DNA repair and replication influence the number of mutations per adduct of polycyclic aromatic hydrocarbons in mammalian cells.

2.50
Hdl Handle:
http://hdl.handle.net/10146/196510
Title:
DNA repair and replication influence the number of mutations per adduct of polycyclic aromatic hydrocarbons in mammalian cells.
Authors:
Lagerqvist, Anne; Håkansson, Daniel; Lundin, Cecilia; Prochazka, Gabriela; Dreij, Kristian; Segerbäck, Dan; Jernström, Bengt; Törnqvist, Margareta; Frank, Heinz; Seidel, Albrecht; Erixon, Klaus; Jenssen, Dag
Abstract:
Polycyclic aromatic hydrocarbons (PAH) are an important class of environmental contaminants many of which require metabolic activation to DNA-reactive bay or fjord region diolepoxides (DE) in order to exert their mutagenic and carcinogenic effects. In this study, the mutagenicity of the bay region diolepoxides (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and (±)-anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrodibenzo[a,h]anthracene (DBADE) and the fjord region diolepoxides (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]-pyrene (DBPDE) and (±)-anti-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]-phenanthrene (BPhDE) was compared in nucleotide excision repair (NER) proficient and deficient hamster cell lines. The (32)P-postlabelling assay was applied to analyze DNA adduct levels and the Hprt gene mutation assay for monitoring mutations. Previously, we found that the mutagenicity per adduct was four times higher for DBPDE compared to BPDE in NER proficient cells. In these same cells, the mutagenicity of DBADE and BPhDE adducts was now found to be significantly lower compared to that of BPDE. In NER deficient cells the highest mutagenicity per adduct was found for BPDE and there was a tenfold and fivefold difference when comparing the BPDE data with the DBADE and BPhDE data, respectively. In order to investigate to what extent the mutagenicity of the different adducts in NER proficient cells was influenced by repair or replication bypass, we measured the overall NER incision rate, the rate of adduct removal, the rate of replication bypass and the frequency of induced recombination in the Hprt gene. Since NER turned out to be an important pathway for the yield of mutations, we further analyzed the role of transcription coupled NER versus global genome NER. However, our data demonstrate that neither of these pathways seems to be the sole factor determining the mutation frequency of the four PAH-DE and that the differences in the repair efficiency of these compounds could not be related to the presence of a bay or fjord region in the parent PAH.
Citation:
DNA Repair (Amst.) 2011, 10 (8):877-886
Journal:
DNA Repair
Issue Date:
15-Aug-2011
URI:
http://hdl.handle.net/10146/196510
DOI:
10.1016/j.dnarep.2011.06.002
PubMed ID:
21727035
Additional Links:
http://www.sciencedirect.com/science/article/pii/S1568786411001546
Type:
Article
Language:
en
ISSN:
1568-7856
Sponsors:
This work was supported by The European Commission; projects AMBIPAH (QLK4-CT-2002-02402), DIEPHY (FOOD-CT-2003-505609), ECNIS (FOOD-CT-2005-513943) and The Swedish Research Council Formas.
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorLagerqvist, Anneen
dc.contributor.authorHåkansson, Danielen
dc.contributor.authorLundin, Ceciliaen
dc.contributor.authorProchazka, Gabrielaen
dc.contributor.authorDreij, Kristianen
dc.contributor.authorSegerbäck, Danen
dc.contributor.authorJernström, Bengten
dc.contributor.authorTörnqvist, Margaretaen
dc.contributor.authorFrank, Heinzen
dc.contributor.authorSeidel, Albrechten
dc.contributor.authorErixon, Klausen
dc.contributor.authorJenssen, Dagen
dc.date.accessioned2011-12-08T12:51:57Z-
dc.date.available2011-12-08T12:51:57Z-
dc.date.issued2011-08-15-
dc.identifier.citationDNA Repair (Amst.) 2011, 10 (8):877-886en
dc.identifier.issn1568-7856-
dc.identifier.pmid21727035-
dc.identifier.doi10.1016/j.dnarep.2011.06.002-
dc.identifier.urihttp://hdl.handle.net/10146/196510-
dc.description.abstractPolycyclic aromatic hydrocarbons (PAH) are an important class of environmental contaminants many of which require metabolic activation to DNA-reactive bay or fjord region diolepoxides (DE) in order to exert their mutagenic and carcinogenic effects. In this study, the mutagenicity of the bay region diolepoxides (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and (±)-anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrodibenzo[a,h]anthracene (DBADE) and the fjord region diolepoxides (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]-pyrene (DBPDE) and (±)-anti-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]-phenanthrene (BPhDE) was compared in nucleotide excision repair (NER) proficient and deficient hamster cell lines. The (32)P-postlabelling assay was applied to analyze DNA adduct levels and the Hprt gene mutation assay for monitoring mutations. Previously, we found that the mutagenicity per adduct was four times higher for DBPDE compared to BPDE in NER proficient cells. In these same cells, the mutagenicity of DBADE and BPhDE adducts was now found to be significantly lower compared to that of BPDE. In NER deficient cells the highest mutagenicity per adduct was found for BPDE and there was a tenfold and fivefold difference when comparing the BPDE data with the DBADE and BPhDE data, respectively. In order to investigate to what extent the mutagenicity of the different adducts in NER proficient cells was influenced by repair or replication bypass, we measured the overall NER incision rate, the rate of adduct removal, the rate of replication bypass and the frequency of induced recombination in the Hprt gene. Since NER turned out to be an important pathway for the yield of mutations, we further analyzed the role of transcription coupled NER versus global genome NER. However, our data demonstrate that neither of these pathways seems to be the sole factor determining the mutation frequency of the four PAH-DE and that the differences in the repair efficiency of these compounds could not be related to the presence of a bay or fjord region in the parent PAH.en
dc.description.sponsorshipThis work was supported by The European Commission; projects AMBIPAH (QLK4-CT-2002-02402), DIEPHY (FOOD-CT-2003-505609), ECNIS (FOOD-CT-2005-513943) and The Swedish Research Council Formas.en
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science/article/pii/S1568786411001546en
dc.subjectPolycyclic aromatic hydrocarbonsen
dc.subjectNucleotide excision repairen
dc.subjectDNA adductsen
dc.subjectReplication bypassen
dc.subjectMutationsen
dc.subjectMutagenicityen
dc.subject.mesh7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxideen
dc.subject.meshAnimalsen
dc.subject.meshBenz(a)Anthracenesen
dc.subject.meshCell Lineen
dc.subject.meshCricetinaeen
dc.subject.meshDNA Adductsen
dc.subject.meshDNA Repairen
dc.subject.meshDNA Replicationen
dc.subject.meshDose-Response Relationship, Drugen
dc.subject.meshEpoxy Compoundsen
dc.subject.meshHalf-Lifeen
dc.subject.meshMutagensen
dc.subject.meshMutationen
dc.subject.meshPolycyclic Hydrocarbons, Aromaticen
dc.titleDNA repair and replication influence the number of mutations per adduct of polycyclic aromatic hydrocarbons in mammalian cells.en
dc.typeArticleen
dc.identifier.journalDNA Repairen
All Items in ECNIS-NIOM are protected by copyright, with all rights reserved, unless otherwise indicated.