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      Amino Acid Transporter LAT1 (SLC7A5) Mediates MeHg-Induced Oxidative Stress Defense in the Human Placental Cell Line HTR-8/SVneo

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          Abstract

          The placental barrier can protect the fetus from contact with harmful substances. The potent neurotoxin methylmercury (MeHg), however, is very efficiently transported across the placenta. Our previous data suggested that L-type amino acid transporter (LAT)1 is involved in placental MeHg uptake, accepting MeHg-L-cysteine conjugates as substrate due to structural similarity to methionine. The aim of the present study was to investigate the antioxidant defense of placental cells to MeHg exposure and the role of LAT1 in this response. When trophoblast-derived HTR-8/SVneo cells were LAT1 depleted by siRNA-mediated knockdown, they accumulated less MeHg. However, they were more susceptible to MeHg-induced toxicity. This was evidenced in decreased cell viability at a usually noncytotoxic concentration of 0.03 µM MeHg (~6 µg/L). Treatment with ≥0.3 µM MeHg increased cytotoxicity, apoptosis rate, and oxidative stress of HTR-8/SVneo cells. These effects were enhanced under LAT1 knockdown. Reduced cell number was seen when MeHg-exposed cells were cultured in medium low in cysteine, a constituent of the tripeptide glutathione (GSH). Because LAT1-deficient HTR-8/SVneo cells have lower GSH levels than control cells (independent of MeHg treatment), we conclude that LAT1 is essential for de novo synthesis of GSH, required to counteract oxidative stress. Genetic predisposition to decreased LAT1 function combined with MeHg exposure could increase the risk of placental damage.

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          Glutathione synthesis.

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          Glutathione (GSH) is present in all mammalian tissues as the most abundant non-protein thiol that defends against oxidative stress. GSH is also a key determinant of redox signaling, vital in detoxification of xenobiotics, and regulates cell proliferation, apoptosis, immune function, and fibrogenesis. Biosynthesis of GSH occurs in the cytosol in a tightly regulated manner. Key determinants of GSH synthesis are the availability of the sulfur amino acid precursor, cysteine, and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL), which is composed of a catalytic (GCLC) and a modifier (GCLM) subunit. The second enzyme of GSH synthesis is GSH synthetase (GS). This review summarizes key functions of GSH and focuses on factors that regulate the biosynthesis of GSH, including pathological conditions where GSH synthesis is dysregulated. GCL subunits and GS are regulated at multiple levels and often in a coordinated manner. Key transcription factors that regulate the expression of these genes include NF-E2 related factor 2 (Nrf2) via the antioxidant response element (ARE), AP-1, and nuclear factor kappa B (NFκB). There is increasing evidence that dysregulation of GSH synthesis contributes to the pathogenesis of many pathological conditions. These include diabetes mellitus, pulmonary and liver fibrosis, alcoholic liver disease, cholestatic liver injury, endotoxemia and drug-resistant tumor cells. GSH is a key antioxidant that also modulates diverse cellular processes. A better understanding of how its synthesis is regulated and dysregulated in disease states may lead to improvement in the treatment of these disorders. This article is part of a Special Issue entitled Cellular functions of glutathione. Copyright © 2012 Elsevier B.V. All rights reserved.
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            Glutathione: new roles in redox signaling for an old antioxidant

            The physiological roles played by the tripeptide glutathione have greatly advanced over the past decades superimposing the research on free radicals, oxidative stress and, more recently, redox signaling. In particular, GSH is involved in nutrient metabolism, antioxidant defense, and regulation of cellular metabolic functions ranging from gene expression, DNA and protein synthesis to signal transduction, cell proliferation and apoptosis. This review will be focused on the role of GSH in cell signaling by analysing the more recent advancements about its capability to modulate nitroxidative stress, autophagy, and viral infection.
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              This review covers the toxicology of mercury and its compounds. Special attention is paid to those forms of mercury of current public health concern. Human exposure to the vapor of metallic mercury dates back to antiquity but continues today in occupational settings and from dental amalgam. Health risks from methylmercury in edible tissues of fish have been the subject of several large epidemiological investigations and continue to be the subject of intense debate. Ethylmercury in the form of a preservative, thimerosal, added to certain vaccines, is the most recent form of mercury that has become a public health concern. The review leads to general discussion of evolutionary aspects of mercury, protective and toxic mechanisms, and ends on a note that mercury is still an "element of mystery."
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                08 February 2021
                February 2021
                : 22
                : 4
                : 1707
                Affiliations
                [1 ]Karl-Landsteiner Private University for Health Sciences, A-3500 Krems, Austria; sebastian.granitzer@ 123456kl.ac.at (S.G.); raimund.widhalm@ 123456kl.ac.at (R.W.)
                [2 ]Institute of Medical Genetics, Medical University of Vienna, A-1090 Vienna, Austria; martin.forsthuber@ 123456meduniwien.ac.at (M.F.); markus.hengstschlaeger@ 123456meduniwien.ac.at (M.H.)
                [3 ]Department of Pathophysiology and Allergy Research, Medical University of Vienna, A-1090 Vienna, Austria; isabella.ellinger@ 123456meduniwien.ac.at
                [4 ]Department of Obstetrics and Gynecology, Medical University of Graz, A-8036 Graz, Austria; gernot.desoye@ 123456medunigraz.at
                [5 ]Department of Obstetrics and Gynecology, Medical University Vienna, A-1090 Vienna, Austria; harald.zeisler@ 123456meduniwien.ac.at
                [6 ]Clinical Department of Pediatrics and Adolescent Medicine, University Hospital Tulln, A-3430 Tulln, Austria; Hans.Salzer@ 123456tulln.lknoe.at
                Author notes
                [* ]Correspondence: claudia.gundacker@ 123456meduniwien.ac.at ; Tel.: +43-1-40160-56503
                Author information
                https://orcid.org/0000-0002-7413-2343
                https://orcid.org/0000-0001-6335-076X
                https://orcid.org/0000-0002-5715-3230
                https://orcid.org/0000-0003-4093-3780
                Article
                ijms-22-01707
                10.3390/ijms22041707
                7915079
                33567754
                59c7f108-dc81-44f5-8d48-372b1fffd5a5
                © 2021 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
                : 30 December 2020
                : 05 February 2021
                Categories
                Article

                Molecular biology
                lat1,placenta,htr-8/svneo,mehg,mercury,oxidative stress,gsh
                Molecular biology
                lat1, placenta, htr-8/svneo, mehg, mercury, oxidative stress, gsh

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