Article

Requirement of Arsenic Biomethylation for Oxidative DNA Damage

Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, Center for Cancer Research, National Cancer Institute at National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Journal of the National Cancer Institute (Impact Factor: 12.58). 11/2009; 101(24):1670-81. DOI: 10.1093/jnci/djp414
Source: PubMed

ABSTRACT

Background Inorganic arsenic is an environmental carcinogen that may act through multiple mechanisms including formation of methylated
derivatives in vivo. Sodium arsenite (up to 5.0 μM) renders arsenic methylation–competent TRL1215 rat liver epithelial cells
tumorigenic in nude mice at 18 weeks of exposure and arsenic methylation-deficient RWPE-1 human prostate epithelial cells
tumorigenic at 30 weeks of exposure. We assessed the role of arsenic biomethylation in oxidative DNA damage (ODD) using a
recently developed immuno-spin trapping method.

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    • "Other reports have previously indicated that ODD is meaningful for arsenic-induced cancer and disease, although based on indirect evidences. Among them, the work of Kojima et al. (2009) showed that chronic arsenite exposure of methylation-competent cells was followed by a rise in ODD with a subsequent acquisition of the in vitro characteristics of transformed cells. Results lead authors to conclude that biomethylation of arsenic compounds appear to be mandatory for ODD generation and linked to an increase in their carcinogenicity (Sampayo-Reyes et al. 2010). "
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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 arsenicinduced 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-OHdG 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, de-regulated 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 de-regulation and needed 10 weeks of additional exposure to the highest arsenite doses to show tumor enhancing effects. Thus, Ogg1 genetic background and arsenicinduced 8-OH-dG proved relevant for arsenic-mediated carcinogenic effects. To our knowledge, this is the first study directly linking ODD with arsenic carcinogenesis. Key words: arsenic, Ogg1, 8-OH-dG, carcinogenesis, oxidative DNA damage, fibroblasts, chronic exposure.
    Full-text · Article · Sep 2015 · Archives of Toxicology
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    • "After entering the cells, arsenic undergoes methylation reaction by the arsenite methyltransferase (AS3MT) enzyme producing several methylated arsenic compounds (Kojima et al., 2009). Arsenic methylation was initially believed to be a detoxification reaction (Gebel, 2002), but more recent evidence invalidated such a hypothesis showing an increased toxicity of specific methylated intermediate metabolites (Kojima et al., 2009; Sun et al., 2014). "
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    ABSTRACT: A complex interplay between multiple biological effects shapes the aging process. The advent of genome-wide quantitative approaches in the epigenetic field has highlighted the effective impact of epigenetic deregulation, particularly of DNA methylation, on aging. Age-associated alterations in DNA methylation are commonly grouped in the phenomenon known as "epigenetic drift" which is characterized by gradual extensive demethylation of genome and hypermethylation of a number of promoter-associated CpG islands. Surprisingly, specific DNA regions show directional epigenetic changes in aged individuals suggesting the importance of these events for the aging process. However, the epigenetic information obtained until now in aging needs a re-consideration due to the recent discovery of 5-hydroxymethylcytosine, a new DNA epigenetic mark present on genome. A recapitulation of the factors involved in the regulation of DNA methylation and the changes occurring in aging will be described in this review also considering the data available on 5hmC in aging. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Full-text · Article · Feb 2015 · Mechanisms of Ageing and Development
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    • "Numerous studies have indicated that arsenic induces DNA damage (Kessel et al., 2002; Bhadauria and Flora, 2007; Lee and Ho, 1995; Dong and Luo, 1993; Kojima et al., 2009) and chromosome aberration such as chromosomal aneuploidy (Ochi et al., 1984; Sciandrello et al., 2002, 2004). MMA and DMA are directly genotoxic (Mass et al., 2001). "
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    ABSTRACT: Chronic exposure to arsenic may cause cancer. Many mechanisms have been suggested for arsenic carcinogenesis. Autophagy, an evolutionarily conserved cellular catabolic mechanism, has been implicated in cancer biology. Although being claimed as a type of cell death, autophagy may actually serve as a cell self-defense mechanism. In this review article, current understandings of the mechanisms of arsenic carcinogenesis, functions of autophagy and the role of autophagy in arsenic carcinogenesis are discussed.
    Full-text · Article · Jul 2014 · Experimental and toxicologic pathology: official journal of the Gesellschaft fur Toxikologische Pathologie
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