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      Challenging the Metallothionein ( MT) Gene of Biomphalaria glabrata: Unexpected Response Patterns Due to Cadmium Exposure and Temperature Stress

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          Abstract

          Metallothioneins (MTs) are low-molecular-mass, cysteine-rich, metal binding proteins. In most animal species, they are involved in metal homeostasis and detoxification, and provide protection from oxidative stress. Gastropod MTs are highly diversified, exhibiting unique features and adaptations like metal specificity and multiplications of their metal binding domains. Here, we show that the MT gene of Biomphalaria glabrata, one of the largest MT genes identified so far, is composed in a unique way. The encoding for an MT protein has a three-domain structure and a C-terminal, Cys-rich extension. Using a bioinformatic approach involving structural and in silico analysis of putative transcription factor binding sites (TFBs), we found that this MT gene consists of five exons and four introns. It exhibits a regulatory promoter region containing three metal-responsive elements (MREs) and several TFBs with putative involvement in environmental stress response, and regulation of gene expression. Quantitative real-time polymerase chain reaction (qRT-PCR) data indicate that the MT gene is not inducible by cadmium (Cd) nor by temperature challenges (heat and cold), despite significant Cd uptake within the midgut gland and the high Cd tolerance of metal-exposed snails.

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          Metallothionein: an intracellular protein to protect against cadmium toxicity.

          Metallothioneins (MT) are low-molecular-weight, cysteine-rich, metal-binding proteins. MT genes are readily induced by various physiologic and toxicologic stimuli. Because the cysteines in MT are absolutely conserved across species, it was suspected that the cysteines are necessary for function and MT is essential for life. In attempts to determine the function(s) of MT, studies have been performed using four different experimental paradigms: (a) animals injected with chemicals known to induce MT; (b) cells adapted to survive and grow in high concentrations of MT-inducing toxicants; (c) cells transfected with the MT gene; and (d) MT-transgenic and MT-null mice. Most often, results from studies using the first three approaches have indicated multiple functions of MT in cell biology: MT (a) is a "storehouse" for zinc, (b) is a free-radical scavenger, and (c) protects against cadmium (Cd) toxicity. However, studies using MT-transgenic and null mice have not strongly supported the first two proposed functions but strongly support its function in protecting against Cd toxicity. Repeated administration of Cd to MT-null mice results in nephrotoxicity at one tenth the dose that produces nephrotoxicity in control mice. Human studies indicate that 7% of the general population have renal dysfunction from Cd exposure. Therefore, if humans did not have MT, "normal" Cd exposure would be nephrotoxic to humans. Thus, it appears that during evolution, the ability of MT to protect against Cd toxicity might have taken a more pivotal role in the maintenance of life processes, as compared with its other proposed functions (i.e. storehouse for zinc and free radical scavenger).
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            Trace metal concentrations in aquatic invertebrates: why and so what?

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              The global burden of neglected tropical diseases.

              A Fenwick (2012)
              The first comprehensive study on the global burden of disease and risk factors was commissioned by the World Bank in 1992. A follow-up study was performed in 2005, and another iteration was commissioned by the World Health Organization in 2010, due for publication in 2011. The author suggests that the global burden of neglected tropical diseases (NTDs) has been seriously underestimated. The way forward is the integration of control efforts, with programmes coming together to deliver a package of drugs against NTDs. Barriers to continent-wide coverage of drugs against NTDs are political will (missing in those countries with poor governance), funding (approximately half of the $1.5-2 billion is needed) and human resources. However, if the donors who give so much to malaria, tuberculosis and human immunodeficiency virus would share just 10% of the amount allocated to the big three, the most common NTDs could become diseases of the past. This could well happen within 7 years, and the targets of GET2020 (Global Elimination of Trachoma by 2020) to eliminate trachoma and GAELF (the Global Alliance to Eliminate Lymphatic Filariasis) to eliminate lymphatic filariasis by 2020 are achievable. Copyright © 2011 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                11 August 2017
                August 2017
                : 18
                : 8
                : 1747
                Affiliations
                Institute of Zoology and Center of Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Technikerstrasse 25, A-6020 Innsbruck, Austria; michael.niederwanger@ 123456uibk.ac.at (M.N.); martin.dvorak@ 123456uibk.ac.at (M.D.); raimund.schnegg@ 123456uibk.ac.at (R.S.); Veronika.Pedrini-Martha@ 123456uibk.ac.at (V.P.-M.); csap9255@ 123456student.uibk.ac.at (K.B.); massimo.bidoli@ 123456student.uibk.ac.at (M.B.)
                Author notes
                [* ]Correspondence: reinhard.dallinger@ 123456uibk.ac.at ; Tel.: +43-512-507-51861; Fax: +43-512-507-51899
                Author information
                https://orcid.org/0000-0002-7229-4146
                Article
                ijms-18-01747
                10.3390/ijms18081747
                5578137
                28800079
                e57d3f04-1147-4817-aa68-7a129c1b63fd
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 July 2017
                : 07 August 2017
                Categories
                Article

                Molecular biology
                metallothionein,metal binding domain,cadmium tolerance,heat shock,cold shock,biomphalaria glabrata,gastropoda,hygrophila

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