Oxidative DNA damage enhances the carcinogenic potential of in vitro chronic arsenic exposures
| Autor: | Balasubramanyam Annangi, Ricard Marcos, Alba Hernández, Jordi Bach, Jana Peremartí |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Sodium arsenite Arsenites Health Toxicology and Mutagenesis Blotting Western Matrix metalloproteinase Biology Real-Time Polymerase Chain Reaction Toxicology medicine.disease_cause DNA Glycosylases Mice 03 medical and health sciences chemistry.chemical_compound medicine Animals Humans Zymography Carcinogen Cell Proliferation Arsenite Dose-Response Relationship Drug Cell growth General Medicine Fibroblasts HCT116 Cells Sodium Compounds Molecular biology Carcinogens Environmental In vitro Oxidative Stress 030104 developmental biology chemistry Gene Knockdown Techniques Environmental Pollutants Carcinogenesis DNA Damage HeLa Cells |
| Zdroj: | Archives of Toxicology. 90:1893-1905 |
| ISSN: | 1432-0738 0340-5761 |
| Popis: | Chronic exposure to arsenic is known to increase the incidence of cancer in humans. Our previous work demonstrated that environmentally relevant arsenic exposures generate an accelerated accumulation of pre-carcinogen 8-OH-dG DNA lesions under Ogg1-deficient backgrounds, but it remains unproved whether this observed arsenic-induced oxidative DNA damage (ODD) is certainly important in terms of cancer. Here, isogenic MEF Ogg1 +/+ cells and MEF Ogg1 −/− cells—unable to properly eliminate 8-OH-dG from DNA—were exposed to 0.5, 1 and 2 µM of sodium arsenite for 40 weeks. The acquisition of an in vitro cancer-like phenotype was assessed throughout the exposure; matrix metalloproteinase (MMP) activities were measured by zymography, colony formation and promotion were evaluated by soft agar assay, and cellular invasiveness was measured by the transwell assay. Alterations in cellular morphology, growth and differentiation status were also included as complementary measures of transformation. MEF Ogg1 −/− cells showed a cancer-associated phenotype after 30 weeks of exposure, as indicated by morphological changes, increased proliferation, deregulated differentiation status, increased MMPs secretion, anchorage-independent cell growth and enhancement of tumor growth and invasiveness. Conversely, MEF Ogg1 +/+ cells did not present changes in morphology or proliferation, exhibited a milder degree of gene deregulation and needed 10 weeks of additional exposure to the highest arsenite doses to show tumor enhancing effects. Thus, Ogg1 genetic background and arsenic-induced 8-OH-dG proved relevant for arsenic-mediated carcinogenic effects. To our knowledge, this is the first study directly linking ODD with arsenic carcinogenesis. |
| Databáze: | OpenAIRE |
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