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

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.

Maternal DNA methylation signatures of arsenic exposure is associated with adult offspring insulin resistance in the Strong Heart Study

“…Likewise; LAT1 plays an active role in metabolic processes involved in T -cell differentiation and effector function ( Sinclair et al, 2013 ), facilitating the metabolic demands of T -cells to propagate a pro-inflammatory response; which; if persistent, has been linked to T2D pathogenesis ( Jagannathan-Bogdan et al, 2011 ; Shoelson et al, 2006 ). On the other hand; in vitro studies using a human placental cell line found LAT1 has a protective role against oxidative stress and inflammation induced by metal toxicity ( Granitzer et al, 2021 ). Taken together; depending on the cellular context, LAT1 may have a fundamental role in environmental toxicant-induced oxidative damage and inflammation.…”

Exposome and foetoplacental vascular dysfunction in gestational diabetes mellitus

“…Hg is highly toxic and is still present in electrical and electronic devices and is also contained in some thermometers specifically for the measurement of high temperatures. Methylmercury (MeHg) is the principal constituent of organic Hg and damages foetal development since it crosses the placenta and blood-brain barrier (Clarkson and Magos, 2006;Granitzer et al, 2021). MeHg is present in high levels in seafood and some fishes.…”

The Impact of Oxidative Stress of Environmental Origin on the Onset of Placental Diseases

“…The formation of thiol-MeHg bonds is likely also responsible for the placental accumulation because MeHg, similar to Hg 2+ , is known to bind to thiol-containing molecules—for example, proteins, cysteine, and glutathione. Recently the amino acid transporter LAT1 (SLC7A5) has been involved in the transport of MeHg in HTR-8/SV-neo cells [ 59 ]. Regarding the actual mechanism of action of MeHg, it has been demonstrated that 1 μg/mL methylmercury decreased viability, proliferation, and migration and led to the decreased expression of SOD1 in the HTR8/SV-neo trophoblast cells [ 60 ].…”