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Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Research Trends and Scientific Gaps

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      Abstract

      Background

      Millions of individuals worldwide, particularly those living in rural and developing areas, are exposed to harmful levels of inorganic arsenic (iAs) in their drinking water. Inorganic As exposure during key developmental periods is associated with a variety of adverse health effects, including those that are evident in adulthood. There is considerable interest in identifying the molecular mechanisms that relate early-life iAs exposure to the development of these latent diseases, particularly in relationship to cancer.

      Objectives

      This work summarizes research on the molecular mechanisms that underlie the increased risk of cancer development in adulthood that is associated with early-life iAs exposure.

      Discussion

      Epigenetic reprogramming that imparts functional changes in gene expression, the development of cancer stem cells, and immunomodulation are plausible underlying mechanisms by which early-life iAs exposure elicits latent carcinogenic effects.

      Conclusions

      Evidence is mounting that relates early-life iAs exposure and cancer development later in life. Future research should include animal studies that address mechanistic hypotheses and studies of human populations that integrate early-life exposure, molecular alterations, and latent disease outcomes.

      Citation

      Bailey KA, Smith AH, Tokar EJ, Graziano JH, Kim KW, Navasumrit P, Ruchirawat M, Thiantanawat A, Suk WA, Fry RC. 2016. Mechanisms underlying latent disease risk associated with early-life arsenic exposure: current research trends and scientific gaps. Environ Health Perspect 124:170–175;  http://dx.doi.org/10.1289/ehp.1409360

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      Most cited references 81

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        Oxygen-free radicals, more generally known as reactive oxygen species (ROS) along with reactive nitrogen species (RNS) are well recognised for playing a dual role as both deleterious and beneficial species. The "two-faced" character of ROS is substantiated by growing body of evidence that ROS within cells act as secondary messengers in intracellular signalling cascades, which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. The cumulative production of ROS/RNS through either endogenous or exogenous insults is termed oxidative stress and is common for many types of cancer cell that are linked with altered redox regulation of cellular signalling pathways. Oxidative stress induces a cellular redox imbalance which has been found to be present in various cancer cells compared with normal cells; the redox imbalance thus may be related to oncogenic stimulation. DNA mutation is a critical step in carcinogenesis and elevated levels of oxidative DNA lesions (8-OH-G) have been noted in various tumours, strongly implicating such damage in the etiology of cancer. It appears that the DNA damage is predominantly linked with the initiation process. This review examines the evidence for involvement of the oxidative stress in the carcinogenesis process. Attention is focused on structural, chemical and biochemical aspects of free radicals, the endogenous and exogenous sources of their generation, the metal (iron, copper, chromium, cobalt, vanadium, cadmium, arsenic, nickel)-mediated formation of free radicals (e.g. Fenton chemistry), the DNA damage (both mitochondrial and nuclear), the damage to lipids and proteins by free radicals, the phenomenon of oxidative stress, cancer and the redox environment of a cell, the mechanisms of carcinogenesis and the role of signalling cascades by ROS; in particular, ROS activation of AP-1 (activator protein) and NF-kappaB (nuclear factor kappa B) signal transduction pathways, which in turn lead to the transcription of genes involved in cell growth regulatory pathways. The role of enzymatic (superoxide dismutase (Cu, Zn-SOD, Mn-SOD), catalase, glutathione peroxidase) and non-enzymatic antioxidants (Vitamin C, Vitamin E, carotenoids, thiol antioxidants (glutathione, thioredoxin and lipoic acid), flavonoids, selenium and others) in the process of carcinogenesis as well as the antioxidant interactions with various regulatory factors, including Ref-1, NF-kappaB, AP-1 are also reviewed.
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          Extensive research during the past 2 decades has revealed the mechanism by which continued oxidative stress can lead to chronic inflammation, which in turn could mediate most chronic diseases including cancer, diabetes, and cardiovascular, neurological, and pulmonary diseases. Oxidative stress can activate a variety of transcription factors including NF-κB, AP-1, p53, HIF-1α, PPAR-γ, β-catenin/Wnt, and Nrf2. Activation of these transcription factors can lead to the expression of over 500 different genes, including those for growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules. How oxidative stress activates inflammatory pathways leading to transformation of a normal cell to tumor cell, tumor cell survival, proliferation, chemoresistance, radioresistance, invasion, angiogenesis, and stem cell survival is the focus of this review. Overall, observations to date suggest that oxidative stress, chronic inflammation, and cancer are closely linked. Copyright © 2010 Elsevier Inc. All rights reserved.
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            Author and article information

            Affiliations
            [1 ]Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, Chapel Hill, North Carolina, USA
            [2 ]Arsenic Health Effects Research Program, School of Public Health, University of California, Berkeley, Berkeley, California, USA
            [3 ]National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina, USA
            [4 ]Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York, USA
            [5 ]School of Environmental Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea
            [6 ]Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, Thailand
            [7 ]Superfund Research Program, NIEHS, NIH, DHHS, Research Triangle Park, North Carolina, USA
            Author notes
            [* ]Address correspondence to R.C. Fry, Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, 135 Dauer Dr., CB 7431, University of North Carolina, Chapel Hill, NC 27599-7295 USA. Telephone: (919) 843-6864. E-mail: rfry@ 123456unc.edu
            Journal
            Environ Health Perspect
            Environ. Health Perspect
            EHP
            Environmental Health Perspectives
            National Institute of Environmental Health Sciences
            0091-6765
            1552-9924
            26 June 2015
            February 2016
            : 124
            : 2
            : 170-175
            26115410 4749078 ehp.1409360 10.1289/ehp.1409360

            Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, “Reproduced with permission from Environmental Health Perspectives”); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright.

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