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

Granitzer S, Widhalm R, Forsthuber M, Ellinger I, Desoye G, Hengstschläger M, Zeisler H, Salzer H, Gundacker C. Amino Acid Transporter LAT1 (SLC7A5) Mediates MeHg-Induced Oxidative Stress Defense in the Human Placental Cell Line HTR-8/SVneo.

Int J Mol Sci. 2021 Feb 8;22(4):1707. doi: 10.3390/ijms22041707. PMID: 33567754; PMCID: PMC7915079.

The placental barrier can protect the fetus from contact with harmful substances. The potent neurotoxin methylmercury (MeHg) that can be taken up via fish and seafood 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.

Data were generated in the project Life Science 2015 (LS15_014) “Mercury toxicokinetics in human placenta: making the bridge between genotype and phenotype in healthy and diseased placentas “ in a collaboration between Medical University of Vienna and Karl Landsteiner University of Health Sciences