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Both replication bypass fidelity and repair efficiency influence the yield of mutations per target dose in intact mammalian cells induced by benzo(a)pyrene-diol-epoxide and dibenzo(a,l)-pyrene-diol-epoxide.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
Department of Biosciences and Nutrition, Novum, Karolinska Institute.
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2008 (Engelska)Ingår i: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, DNA repair, Vol. 7, nr 8, s. 1202-1012Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Mutations induced by polycyclic aromatic hydrocarbons (PAH) are expected to be produced when error-prone DNA replication occurs across unrepaired DNA lesions formed by reactive PAH metabolites such as diol epoxides. The mutagenicity of the two PAH-diol epoxides (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DBPDE) was compared in nucleotide excision repair (NER) proficient and deficient hamster cell lines. We applied the 32P-postlabelling assay to analyze adduct levels and the hprt gene mutation assay for monitoring mutations. It was found that the mutagenicity per target dose was 4 times higher for DBPDE compared to BPDE in NER proficient cells while in NER deficient cells, the mutagenicity per target dose was 1.4 times higher for BPDE. 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. The results suggest that NER of BPDE lesions are 5 times more efficient than for DBPDE lesions, in NER proficient cells. However, DBPDE adducts block replication more efficiently and also induce 6 times more recombination events in the hprt gene than adducts of BPDE, suggesting that DBPDE adducts are, to a larger extent, bypassed by homologous recombination. The results obtained here indicate that the mutagenicity of PAH is influenced not only by NER, but also by replication bypass fidelity. This has been postulated earlier based on results using in vitro enzyme assays, but is now also being recognized in terms of forward mutations in intact mammalian cells.

Ort, förlag, år, upplaga, sidor
Elsevier , 2008. Vol. 7, nr 8, s. 1202-1012
Nyckelord [en]
Benzo[a]pyrene; Dibenzo[a, l]pyrene; Nucleotide excision repair; DNA adducts; Replication bypass; Mutations
Nationell ämneskategori
Biologiska vetenskaper
Forskningsämne
cellbiologi
Identifikatorer
URN: urn:nbn:se:su:diva-25076DOI: 10.1016/j.dnarep.2008.03.022ISI: 000258259000003OAI: oai:DiVA.org:su-25076DiVA, id: diva2:198838
Anmärkning
Part of urn:nbn:se:su:diva-7684Tillgänglig från: 2008-05-14 Skapad: 2008-05-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
Ingår i avhandling
1. Factors Influencing the Yield of Mutations Induced by Polycyclic Aromatic Hydrocarbons in Mammalian Cells
Öppna denna publikation i ny flik eller fönster >>Factors Influencing the Yield of Mutations Induced by Polycyclic Aromatic Hydrocarbons in Mammalian Cells
2008 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Environmental contaminants are ubiquitously present in the urban environment, this has the implication that humans are exposed to toxic and carcinogenic chemicals. Polycyclic aromatic hydrocarbons (PAH) are one type of environmental contaminants, which are produced by combustion of organic compounds. A wide variety of different PAH areformed of which most need metabolic activation to be transformed into the ultimate carcinogenic metabolite, a reactive diol epoxide (PAH-DE) that binds to DNA. PAH induced DNA damage is occasionally removed by different repair processes.

This thesis focuses on four PAH-DE(benzo(a)pyrene-diol-epoxide (BPDE), dibenzo(a,l)pyrene-diol-epoxide (DBPDE), dibenzo(a,h)-anthracene-diol-epoxide (DBADE) and benzo(c)phenanthrene-diol-epoxide (BPhDE)) and the role of repair of the induced adducts and their efficiency to induce mutations. The highest level of adducts per µMh was found for the two PAH-DE with fjord region conformation (DBPDE and BPhDE). The highest mutation frequency was exerted by DBPDE followed by BPDE, DBADE and BPhDE explained by differences in both nucleotide excision repair (NER) and replication fidelity. When investigating the repair efficiencies and the effect on replication fork (RF) progression we found that NER enhanced the RF progression whereas HR delayed this process. Inhibition of translesion synthesis was found to delay the RF progression in both wild-type, NER and HR deficient cells. BPDE-induced adducts were most efficiently repaired by NER, whereas DBPDE adducts were not repaired. Antioxidants were tested against PAH-DE mutagenicity and their effects were not dependent on the fjord or bay region structures but on some other property of in the individual compounds.

All together, the results indicate that it is not possible to categorize the mutagenic potency of PAH-DE according to common structural features (bay/fjord), why these compounds need to be evaluated individually.

Ort, förlag, år, upplaga, sidor
Stockholm: Institutionen för genetik, mikrobiologi och toxikologi, 2008. s. 144
Nationell ämneskategori
Farmakologi och toxikologi
Forskningsämne
toxikologisk genetik
Identifikatorer
urn:nbn:se:su:diva-7684 (URN)978-91-7155-615-8 (ISBN)
Disputation
2008-06-04, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00
Opponent
Handledare
Tillgänglig från: 2008-05-14 Skapad: 2008-05-08 Senast uppdaterad: 2018-01-13Bibliografiskt granskad

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Lagerqvist, AnneHåkansson, DanielJenssen, DagTörnqvist, MargaretaErixon, Klaus
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Institutionen för genetik, mikrobiologi och toxikologiInstitutionen för material- och miljökemi (MMK)
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DNA Repair
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