3-Nitrobenzanthrone and 3-aminobenzanthrone induce DNA damage and cell signalling in Hepa1c1c7 cells.

5.00
Hdl Handle:
http://hdl.handle.net/10146/113106
Title:
3-Nitrobenzanthrone and 3-aminobenzanthrone induce DNA damage and cell signalling in Hepa1c1c7 cells.
Authors:
Landvik, N.E.; Arlt, V.M.; Nagy, E.; Solhaug, A.; Tekpli, X.; Schmeiser, H.H.; Refsnes, M.; Phillips, D.H.; Lagadic-Gossmann, D.; Holme, J.A.
Abstract:
3-Nitrobenzanthrone (3-NBA) is a mutagenic and carcinogenic environmental pollutant found in diesel exhaust and urban air pollution. In the present work we have characterised the effects of 3-NBA and its metabolite 3-aminobenzanthrone (3-ABA) on cell death and cytokine release in mouse hepatoma Hepa1c1c7 cells. These effects were related to induced DNA damage and changes in cell signalling pathways. 3-NBA resulted in cell death and caused most DNA damage as judged by the amount of DNA adducts ((32)P-postlabelling assay), single strand (ss)DNA breaks and oxidative DNA lesions (comet assay) detected. An increased phosphorylation of H2AX, chk1, chk2 and partly ATM was observed using flow cytometry and/or Western blotting. Both compounds increased phosphorylation of p53 and MAPKs (ERK, p38 and JNK). However, only 3-NBA caused an accumulation of p53 in the nucleus and a translocation of Bax to the mitochondria. The p53 inhibitor pifithrin-alpha inhibited 3-NBA-induced apoptosis, indicating that cell death was a result of the triggering of DNA signalling pathways. The highest phosphorylation of Akt and degradation of IkappaB-alpha (suggesting activation of NF-kappaB) were also seen after treatment with 3-NBA. In contrast 3-ABA increased IL-6 release, but caused little or no toxicity. Cytokine release was inhibited by PD98059 and curcumin, suggesting that ERK and NF-kappaB play a role in this process. In conclusion, 3-NBA seems to have a higher potency to induce DNA damage compatible with its cytotoxic effects, while 3-ABA seems to have a greater effect on the immune system.
Citation:
Mutat. Res. 2010, 684 (1-2):11-23
Journal:
Mutation Research
Issue Date:
3-Feb-2010
URI:
http://hdl.handle.net/10146/113106
DOI:
10.1016/j.mrfmmm.2009.11.004
PubMed ID:
19941874
Additional Links:
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T2C-4XSJVXK-2&_user=1843694&_coverDate=02%2F03%2F2010&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_acct=C000055040&_version=1&_urlVersion=0&_userid=1843694&md5=f686d440208d7cf623e41bf2eb4897b5&searchtype=a
Type:
Article
Language:
en
ISSN:
0027-5107
Sponsors:
The study has been supported in part by an Aurora grant (Egide) and Cancer Research UK which has been greatly appreciated. Volker M. Arlt, Eszter Nagy and David H. Phillips are member of ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating with the European Union 6th Framework Program, Priority 5: “Food Quality and Safety” (Contract No. 513943). We also thank Leni Ekeren for skilled technical assistance.
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Full metadata record

DC FieldValue Language
dc.contributor.authorLandvik, N.E.en
dc.contributor.authorArlt, V.M.en
dc.contributor.authorNagy, E.en
dc.contributor.authorSolhaug, A.en
dc.contributor.authorTekpli, X.en
dc.contributor.authorSchmeiser, H.H.en
dc.contributor.authorRefsnes, M.en
dc.contributor.authorPhillips, D.H.en
dc.contributor.authorLagadic-Gossmann, D.en
dc.contributor.authorHolme, J.A.en
dc.date.accessioned2010-10-18T08:34:13Z-
dc.date.available2010-10-18T08:34:13Z-
dc.date.issued2010-02-03-
dc.identifier.citationMutat. Res. 2010, 684 (1-2):11-23en
dc.identifier.issn0027-5107-
dc.identifier.pmid19941874-
dc.identifier.doi10.1016/j.mrfmmm.2009.11.004-
dc.identifier.urihttp://hdl.handle.net/10146/113106-
dc.description.abstract3-Nitrobenzanthrone (3-NBA) is a mutagenic and carcinogenic environmental pollutant found in diesel exhaust and urban air pollution. In the present work we have characterised the effects of 3-NBA and its metabolite 3-aminobenzanthrone (3-ABA) on cell death and cytokine release in mouse hepatoma Hepa1c1c7 cells. These effects were related to induced DNA damage and changes in cell signalling pathways. 3-NBA resulted in cell death and caused most DNA damage as judged by the amount of DNA adducts ((32)P-postlabelling assay), single strand (ss)DNA breaks and oxidative DNA lesions (comet assay) detected. An increased phosphorylation of H2AX, chk1, chk2 and partly ATM was observed using flow cytometry and/or Western blotting. Both compounds increased phosphorylation of p53 and MAPKs (ERK, p38 and JNK). However, only 3-NBA caused an accumulation of p53 in the nucleus and a translocation of Bax to the mitochondria. The p53 inhibitor pifithrin-alpha inhibited 3-NBA-induced apoptosis, indicating that cell death was a result of the triggering of DNA signalling pathways. The highest phosphorylation of Akt and degradation of IkappaB-alpha (suggesting activation of NF-kappaB) were also seen after treatment with 3-NBA. In contrast 3-ABA increased IL-6 release, but caused little or no toxicity. Cytokine release was inhibited by PD98059 and curcumin, suggesting that ERK and NF-kappaB play a role in this process. In conclusion, 3-NBA seems to have a higher potency to induce DNA damage compatible with its cytotoxic effects, while 3-ABA seems to have a greater effect on the immune system.en
dc.description.sponsorshipThe study has been supported in part by an Aurora grant (Egide) and Cancer Research UK which has been greatly appreciated. Volker M. Arlt, Eszter Nagy and David H. Phillips are member of ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating with the European Union 6th Framework Program, Priority 5: “Food Quality and Safety” (Contract No. 513943). We also thank Leni Ekeren for skilled technical assistance.en
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T2C-4XSJVXK-2&_user=1843694&_coverDate=02%2F03%2F2010&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_acct=C000055040&_version=1&_urlVersion=0&_userid=1843694&md5=f686d440208d7cf623e41bf2eb4897b5&searchtype=aen
dc.subjectBenz(a)Anthracenesen
dc.subjectEnvironmental Pollutantsen
dc.subjectMutagensen
dc.subjectAnimalsen
dc.subjectMiceen
dc.subjectDNA Damageen
dc.subjectCell Cycleen
dc.subjectChemokine CXCL2en
dc.subject.meshAnimals-
dc.subject.meshBenz(a)Anthracenes-
dc.subject.meshCell Cycle-
dc.subject.meshCell Death-
dc.subject.meshCell Line, Tumor-
dc.subject.meshChemokine CXCL2-
dc.subject.meshDNA Damage-
dc.subject.meshEnvironmental Pollutants-
dc.subject.meshInterleukin-6-
dc.subject.meshLiver Neoplasms, Experimental-
dc.subject.meshMice-
dc.subject.meshMutagens-
dc.subject.meshReceptors, Aryl Hydrocarbon-
dc.subject.meshSignal Transduction-
dc.title3-Nitrobenzanthrone and 3-aminobenzanthrone induce DNA damage and cell signalling in Hepa1c1c7 cells.en
dc.typeArticleen
dc.identifier.journalMutation Researchen

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