Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis
Δημιουργός/Συγγραφέας:	Souza, Terezinha Jennen, Danyel Van Delft, Joost Van Herwijnen, Marcel [EL] Κυρτόπουλος, Σωτήριος Α.[EN] Kyrtopoulos, Soterios A. Kleinjans, Jos
Εκδότης:	Springer Verlag
Ημερομηνία:	2016
Γλώσσα:	Αγγλικά
ISSN:	0340-5761
DOI:	10.1007/s00204-015-1572-z
Άλλο:	PubMed ID: 26238291
Περίληψη:	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.
Τίτλος πηγής δημοσίευσης:	Archives of Toxicology
Τόμος/Κεφάλαιο:	90
Τεύχος:	6
Σελίδες:	1449-1458
Θεματική Κατηγορία:	[EL] Τοξικολογία[EN] Toxicology. Poisons
Λέξεις-Κλειδιά:	BaP metabolites Benzo(a)pyrene Hepatocarcinogenesis Hepatocellular carcinoma Transcriptomics
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
Κάτοχος πνευματικών δικαιωμάτων:	© 2015, The Author(s).
Όροι και προϋποθέσεις δικαιωμάτων:	All Open Access, Hybrid Gold, Green
Σημειώσεις:	Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο