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Int. J. Mol. Sci. 2017, 18(8), 1730; doi:10.3390/ijms18081730

Methylmercury Uptake into BeWo Cells Depends on LAT2-4F2hc, a System L Amino Acid Transporter

1
Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Währinger Strasse 10, Medical University of Vienna, 1090 Wien, Vienna, Austria
2
Center for Pathobiochemistry and Genetics, Institute of Medical Chemistry, Währinger Strasse 10, Medical University of Vienna, 1090 Wien, Vienna, Austria
3
Karl Landsteiner University of Health Sciences, Dr.-Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria
*
Author to whom correspondence should be addressed.
Received: 2 June 2017 / Revised: 28 July 2017 / Accepted: 1 August 2017 / Published: 8 August 2017
(This article belongs to the Special Issue Metal Metabolism in Animals II)
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Abstract

The organic mercury compound methylmercury (MeHg) is able to target the fetal brain. However, the uptake of the toxicant into placental cells is incompletely understood. MeHg strongly binds to thiol-S containing molecules such as cysteine. This MeHg-l-cysteine exhibits some structural similarity to methionine. System L plays a crucial role in placental transport of essential amino acids such as leucine and methionine and thus has been assumed to also transport MeHg-l-cysteine across the placenta. The uptake of methylmercury and tritiated leucine and methionine into the choriocarcinoma cell line BeWo was examined using transwell assay and small interfering (si)RNA mediated gene knockdown. Upon the downregulation of large neutral amino acids transporter (LAT)2 and 4F2 cell-surface antigen heavy chain (4F2hc), respectively, the levels of [3H]leucine in BeWo cells are significantly reduced compared to controls treated with non-targeting siRNA (p < 0.05). The uptake of [3H]methionine was reduced upon LAT2 down-regulation as well as methylmercury uptake after 4F2hc silencing (p < 0.05, respectively). These findings suggest an important role of system L in the placental uptake of the metal. Comparing the cellular accumulation of mercury, leucine, and methionine, it can be assumed that (1) MeHg is transported through system L amino acid transporters and (2) system L is responsible for the uptake of amino acids and MeHg primarily at the apical membrane of the trophoblast. The findings together can explain why mercury in contrast to other heavy metals such as lead or cadmium is efficiently transported to fetal blood. View Full-Text
Keywords: methylmercury; leucine; methionine; human placenta; SLC7A5; SLC7A8; SLC3A2; Forskolin methylmercury; leucine; methionine; human placenta; SLC7A5; SLC7A8; SLC3A2; Forskolin
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Balthasar, C.; Stangl, H.; Widhalm, R.; Granitzer, S.; Hengstschläger, M.; Gundacker, C. Methylmercury Uptake into BeWo Cells Depends on LAT2-4F2hc, a System L Amino Acid Transporter. Int. J. Mol. Sci. 2017, 18, 1730.

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