Oxidative stress in MeHg-induced neurotoxicity

Abstract

Methylmercury (MeHg) is an environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. Although the molecular mechanisms mediating MeHg-induced neurotoxicity are not completely understood, several lines of evidence indicate that oxidative stress represents a critical event related to the neurotoxic effects elicited by this toxicant. The objective of this review is to summarize and discuss data from experimental and epidemiological studies that have been important in clarifying the molecular events which mediate MeHg-induced oxidative damage and, consequently, toxicity. Although unanswered questions remain, the electrophilic properties of MeHg and its ability to oxidize thiols have been reported to play decisive roles to the oxidative consequences observed after MeHg exposure. However, a close examination of the relationship between low levels of MeHg necessary to induce oxidative stress and the high amounts of sulfhydryl-containing antioxidants in mammalian cells (e.g., glutathione) have led to the hypothesis that nucleophilic groups with extremely high affinities for MeHg (e.g., selenols) might represent primary targets in MeHg-induced oxidative stress. Indeed, the inhibition of antioxidant selenoproteins during MeHg poisoning in experimental animals has corroborated this hypothesis. The levels of different reactive species (superoxide anion, hydrogen peroxide and nitric oxide) have been reported to be increased in MeHg-exposed systems, and the mechanisms concerning these increments seem to involve a complex sequence of cascading molecular events, such as mitochondrial dysfunction, excitotoxicity, intracellular calcium dyshomeostasis and decreased antioxidant capacity. This review also discusses potential therapeutic strategies to counteract MeHg-induced toxicity and oxidative stress, emphasizing the use of organic selenocompounds, which generally present higher affinity for MeHg when compared to the classically studied agents.

<i>S</i>-Mercuration of cellular proteins by methylmercury and its toxicological implications

“…They didn't determine how GPx1 was inhibited, but suggested that selenol groups (which have lower pKa values than do thiol groups) in the enzyme were involved. However, thiols are much more abundant than selenols (Farina et al, 2011). In fact, thiol groups can be found in both low-molecularweight (mainly reduced glutathione, GSH) and high-molecular-weight proteins, whereas selenol groups are found only in a restricted group of selenoproteins (Araie and Shiraiwa, 2009;Lobanov et al, 2009).…”

“…In fact, thiol groups can be found in both low-molecularweight (mainly reduced glutathione, GSH) and high-molecular-weight proteins, whereas selenol groups are found only in a restricted group of selenoproteins (Araie and Shiraiwa, 2009;Lobanov et al, 2009). Consequently, MeHg is expected to be found primarily in thiol-containing proteins (and much less in selenol-containing proteins) in edible fish muscles, which are the most important environmental sources of MeHg to humans (Farina et al, 2011). MeHg has also been found to cause the inactivation of thioredoxin reductase (another selenoprotein; TrxR) both in vivo and in vitro (Branco et al, 2011;Carvalho et al, 2011;Wagner et al, 2010).…”

Flavonoid constituents of Dobera glabra leaves: amelioration impact against CCl4-induced changes in the genetic materials in male rats

“…Oxidative stress is the situation of imbalance between the generation and the elimination of reactive oxygen species (ROS) (Khalil et al 2015), which is characterized by oxidizing biological macromolecules comprising nucleic acid, cellular protein and lipid (Farina et al 2011). Carbon tetrachloride (CCl 4 ) is one of the most common mutagens which increase ROS generation.…”

Mercury Exposure and Heart Diseases

“…Exposure to mercury increases the production of free radicals, reactive oxygen species (ROS) and superoxide anions on account of Fenton reaction [55][56][57][58][59][60]. Mercury binds to thiol (-SH) containing molecules and binds to selenium, forming selenium-mercury complexes, reducing the glutathione peroxidase, catalase and superoxide dismutase activities due to the absence of selenium in the active site of these enzymes [57,58,[60][61][62]. The increment of ROS and the reduction of antioxidant enzymes activity increase the risk of developing cardiovascular disease [63,64].…”