1. Home page
  2. Search

New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis

This item is provided by the institution :
National Hellenic Research Foundation (NHRF)   

Repository :
Helios - Repository of the National Hellenic Research Foundation (NHRF)  | repositories EKT   

see the original item page
in the repository's web site and access all digital files if the item*



New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis
Van Herwijnen, Marcel
Van Delft, Joost
Kleinjans, Jos
Souza, Terezinha
Κυρτόπουλος, Σωτήριος Α.
Jennen, Danyel
Άρθρο σε επιστημονικό περιοδικό
2016
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.
Τοξικολογία (EL)
Toxicology. Poisons (EN)
Hepatocarcinogenesis (EN)
Transcriptomics (EN)
Hepatocellular carcinoma (EN)
Benzo(a)pyrene (EN)
BaP metabolites (EN)
English
Springer Verlag
Archives of Toxicology
© 2015, The Author(s).
National Hellenic Research Foundation (NHRF)
Helios - Repository of the National Hellenic Research Foundation (NHRF)



*Institutions are responsible for keeping their URLs functional (digital file, item page in repository site)