Table 1.

Some mechanisms of toxic action proposed for MeHg

Mechanism	Results	Reference(s)
Altered membrane permeability	MeHg attaches to cystine, enabling it to enter cells via a neutral amino acid transporter that also transports methionine into cells; also increases mitochondrial membrane permeability	Clarkson (1995); Clarkson et al. (2007); Pochini et al. (2013); Simmons-Willis et al. (2002)
Altered intracellular calcium homeostasis	Blocks cellular membrane Ca++ channels; causes release of mitochondrial Ca++ into the cytosol	Hare et al. (1993); Kang et al. (2006) Limke et al. (2004b); Marty and Atchison (1997); Minnema et al. (1987); Peng et al. (2002); Sirois and Atchison (2000); Szalai et al. (1999)
Oxidative stress/reactive oxygen species (ROS)	MeHg causes increase in ROS and subsequent depolarization of the mitochondrial membrane; decreases aconitase activity	Dreiem and Seegal (2007); Garg and Chang (2006); Myhre et al. (2003); Yin et al. (2007)
Effects on receptor binding/neurotransmitter release	Blocks GABA receptor sites; binds to NMDARs, inducing their expression; causes up-regulation of muscarinic ACh receptors	Basu et al. (2008); Coccini et al. (2000); Cooper et al. (2003); Fonfria et al. (2001); Ndountse and Chan (2008); Yuan and Atchison (2003)
Generation of arachidonic acid	Promotes the release of arachidonic acid, resulting in neurotoxicity	Shanker et al. (2002); Verity et al. (1994)
Effects on cycle/cell division	Causes arrest in the GM2/M-phase of the cell cycle through microtubule disruption	Burke et al. (2006); Castoldi et al. (2000); Gribble et al. (2005); Kim et al. (2007); Ou et al. (1999b); Rodier et al. (1984)
Effects on glutathione activity	Decreases glutathione activity, particularly in the cerebellum and mitochondria, thus providing less protection from oxidative stress due to MeHg	Carocci et al. (2014); Choi et al. (1996); Franco et al. (2006); Mori et al. (2007); Ndountse and Chan (2008)
Involvement with nitric oxide synthetase	MeHg causes an increase in nNOS protein, causing the overproduction of NO	Chuu et al. (2001); Shinyashiki et al. (1998)
Glutamate—glutamine uptake and homeostasis in glial cells	Disrupts glutamate homeostasis by disrupting glutamine/glutamate cycling; causes glutamate release from pre-synaptic neurons	Farina et al. (2003a, b); Manfroi et al. (2004); Yin et al. (2007)
Activation of calpain cascade leading to apoptosis	Cascade begins with increased intracellular Ca++ leading to microtubule degradation and cell death	Sakaue et al. (2005)