Methylmercury neurotoxicity: Role of oxidative stress

Methylmercury (MeHg) is a highly toxic compound that successfully traverses the blood brain barrier with deleterious effects to the central nervous system. Exposure is generally through the ingestion of contaminated fish. Two well-known disastrous exposures to methylmercury occurred in Japan in the 1950s and in Iraq in the 1970s. Acute methylmercury exposures such as these resulted in parasthesia, ataxia, and narrowing of the visual field. Exposures in utero resulted in microcephaly, cerebropalsy, seizures, and mental retardation. Since the developing fetus as well as the neonate are particularly vulnerable, the study of chronic low-dose exposures in utero which may result in developmental delays has become increasingly of interest. The known neurotoxic mechanisms are multifactorial. Methylmercury inhibits protein synthesis by post- transcriptionally interfering with chain elongation resulting from inhibition of aminoacyl-tRNA synthetase enzymes. Abnormalities in protein phosphorylation, critical to intercellular communication, were found both in vitro and in vivo. Methylmercury's high affinity for tubulin sulfhydryl groups was implicated in the disruption of microtubules. The resulting interference with tubulin polymerization can negatively affect cell proliferation and migration. Methylmercury altered neurotransmitter functions by stimulating spontaneous transmitter release and inhibiting glutamate uptake resulting in excitotoxicity. Methylmercury disrupted Ca2+ homeostasis by increasing intracellular concentrations of this ion. Methylmercury may overwhelm the cell's natural protective mechanisms provided by glutathione, metallothioneins, and heat shock protein, thereby producing the generation of reactive oxygen species (ROS). The resulting oxidative stress produced damage to cellular membranes through lipid peroxidation as well as damage to a variety of vital cellular macromolecules. The observed protective effect of antioxidants supports the critical role of oxidative stress in neurotoxicity. Though much has already been discerned regarding the various mechanisms involved in methylmercury-induced neurotoxicity, the interplay between these modes and whether or not they occur sequentially or synchronously has yet to be determined. Attention in this review is focused on oxidative stress since recent studies suggests that oxidative stress may be the initiating event from which other modes of cellular damage originate. © 2007 Taylor & Francis.