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

Sebastian Granitzer, Raimund Widhalm, Martin Forsthuber, Isabella Ellinger, Gernot Desoye, Markus Hengstschläger, Harald Zeisler, Hans Salzer, Claudia Gundacker

Research output: Journal article (peer-reviewed)Journal article

6 Citations (Scopus)

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.

Original languageEnglish
Article number1707
Pages (from-to)1-15
Number of pages15
JournalInternational Journal of Molecular Sciences
Volume22
Issue number4
DOIs
Publication statusPublished - 2 Feb 2021

Keywords

  • Apoptosis
  • Cell Survival
  • Cells, Cultured
  • Female
  • Glutathione/metabolism
  • Humans
  • Large Neutral Amino Acid-Transporter 1/metabolism
  • Methylmercury Compounds/analysis
  • Oxidative Stress/drug effects
  • Placenta/drug effects
  • Pregnancy
  • Protective Agents/analysis

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