Methylmercury alters glutathione homeostasis by inhibiting glutaredoxin 1 and enhancing glutathione biosynthesis in cultured human astrocytoma cells

Robitaille, Stephan; Mailloux, Ryan J.; Chan, Hing Man

doi:10.1016/j.toxlet.2016.05.013

Cited by 23 publications

(15 citation statements)

References 52 publications

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“…The depletion of total GSH in hPLF exposed to 3 μ M MeHg is explained by the interaction with intracellular thiols being the main target of MeHg. However, the mechanism of MeHg toxicity in hPLFs was different from those observed in glioblastoma cells [5]. No changes in the GSH levels were observed in exposed glioblastoma cells exposed to 1 μ M MeHg taking place a significant increase of GSSH levels (12-fold).…”

Section: Discussionmentioning

confidence: 99%

“…This protein is the substrate for glutathione S-transferase (GST) and plays a key role in cellular detoxification of xenobiotics and in excessive production of oxygen species. The decreased level of total GSH or the ratio between GSH/GSSG results in oxidative stress and evidences an important molecular mechanism in MeHg-induced toxicity [4, 5]. Related to mercury exposure, oxidative stress is also associated with mitochondrial dysfunction [6] and alterations on membrane permeability and macromolecule structure (DNA, protein, and lipids), due to their high affinity for sulphydryl groups and thiols [7].…”

Section: Introductionmentioning

confidence: 99%

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Oxidative Damage in Human Periodontal Ligament Fibroblast (hPLF) after Methylmercury Exposure

Nogueira

Vasconcelos

Mitre

et al. 2019

Oxidative Medicine and Cellular Longevity

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Human exposure to mercury (Hg) is primary associated with its organic form, methylmercury (MeHg), through the ingestion of contaminated seafood. However, Hg contamination is also positively correlated with the number of dental restorations, total surface of amalgam, and organic mercury concentration in the saliva. Among the cells existing in the oral cavity, human periodontal ligament fibroblast (hPLF) cells are important cells responsible for the production of matrix and extracellular collagen, besides sustentation, renewal, repair, and tissue regeneration. In this way, the present study is aimed at investigating the potential oxidative effects caused by MeHg on hPLF. Firstly, we analyzed the cytotoxic effects of MeHg (general metabolism status, cell viability, and mercury accumulation) followed by the parameters related to oxidative stress (total antioxidant capacity, GSH levels, and DNA damage). Our results demonstrated that MeHg toxicity increased in accordance with the rise of MeHg concentration in the exposure solutions (1-7 μM) causing 100% of cell death at 7 μM MeHg exposure. The general metabolism status was firstly affected by 2 μM MeHg exposure (43.8 ± 1.7%), while a significant decrease of cell viability has arisen significantly only at 3 μM MeHg exposure (68.7 ± 1.4%). The ratio among these two analyses (named fold change) demonstrated viable hPLF with compromised cellular machinery along with the range of MeHg exposure. Subsequently, two distinct MeHg concentrations (0.3 and 3 μM) were chosen based on LC50 value (4.2 μM). hPLF exposed to these two MeHg concentrations showed an intracellular Hg accumulation as a linear-type saturation curve indicating that metal accumulated diffusively in the cells, typical for metal organic forms such as methyl. The levels of total GSH decreased 50% at exposure to 3 μM MeHg when compared to control. Finally, no alteration in the DNA integrity was observed at 0.3 μM MeHg exposure, but 3 μM MeHg caused significant damage. In conclusion, it was observed that MeHg exposure affected the general metabolism status of hPLF with no necessary decrease on the cell death. Additionally, although the oxidative imbalance in the hPLF was confirmed only at 3 μM MeHg through the increase of total GSH level and DNA damage, the lower concentration of MeHg used (0.3 μM) requires attention since the intracellular mercury accumulation may be toxic at chronic exposures.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oxidative Damage in Human Periodontal Ligament Fibroblast (hPLF) after Methylmercury Exposure

