• Aberrant iron metabolism in the brain is typified by Hallervorden-Spatz syndrome. In this disorder, large amounts of iron are deposited in the globus pallidus and the pars reticulata of the substantia nigra. It is characterized by extrapyramidal dysfunction, as demonstrated by dystonia, rigidity, and choreoathetosis; onset during the first two decades of life; and progression of signs and symptoms. Corroborative findings include corticospinal tract involvement, ie, spasticity and extensor toe signs, progressive intellectual impairment, retinitis pigmentosa and optic atrophy (usually associated visual evoked response and electroretinogram abnormalities), seizures, familial occurrence, hypointense areas in the basal ganglia on magnetic resonance imaging scans (particularly in the substantia nigra), abnormal cytosomes in circulating lymphocytes, and sea-blue histiocytes in bone marrow. Iron function in normal brain metabolism is manifold, but high concentrations of iron in the basal ganglia area may signal a unique relationship. Data support the likelihood that iron plays a role in the modulation of dopamine binding to postsynaptic receptors. In addition, transferrin receptors and iron are also concentrated in oligodendrocytes in normal brain and, thus, may have a function in myelination. A role of iron also seems likely in oxidation and peroxidation reactions involving membranes and DNA, a capability that becomes uncontrolled when protective biologic mechanisms become inadequate.

Hallervorden-Spatz syndrome and brain iron metabolism.

Mercury is a ubiquitous contaminant, and a range of chemical species is generated by human activity and natural environmental change. Elemental mercury and its inorganic and organic compounds have different toxic properties, but all them are considered hazardous in human exposure. In an equimolecular exposure basis, organomercurials with a short aliphatic chain are the most harmful compounds and they may cause irreversible damage to the nervous system. Methylmercury (CH(3)Hg(+)) is the most studied following the neurotoxic outbreaks identified as Minamata disease and the Iraq poisoning. The first description of the CNS pathology dates from 1954. Since then, the clinical neurology, the neuropathology and the mechanisms of neurotoxicity of organomercurials have been widely studied. The high thiol reactivity of CH(3)Hg(+), as well as all mercury compounds, has been suggested to be the basis of their harmful biological effects. However, there is clear selectivity of CH(3)Hg(+) for specific cell types and brain structures, which is not yet fully understood. The main mechanisms involved are inhibition of protein synthesis, microtubule disruption, increase of intracellular Ca(2+) with disturbance of neurotransmitter function, oxidative stress and triggering of excitotoxicity mechanisms. The effects are more damaging during CNS development, leading to alterations of the structure and functionality of the nervous system. The major source of CH(3)Hg(+) exposure is the consumption of fish and, therefore, its intake is practically unavoidable. The present concern is on the study of the effects of low level exposure to CH(3)Hg(+) on human neurodevelopment, with a view to establishing a safe daily intake. Recommendations are 0.4 micro g/kg body weight/day by the WHO and US FDA and, recently, 0.1 micro g/kg body weight/day by the US EPA. Unfortunately, these levels are easily attained with few meals of fish per week, depending on the source of the fish and its position in the food chain.

Neurotoxicity of organomercurial compounds

The number of reports concerning the chemical toxicology of metals which are released in the environment by natural as well as anthropogenic sources, have been increasing constantly. Lead, cadmium,...

The present status of biological effects of toxic metals in the environment: lead, cadmium, and manganese

The importance of glutamate, glycine, and γ-aminobutyric acid transport and regulation in manganese, mercury and lead neurotoxicity

Along with the knowledge that the calcium ion is involved in the regulation of a number of physiological processes has also come the understanding that Ca2+ can play a determinant role in various pathologic and toxicologic processes. It has long been known that Ca2+ accumulates in necrotic tissue,' and subsequent work has revealed that a disruption of intracellular Ca2+ homeostasis is frequently associated with the early development of cell inj~ry.2.~ This led to the formulation of the calcium hypothesis of cell injury, which proposes that perturbation of the intracellular C a 2 + homeostasis may be a common step in the development of cytotoxicity.2 During recent years, it has become progressively clear that sustained increases in intracellular CaZ+ can activate cytotoxic mechanisms associated with irreversible injury in various cell systems and organs (FIG. 1). Thus, Ca2+ appears to mediate the neurotoxicity of cyanide, chlordecone, and heavy me&, including lead, mercury and organotin compounds (see Ref. 4 for review). In addition, intracellular Ca2+ accumulation due to excessive stimulation of excitatory amino acid receptors5 and enhanced Ca2+ influx through membrane channels6 appears to play an important role in brain ischemia. An elevation of intracellular Ca2+ also seems to contribute to cell killing by several hepatotoxic agents, such as acetaminophen,7-9 diquat and CCl4,9 quinones, lo cyanids11 and maitotoxin, a polyhydmxy polyether compound that causes intracellular Ca2+ accurnulation.l2 An increased intracellular Ca2' level has also been reported to be the determinant hctor in the development of cardiotoxicity after exposure to the environmental contaminant, E D 4 1 3 and in thymocyte killing by X D D and tributyltin. 14,15 Moreover, intracellular Caz+ overload is involved in the development of reperfusion injury in the head6 and oxidative damage to kidney membranes during cold ischemia.\" There is also increasing evidence that Ca2+ plays an important role in cell killing in the immune system. Thus, the killing of immature thymocytes by glucocorticoids,18J9 the killing of target cells by cytotoxic T lymphocytes2° and by natural killer and complement-mediated cell killing22 appear all to be (32'dependent. Finally, recent studies have suggested that both bacterial toxinsz3 and viral components such as the HIV envelope glycoprotein, gp 120,u can promote killing of infected cells by increasing intracellular Ca2+ levels. Normally, intracellular Ca2+ homeostasis is maintained by the concerted operation of cellular transport and compartmentalization systems. However, alteration of these processes during cell injury can result in enhanced Ca2+ influx, ~ l e a ~ e of Ca2+ from

Ca2+ and cell death.

The effect of various concentrations of several lead and mercury compounds upon various high affinity receptor sites within discrete brain regions has been measured. The specific binding of radioactive spiroperidol and quinuclidinyl benzilate to striatal and cortical membranes respectively, was much more severely inhibited in the presence of tri-n-butyl lead acetate than by lead acetate. This suggested that the hydrophobic organic lead derivative was able to interfere with receptor structure more readily than the lead acetate. On the other hand mercuric chloride was more effective in blocking these two neurotransmitter receptor sites than was the organic methylmercuric chloride. This implied that sulfhydryl groups may be within, or proximal to the allosteric binding site. The relative ineffectiveness of all heavy metal compounds studied in blocking the glycine. GABA or the diazepam receptors indicated that the mechanism of binding may not be similar with different receptor proteins. Since micromolar concentrations of some lead and mercury compounds suffice to severely inhibit neurotransmitter binding sites, such a direct interference with postsynaptic events may in part account for the neurological consequences of heavy metal poisoning.

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Ashok K. Agrawal

Papers

The inhibition of cerebral high affinity receptor sites by lead and mercury compounds.