Oxidative Stress in Methylmercury-Induced Cell Toxicity

Alessandra Antunes Dos Santos,Elisavet Renieri,Anatoly Skalny,Michael Aschner,Beatriz Ferrer,Filipe Marques Gonçalves,Aristides Tsatsakis,Marcelo Farina,João Rocha

doi:10.3390/toxics6030047

Abstract

Methylmercury (MeHg) is a hazardous environmental pollutant, which elicits significant toxicity in humans. The accumulation of MeHg through the daily consumption of large predatory fish poses potential health risks, and the central nervous system (CNS) is the primary target of toxicity. Despite well-described neurobehavioral effects (i.e., motor impairment), the mechanisms of MeHg-induced toxicity are not completely understood. However, several lines of evidence point out the oxidative stress as an important molecular mechanism in MeHg-induced intoxication. Indeed, MeHg is a soft electrophile that preferentially interacts with nucleophilic groups (mainly thiols and selenols) from proteins and low-molecular-weight molecules. Such interaction contributes to the occurrence of oxidative stress, which can produce damage by several interacting mechanisms, impairing the function of various molecules (i.e., proteins, lipids, and nucleic acids), potentially resulting in modulation of different cellular signal transduction pathways. This review summarizes the general aspects regarding the interaction between MeHg with regulators of the antioxidant response system that are rich in thiol and selenol groups such as glutathione (GSH), and the selenoenzymes thioredoxin reductase (TrxR) and glutathione peroxidase (Gpx). A particular attention is directed towards the role of the PI3K/Akt signaling pathway and the nuclear transcription factor NF-E2-related factor 2 (Nrf2) in MeHg-induced redox imbalance.

Highlights

Mercury (Hg) is a global pollutant ubiquitously present in the environment with a potential toxic effect in humans
MeHg’s affinity for sulfhydryls and selenols interferes with several important regulators of the antioxidant response that are rich in thiol and selenol groups
Selenium plays a crucial role in antioxidant defense, as one Se atom is absolutely required at the active site of all selenoenzymes, such as glutathione peroxidases (GPx) and thioredoxin reductase (TrxR), in the form of selenocystein [82]

Summary

Introduction

Mercury (Hg) is a global pollutant ubiquitously present in the environment with a potential toxic effect in humans. Even though the relationship between MeHg-induced motor deficit and cerebellar damage is a well-described phenomenon [29], the cellular mechanisms mediating MeHg-induced neurotoxicity have yet to be fully understood In this regard, it is well documented that the electrophilic abilities of MeHg allow this toxicant to bind to soft nucleophilic groups, such as thiol (-SH) and selenol groups [1,12,30], disrupting the structure and activity of a large number of proteins and lead to disruption of various intracellular functions. A number of mechanisms have been identified as critical factors in MeHg-induced cell damage, including induction of oxidative stress via overproduction of reactive oxygen species (ROS) or reduction of antioxidant defenses and disruption of glutamate and calcium (Ca2+ ) homeostasis [1,31,32,33]. MeHg-induced redox imbalance, as well as the regulation/modulation induced by this metal of the transcription factor Nrf and PI3K/Akt signaling pathway

Thiols and Selenols Play Fundamental Roles in MeHg-Induced Toxicity

Selenoenzymes

MeHg Regulation of Nrf2 Activity

Conclusions