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D001564:Benzo(a)pyrene; D016604:Aflatoxin B1
keywords: HepaRG cells; aflatoxin B1; benzo[a]pyrene; microRNA