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Factors Influencing the Yield of Mutations Induced by Polycyclic Aromatic Hydrocarbons in Mammalian Cells
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Stockholm: Institutionen för genetik, mikrobiologi och toxikologi , 2008. , 144 p.
National Category
Pharmacology and Toxicology
Research subject
Toxicological Genetics
Identifiers
URN: urn:nbn:se:su:diva-7684ISBN: 978-91-7155-615-8 (print)OAI: oai:DiVA.org:su-7684DiVA: diva2:198841
Public defence
2008-06-04, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00
Opponent
Supervisors
Available from: 2008-05-14 Created: 2008-05-08Bibliographically approved
List of papers
1. A method to monitor replication fork progression in mammalian cells: nucleotide excision repair enhances and homologous recombination delays elongation along damaged DNA.
Open this publication in new window or tab >>A method to monitor replication fork progression in mammalian cells: nucleotide excision repair enhances and homologous recombination delays elongation along damaged DNA.
2004 In: Nucleic acids research, Vol. 32, no 20, e157- p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25074 (URN)
Note
Part of urn:nbn:se:su:diva-7684Available from: 2008-05-14 Created: 2008-05-08Bibliographically approved
2. Caffeine delays replication fork progression and enhances UV induced homologous recombination induced in Chinese hamster cell lines.
Open this publication in new window or tab >>Caffeine delays replication fork progression and enhances UV induced homologous recombination induced in Chinese hamster cell lines.
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2006 In: DNA repair and mutagenesis, Vol. 5, no (12), 1449-58 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25075 (URN)
Note
Part of urn:nbn:se:su:diva-7684Available from: 2008-05-14 Created: 2008-05-08Bibliographically approved
3. 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.
Open this publication in new window or tab >>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.
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2008 (English)In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, DNA repair, Vol. 7, no 8, 1202-1012 p.Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Elsevier, 2008
Keyword
Benzo[a]pyrene; Dibenzo[a, l]pyrene; Nucleotide excision repair; DNA adducts; Replication bypass; Mutations
National Category
Biological Sciences
Research subject
Cellbiology
Identifiers
urn:nbn:se:su:diva-25076 (URN)10.1016/j.dnarep.2008.03.022 (DOI)000258259000003 ()
Note
Part of urn:nbn:se:su:diva-7684Available from: 2008-05-14 Created: 2008-05-08 Last updated: 2017-12-13Bibliographically approved
4. Replication bypass, repair efficiency and the yield of mutations per target dose of polycyclic aromatic hydrocarbons in intact mammalian cells.
Open this publication in new window or tab >>Replication bypass, repair efficiency and the yield of mutations per target dose of polycyclic aromatic hydrocarbons in intact mammalian cells.
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Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-25077 (URN)
Note
Part of urn:nbn:se:su:diva-7684Available from: 2008-05-14 Created: 2008-05-08 Last updated: 2010-01-13Bibliographically approved
5. The role of the structure of polycyclic aromatic hydrocarbons for the activity of antimutagens in mammalian cells.
Open this publication in new window or tab >>The role of the structure of polycyclic aromatic hydrocarbons for the activity of antimutagens in mammalian cells.
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Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-25078 (URN)
Note
Part of urn:nbn:se:su:diva-7684Available from: 2008-05-14 Created: 2008-05-08 Last updated: 2010-01-13Bibliographically approved

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