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Oxidative DNA damage enhances the carcinogenic potential of in vitro chronic arsenic exposures

  • Inorganic Compounds
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Abstract

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.

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Acknowledgments

We wish to thank Dr. M. Mellone and Dr. GJ. Thomas for his expertise and advice on the cell transformation assays.

Funding

This work was supported by the Generalitat de Catalunya [2009SGR-725]; Universitat Autònoma de Barcelona [APOSTA-2011 to A.H., Post doc-UAB to A.B. and PIF-UAB to J.B. and J.P.] and the Spanish Ministry of Education and Science [SAF2008-02933 and SAF2011-23146].

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Authors and Affiliations

  1. Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, Spain

    Jordi Bach, Jana Peremartí, Balasubramanyam Annangi, Ricard Marcos & Alba Hernández

  2. CIBER Epidemiología y Salud Pública, ISCIII, Madrid, Spain

    Ricard Marcos & Alba Hernández

  3. Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Edifici Cn, Campus de Bellaterra, 08193, Cerdanyola del Vallès, Barcelona, Spain

    Ricard Marcos & Alba Hernández

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  1. Jordi Bach
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  2. Jana Peremartí
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  4. Ricard Marcos
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Correspondence to Ricard Marcos.

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Bach, J., Peremartí, J., Annangi, B. et al. Oxidative DNA damage enhances the carcinogenic potential of in vitro chronic arsenic exposures. Arch Toxicol 90, 1893–1905 (2016). https://doi.org/10.1007/s00204-015-1605-7

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