Mechanisms of methylmercury-induced neurotoxicity: evidence from experimental studies

Abstract

Neurological disorders are common, costly, and can cause enduring disability. Although mostly unknown, a few environmental toxicants are recognized causes of neurological disorders and subclinical brain dysfunction. One of the best known neurotoxins is methylmercury (MeHg), a ubiquitous environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. In the aquatic environment, MeHg is accumulated in fish, which represent a major source of human exposure. Although several episodes of MeHg poisoning have contributed to the understanding of the clinical symptoms and histological changes elicited by this neurotoxicant in humans, experimental studies have been pivotal in elucidating the molecular mechanisms that mediate MeHg-induced neurotoxicity. The objective of this mini-review is to summarize data from experimental studies on molecular mechanisms of MeHg-induced neurotoxicity. While the full picture has yet to be unmasked, in vitro approaches based on cultured cells, isolated mitochondria and tissue slices, as well as in vivo studies based mainly on the use of rodents, point to impairment in intracellular calcium homeostasis, alteration of glutamate homeostasis and oxidative stress as important events in MeHg-induced neurotoxicity. The potential relationship among these events is discussed, with particular emphasis on the neurotoxic cycle triggered by MeHg-induced excitotoxicity and oxidative stress. The particular sensitivity of the developing brain to MeHg toxicity, the critical role of selenoproteins and the potential protective role of selenocompounds are also discussed. These concepts provide the biochemical bases to the understanding of MeHg neurotoxicity, contributing to the discovery of endogenous and exogenous molecules that counteract such toxicity and provide efficacious means for ablating this vicious cycle.

Figure 1. Progressive motor impairment in MeHg exposed mice

Animals were exposed to methylmercury (CH₃Hg⁺; MeHg) (40 mg/L, diluted in drinking water) (Dietrich et al., 2004). The figure represents a footprint test evaluation in a randomly selected animal. Low-, medium- and high-impairment represent footprint tests performed at 7, 14 and 21 days after the beginning of the treatment, respectively.

Figure 2. Effects of MeHg on the GSH antioxidant system

(i) Methylmercury (CH₃Hg⁺; MeHg) disrupts mitochondrial electron transport chain, leading to increased formation of reactive oxygen species, such as hydrogen peroxide (H₂O₂) and superoxide anion (O₂•−) (Franco et al., 2007; Mori et al., 2007). (ii) MeHg also reacts with reduced glutathione (GSH), leading to GSH depletion due to the formation of a MeHg–GSH (GS–HgCH₃) complex, which is excreted from the body. MeHg hampers the physiological increase in glutathione reductase (GR) and glutathione peroxidase (GPx) activities in the rodent CNS during the early postnatal period (iii and iv) (Stringari et al., 2008), but also decreases GPx activity in adult animals (Farina et al., 2003a, Franco et al., 2009). All these events (i–iv) culminate in increased ROS generation and oxidative stress (v).

Figure 3. Interrelated association among MeHg-induced oxidative stress, Ca²⁺ and glutamate dyshomeostasis

The figure shows a tripartite synapses, where methylmercury (CH₃Hg⁺; MeHg) inhibits astrocytic glutamate uptake (i) and increases glutamate release (ii), leading to elevated extracellular glutamate levels. High levels of extracellular glutamate overactivate N-methyl D-aspartate (NMDA)-type glutamate receptor (iii). Overactivation of NMDA glutamate receptors leads to increased influx of Ca²⁺ into postsynaptic neurons, causing activation of cell death pathways (Hidalgo and Donaso, 2008). Alternatively, Ca²⁺ taken up by mitochondria may cause mitochondrial dysfunction and increased reactive oxygen species (ROS) generation (v). This last event is also directly stimulated by MeHg (vi), which seems to be related to misbalance in the electron transport chain (Mori et al., 2007). Increased levels of ROS (mainly H₂O₂) can directly decrease astrocytic glutamate uptake (vii) (Allen et al., 2001), contributing to excitotoxicity. GLU = glutamate.