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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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          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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                Author and article information

                Role: Academic Editor
                Role: Academic Editor
                Int J Mol Sci
                Int J Mol Sci
                International Journal of Molecular Sciences
                08 February 2021
                February 2021
                : 22
                : 4
                : 1707
                [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
                © 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/).

                : 30 December 2020
                : 05 February 2021

                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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