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Urinary Metabolomics Revealed Arsenic Internal Dose-Related Metabolic Alterations: A Proof-of-Concept Study in a Chinese Male Cohort

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      Abstract

      Urinary biomonitoring provides the most accurate arsenic exposure assessment; however, to improve the risk assessment, arsenic-related metabolic biomarkers are required to understand the internal processes that may be perturbed, which may, in turn, link the exposure to a specific health outcome. This study aimed to investigate arsenic-related urinary metabolome changes and identify dose-dependent metabolic biomarkers as a proof-of-concept of the information that could be obtained by combining metabolomics and targeted analyses. Urinary arsenic species such as inorganic arsenic, methylarsonic acid, dimethylarsinic acid and arsenobetaine were quantified using high performance liquid chromatography (HPLC)-inductively coupled plasma-mass spectrometry in a Chinese adult male cohort. Urinary metabolomics was conducted using HPLC-quadrupole time-of-flight mass spectrometry. Arsenic-related metabolic biomarkers were investigated by comparing the samples of the first and fifth quintiles of arsenic exposure classifications using a partial least-squares discriminant model. After the adjustments for age, body mass index, smoking, and alcohol consumption, five potential biomarkers related to arsenic exposure (i.e., testosterone, guanine, hippurate, acetyl-N-formyl-5-methoxykynurenamine, and serine) were identified from 61 candidate metabolites; these biomarkers suggested that endocrine disruption and oxidative stress were associated with urinary arsenic levels. Testosterone, guanine, and hippurate showed a high or moderate ability to discriminate the first and fifth quintiles of arsenic exposure with area-under-curve (AUC) values of 0.89, 0.87, and 0.83, respectively; their combination pattern showed an AUC value of 0.91 with a sensitivity of 88% and a specificity of 80%. Arsenic dose-dependent AUC value changes were also observed. This study demonstrated that metabolomics can be used to investigate arsenic-related biomarkers of metabolic changes; the dose-dependent trends of arsenic exposure to these biomarkers may translate into the potential use of metabolic biomarkers in arsenic risk assessment. Since this was a proof-of-concept study, more research is needed to confirm the relationships we observed between arsenic exposure and biochemical changes.

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      Most cited references 46

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        Melatonin has been shown to protect against oxidative stress in various, highly divergent experimental systems. There are many reasons for its remarkable protective potential. Signaling effects comprise the upregulation of antioxidant enzymes, such as superoxide dismutases, peroxidases, and enzymes of glutathione supply, down-regulation of prooxidant enzymes, such as nitric oxide synthases and lipoxygenases, and presumably also the control of quinone reductase 2. Other mechanisms are based on direct interactions with several reactive oxygen and nitrogen species. Among these reactions, the capacity of easily undergoing single-electron transfer reactions is of particular importance. Electron donation by melatonin is not only an aspect of direct radical scavenging, but additionally represents the basis for formation of the protective metabolites AFMK (N1-ace-tyl-N2-formyl-5-methoxykynuramine) and AMK (N1-acetyl-5-methoxykynuramine). Recent investigations on mitochondrial metabolism indicate that melatonin as well as AMK are capable of supporting the electron flux through the respiratory chain, of preventing the breakdown of the mitochondrial membrane potential, and of decreasing electron leakage, thereby reducing the formation of superoxide anions. Radical avoidance is a new line of investigation, which exceeds mitochondrial actions and also comprises antiexcitatory effects and contributions to the maintenance of internal circadian phase relationships.
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          The metalloid arsenic is a natural environmental contaminant to which humans are routinely exposed in food, water, air, and soil. Arsenic has a long history of use as a homicidal agent, but in the past 100 years arsenic, has been used as a pesticide, a chemotherapeutic agent and a constituent of consumer products. In some areas of the world, high levels of arsenic are naturally present in drinking water and are a toxicological concern. There are several structural forms and oxidation states of arsenic because it forms alloys with metals and covalent bonds with hydrogen, oxygen, carbon, and other elements. Environmentally relevant forms of arsenic are inorganic and organic existing in the trivalent or pentavalent state. Metabolism of arsenic, catalyzed by arsenic (+3 oxidation state) methyltransferase, is a sequential process of reduction from pentavalency to trivalency followed by oxidative methylation back to pentavalency. Trivalent arsenic is generally more toxicologically potent than pentavalent arsenic. Acute effects of arsenic range from gastrointestinal distress to death. Depending on the dose, chronic arsenic exposure may affect several major organ systems. A major concern of ingested arsenic is cancer, primarily of skin, bladder, and lung. The mode of action of arsenic for its disease endpoints is currently under study. Two key areas are the interaction of trivalent arsenicals with sulfur in proteins and the ability of arsenic to generate oxidative stress. With advances in technology and the recent development of animal models for arsenic carcinogenicity, understanding of the toxicology of arsenic will continue to improve.
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            Author and article information

            Affiliations
            []Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences , 1799 Jimei Road, Xiamen, Fujian 350002, China
            []Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University , Nanjing, Jiangsu 210029, China
            [§ ]Rollins School of Public Health, Emory University , Atlanta, Georgia 30322, United States
            Author notes
            [* ]Phone: (86)-592-6190997; fax: (86)-592-6190997; e-mail: hqshen@ 123456iue.ac.cn .
            Journal
            Environ Sci Technol
            Environ. Sci. Technol
            es
            esthag
            Environmental Science & Technology
            American Chemical Society
            0013-936X
            1520-5851
            18 September 2015
            18 September 2014
            21 October 2014
            : 48
            : 20
            : 12265-12274
            25233106
            4204897
            10.1021/es503659w
            Copyright © 2014 American Chemical Society

            Terms of Use

            Funding
            National Institutes of Health, United States
            Categories
            Article
            Custom metadata
            es503659w
            es-2014-03659w

            General environmental science

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