Effects of methylmercury on spinal cord afferents and efferents—A review

Abstract

Methylmercury (MeHg) is an environmental neurotoxicant of public health concern. It readily accumulates in exposed humans, primarily in neuronal tissue. Exposure to MeHg, either acutely or chronically, causes severe neuronal dysfunction in the central nervous system and spinal neurons; dysfunction of susceptible neuronal populations results in neurodegeneration, at least in part through Ca2+-mediated pathways. Biochemical and morphologic changes in peripheral neurons precede those in central brain regions, despite the fact that MeHg readily crosses the blood-brain barrier. Consequently, it is suggested that unique characteristics of spinal cord afferents and efferents could heighten their susceptibility to MeHg toxicity. Transient receptor potential (TRP) ion channels are a class of Ca2+-permeable cation channels that are highly expressed in spinal afferents, among other sensory and visceral organs. These channels can be activated in numerous ways, including directly via chemical irritants or indirectly via Ca2+ release from intracellular storage organelles. Early studies demonstrated that MeHg interacts with heterologous TRPs, though definitive mechanisms of MeHg toxicity on sensory neurons may involve more complex interaction with, and among, differentially-expressed TRP populations. In spinal efferents, glutamate receptors of the N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and possibly kainic acid (KA) classes are thought to play a major role in MeHg-induced neurotoxicity. Specifically, the Ca2+-permeable AMPA receptors, which are abundant in motor neurons, have been identified as being involved in MeHg-induced neurotoxicity. In this review, we will describe the mechanisms that could contribute to MeHg-induced spinal cord afferent and efferent neuronal degeneration, including the possible mediators, such as uniquely expressed Ca2+-permeable ion channels.

Acute neurotoxicant exposure induces hyperexcitability in mouse lumbar spinal motor neurons

“…Environmental risks factors associated with MNDs include exposure to pesticides, solvents, and heavy metals such as lead and mercury (Wang et al 2017). Consistent with this, MeHg exposure leads to MN degeneration, and the symptoms of MeHg toxicity are similar to those of ALS (Adams et al 1983;Callaghan et al 2011;Colón-Rodríguez et al 2017;Hansen et al 1989;Johnson and Atchison 2009;Praline et al 2007). As a result, mercury exposure has been used as a model to understand the contribution of an environmental agent to excitotoxicity in MN degeneration, as seen in ALS and other spinal degenerative diseases (Bailey et al 2017;Johnson et al 2011;Johnson and Atchison 2009).…”

“…Worldwide, mercury exposure in the form of methylmercury (MeHg), a persistent and contemporaneous environmental neurotoxicant, remains a major health concern (Clarkson and Magos 2006;Horowitz et al 2014). The amount of mercury in the environment continues to grow as a result of metal processing and the use of fossil fuels, including coal (Clarkson 1995(Clarkson , 2002Clarkson and Magos 2006;Colón-Rodríguez et al 2017). Exposure to MeHg through contaminated food and water has been linked to severe neurological disorders including motor, cognitive, and developmental deficits (Clarkson 1995(Clarkson , 1997Colón-Rodríguez et al 2017).…”

“…The amount of mercury in the environment continues to grow as a result of metal processing and the use of fossil fuels, including coal (Clarkson 1995(Clarkson , 2002Clarkson and Magos 2006;Colón-Rodríguez et al 2017). Exposure to MeHg through contaminated food and water has been linked to severe neurological disorders including motor, cognitive, and developmental deficits (Clarkson 1995(Clarkson , 1997Colón-Rodríguez et al 2017). It has been shown that MeHg exposure may lead to or exacerbate motor impairment (Cao et al 2013;Cavanagh and Chen 1971a;Colón-Rodríguez et al 2017;Takaoka et al 2008), but little is known about the cellular and molecular mechanisms of MeHg action on the spinal cord.…”

“…As a model for MN degeneration, it is important to understand how mercury affects MN physiology. MeHg exposure has been linked to severe motor impairment, as observed in acute and chronic poisoning episodes (Bakir et al 1973;Cariccio et al 2019;Cavanagh and Chen 1971a;McAlpine and Araki 1958), and damage to MNs may contribute to MeHg-induced motor impairment since MeHg exposure leads to loss of MNs in vivo (Cao et al 2013;Cavanagh and Chen 1971b;Colón-Rodríguez et al 2017;Takaoka et al 2008). However, little is known about the cellular and molecular mechanisms of MeHg action on the spinal cord.…”

“…MeHg exposure directly increased spinal MN excitability as a result of changes in both intrinsic membrane properties and synaptic inputs. Prolonged hyperexcitability in response to MeHg exposure has been linked to neurodegeneration (Colón-Rodríguez et al 2017). In addition, this hyperexcitability appears to be mediated at least partly by Ca 2ϩdependent mechanisms.…”