Benzo[a]pyrene increases DNA double strand break repair in vitro and in vivo: a possible mechanism for benzo[a]pyrene-induced toxicity
| Autor: | Emily W.Y. Tung, Nicola A. Philbrook, Louise M. Winn, Christine L. Belanger, Saad Ansari |
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| Rok vydání: | 2013 |
| Předmět: |
Male
animal structures DNA Repair DNA repair Health Toxicology and Mutagenesis Blotting Western Gene Expression Mice Transgenic Ataxia Telangiectasia Mutated Proteins CHO Cells Thymus Gland Biology Kidney complex mixtures chemistry.chemical_compound Mice Cricetulus Cricetinae polycyclic compounds Genetics Benzo(a)pyrene Animals DNA Breaks Double-Stranded Homologous Recombination Ku Autoantigen Lung Carcinogen Reverse Transcriptase Polymerase Chain Reaction Antigens Nuclear DNA Repair Pathway beta-Galactosidase Molecular biology Double Strand Break Repair Non-homologous end joining DNA-Binding Proteins chemistry Liver embryonic structures Tumor Suppressor Protein p53 Homologous recombination DNA Spleen Signal Transduction |
| Zdroj: | Mutation research. Genetic toxicology and environmental mutagenesis. 760 |
| ISSN: | 1383-5718 |
| Popis: | Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon and carcinogen that is released into the environment through natural and anthropogenic sources. BaP toxicity is dependent on its metabolism by cytochrome P450s to the reactive metabolite benzo[a]pyrene diol epoxide (BPDE), which is strongly associated with increased mutation frequency. BaP can also be metabolized to benzo[a]pyrene quinones that can undergo redox cycling and induce oxidative stress. The purpose of this study was to examine if BaP exposure induces DNA double strand breaks (DSBs) and subsequently activate DNA DSB repair pathways in the CHO 3–6 cell line and pKZ1 mouse model. In vitro assessment of homologous recombination (HR) showed significantly increased HR frequency following exposure to 10 μM of BaP. In vivo evaluations of BaP-induced DNA DSB repair demonstrated positive staining for intrachromosomal recombination events, which are associated with non-homologous end joining (NHEJ), in the lung and thymus of exposed animals that were statistically significant in the thymus when quantified by Western blotting. Gene expression analyses from mouse tissues showed significantly decreased expression of ATM and Xrcc6 in BaP-treated liver and lung. In addition, BaP exposure significantly reduced the expression of Xrcc5, p53, and DNA-PKcs in lung. Taken together, our results demonstrate that BaP increases DNA DSB repair in vitro and in vivo, and induces expression changes in DNA repair pathway genes. As repair of DNA DSBs is not error-free, aberrant DNA repair may be contributing to the mechanism of BaP-induced toxicity. |
| Databáze: | OpenAIRE |
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