Nogueira

Vasconcelos

Mitre

et al. 2019

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

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“…A suggested mechanism of MeHg-induced astrocytic gliotoxicity implies a decrease in GSH intracellular levels which enhances oxidative stress and may contribute to astrocytic cell death [174,176,177]. S. Robitaille et al stated that 1 µM of MeHg for 24 h induces a 12-fold increase in GSSG resulting in a disruption in redox homeostasis and aberrant S-glutathionylation of proteins through glutaredoxin-1 overactivation [178]. Moreover, MeHg was reported to selectively impair astrocytic Cys uptake, the rate-limiting GSH substrate, through inhibition of Na + -dependent Cys transporters which in turn impairs the activity of GSH system [170].…”

Section: Astrocytesmentioning

confidence: 99%

Cellular and Molecular Mechanisms Mediating Methylmercury Neurotoxicity and Neuroinflammation

Novo

Martins

Raposo

et al. 2021

IJMS

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Methylmercury (MeHg) toxicity is a major environmental concern. In the aquatic reservoir, MeHg bioaccumulates along the food chain until it is consumed by riverine populations. There has been much interest in the neurotoxicity of MeHg due to recent environmental disasters. Studies have also addressed the implications of long-term MeHg exposure for humans. The central nervous system is particularly susceptible to the deleterious effects of MeHg, as evidenced by clinical symptoms and histopathological changes in poisoned humans. In vitro and in vivo studies have been crucial in deciphering the molecular mechanisms underlying MeHg-induced neurotoxicity. A collection of cellular and molecular alterations including cytokine release, oxidative stress, mitochondrial dysfunction, Ca2+ and glutamate dyshomeostasis, and cell death mechanisms are important consequences of brain cells exposure to MeHg. The purpose of this review is to organize an overview of the mercury cycle and MeHg poisoning events and to summarize data from cellular, animal, and human studies focusing on MeHg effects in neurons and glial cells. This review proposes an up-to-date compendium that will serve as a starting point for further studies and a consultation reference of published studies.

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“…The correlation between Hg exposure and endothelial dysfunction was confirmed after follow-up studies on severe cases of poisoning, the first being that of Minamata in Japan, which highlighted various cardiovascular anomalies [ 58 , 73 ]. Endothelial cells are very vulnerable to Hg-induced OS caused either by increasing the production of oxidative agents or by inducing a decrease in antioxidant activity [ 71 , 74 ]. The increase of OS induces, via various pathways, endothelial inflammation first and then endothelial dysfunction, ref.…”

Section: Mercury and Endothelial Dysfunctionmentioning

confidence: 99%

Erythrocytes as a Model for Heavy Metal-Related Vascular Dysfunction: The Protective Effect of Dietary Components

Notariale

Infantino

Palazzo

et al. 2021

IJMS

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Heavy metals are toxic environmental pollutants associated with severe ecological and human health risks. Among them is mercury (Hg), widespread in air, soil, and water, due to its peculiar geo-biochemical cycle. The clinical consequences of Hg exposure include neurotoxicity and nephrotoxicity. Furthermore, increased risk for cardiovascular diseases is also reported due to a direct effect on cardiovascular tissues, including endothelial cells, recently identified as important targets for the harmful action of heavy metals. In this review, we will discuss the rationale for the potential use of erythrocytes as a surrogate model to study Hg-related toxicity on the cardiovascular system. The toxic effects of Hg on erythrocytes have been amply investigated in the last few years. Among the observed alterations, phosphatidylserine exposure has been proposed as an underlying mechanism responsible for Hg-induced increased proatherogenic and prothrombotic activity of these cells. Furthermore, following Hg-exposure, a decrease in NOS activity has also been reported, with consequent lowering of NO bioavailability, thus impairing endothelial function. An additional mechanism that may induce a decrease in NO availability is the generation of an oxidative microenvironment. Finally, considering that chronic Hg exposure mainly occurs through contaminated foods, the protective effect of dietary components is also discussed.

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Methylmercury alters glutathione homeostasis by inhibiting glutaredoxin 1 and enhancing glutathione biosynthesis in cultured human astrocytoma cells

Cited by 23 publications

References 52 publications

Oxidative Damage in Human Periodontal Ligament Fibroblast (hPLF) after Methylmercury Exposure

Oxidative Damage in Human Periodontal Ligament Fibroblast (hPLF) after Methylmercury Exposure

Cellular and Molecular Mechanisms Mediating Methylmercury Neurotoxicity and Neuroinflammation

Erythrocytes as a Model for Heavy Metal-Related Vascular Dysfunction: The Protective Effect of Dietary Components

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