title: New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis.
abstract: Benzo(a)pyrene (BaP) is a ubiquitous carcinogen resulting from incomplete combustion of organic compounds and also present at high levels in cigarette smoke. A wide range of biological effects has been attributed to BaP and its genotoxic metabolite BPDE, but the contribution to BaP toxicity of intermediary metabolites generated along the detoxification path remains unknown. Here, we report for the first time how 3-OH-BaP, 9,10-diol and BPDE, three major BaP metabolites, temporally relate to BaP-induced transcriptomic alterations in HepG2 cells. Since BaP is also known to induce AhR activation, we additionally evaluated TCDD to source the expression of non-genotoxic AhR-mediated patterns. 9,10-Diol was shown to activate several transcription factor networks related to BaP metabolism (AhR), oxidative stress (Nrf2) and cell proliferation (HIF-1α, AP-1) in particular at early time points, while BPDE influenced expression of genes involved in cell energetics, DNA repair and apoptotic pathways. Also, in order to grasp the role of BaP and its metabolites in chemical hepatocarcinogenesis, we compared expression patterns from BaP(-metabolites) and TCDD to a signature set of approximately nine thousand gene expressions derived from hepatocellular carcinoma (HCC) patients. While transcriptome modulation by TCDD appeared not significantly related to HCC, BaP and BPDE were shown to deregulate metastatic markers via non-genotoxic and genotoxic mechanisms and activate inflammatory pathways (NF-κβ signaling, cytokine-cytokine receptor interaction). BaP also showed strong repression of genes involved in cholesterol and fatty acid biosynthesis. Altogether, this study provides new insights into BaP-induced toxicity and sheds new light onto its mechanism of action as a hepatocarcinogen.
authors.affiliation: Department of Toxicogenomics, Maastricht University, 6229 ER, Maastricht, The Netherlands. terezinhamsouza@gmail.com.|Department of Toxicogenomics, Maastricht University, Universiteitsingel 50, 6200 MD, Maastricht, The Netherlands. terezinhamsouza@gmail.com.
authors.forename: Terezinha
authors.identifier: http://orcid.org/0000-0002-9580-3310
authors.initials: T
authors.lastname: Souza
authors.affiliation: Department of Toxicogenomics, Maastricht University, 6229 ER, Maastricht, The Netherlands.
authors.forename: Danyel
authors.initials: D
authors.lastname: Jennen
authors.affiliation: Department of Toxicogenomics, Maastricht University, 6229 ER, Maastricht, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: van Delft
authors.affiliation: Department of Toxicogenomics, Maastricht University, 6229 ER, Maastricht, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: van Herwijnen
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635, Athens, Greece.
authors.forename: Soterios
authors.initials: S
authors.lastname: Kyrtoupolos
authors.affiliation: Department of Toxicogenomics, Maastricht University, 6229 ER, Maastricht, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Kleinjans
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism / Q000633:toxicity; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D001580:Benzopyrenes / Q000378:metabolism / Q000633:toxicity; D002274:Carcinogens, Environmental / Q000378:metabolism / Q000633:toxicity*; D018736:DNA Adducts / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004101:Dihydroxydihydrobenzopyrenes / Q000378:metabolism / Q000633:toxicity; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics*; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D001580:Benzopyrenes; D002274:Carcinogens, Environmental; D018736:DNA Adducts; D004101:Dihydroxydihydrobenzopyrenes; C020738:9,10-dihydro-9,10-dihydroxybenzo(a)pyrene; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C021338:3-hydroxybenzo(a)pyrene
keywords: BaP metabolites; Benzo(a)pyrene; Hepatocarcinogenesis; Hepatocellular carcinoma; Transcriptomics