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NM protein, reduce the iron-binding capacity, and release sequestered iron in cytoplasm. These events finally induce the selective cell death of NM-containing neurons in the SNpc and the accumulation of Lewy bodies, the major pathological characteristics of PD.
See also: Alpha-synuclein; Complex I Deficiency; Dopamine; Mitochondrial Dysfunction; PARK1, Alpha Synuclein; Parkinsons Disease: Definition, Diagnosis, and Management; Proteasome Function in Movement Disorders; Substantia Nigra.

Further Reading
Ben-Shachar D, Riederer P, and Youdim MB (1991) Ironmelanin interaction and lipid peroxidation: Implications for Parkinsons disease. Journal of Neurochemistry 57: 16091614. Bush WD, Garguilo J, Zucca FA, et al. (2006) The surface oxidation potential of human neuromelanin reveals a spherical architecture with a pheomelanin core and a eumelanin surface. Proceeding of the National Academy of Sciences of United State of America 13: 1478514789. Double KL, Dedov VN, Fedoroq H, et al. (2008) The comparative biology of neuromelanin and lipofuscin in the human brain. Cell and Molecular Life Sciences 65: 16691682. Fasano M, Bergamosco B, and Lopino L (2006) Modifications of the iron-neuromelanin system in Parkinsons disease. Journal of Neurochemistry 96: 909916. Fedorow H, Halliday GM, Rickert CH, et al. (2006) Evidence for specific phases in the development of human neuromelanin. Neurobiology of Aging 27: 506512.

Fedorow H, Tribl F, Halliday G, Gerlach M, Riederer P, and Double KL (2005) Neuromelanin in human dopamine neurons: Comparison with peripheral melanins and relevance to Parkinsons disease. Progress in Neurobiology 75: 109124. Halliday GM, Ophof A, Broe M, et al. (2005) a-Synuclein redistributes to neuromelanin lipid in the substantia nigra early in Parkinsons disease. Brain 128: 26542664. Naoi M, Maruyama W, Yi H, et al. (2008) Neuromelanin selectively induces apoptosis in dopaminergic SH-SY5Y cells by deglutathionylation in mitochondria: Involvement of the protein and melanin component. Journal of Neurochemistry 105: 24892500. Riederer P, Reichmann H, Youdim MBH, and Gerlach M (eds.) (2006) Parkinsons Disease and Related Disorders. Journal of Neural Transmission (supplement 70), p. 506. Wien/New York: Springer. Sasaki M, Shibata E, Tohyama K, et al. (2006) Neuromelanin magnetic resonance imaging of locus ceruleus and substantia nigra in Parkinsons disease. NeuroReport 17: 12151218. Shamoto-Nagai M, Maruyama W, Yi H, et al. (2004) Neuromelanin inhibits enzymatic activity of 26S proteasome in human dopaminergic SH-SY5Y cells. Journal of Neural Transmission 111: 12531265. Shamoto-Nagai M, Maruyama W, Yi H, et al. (2006) Neuromelanin increases oxidative stress in mitochondria through release of iron: Mechanism behind the inhibition of 26S proteasomes. Journal of Neural Transmission 113: 633644. Tribl F, Gerlach M, Marcus K, et al. (2005) Subcellular proteomics of neuromelanin granules isolated from the human brain. Molecular and Cellular Proteomics 4.7: 945957. Zecca L, Youdim MBH, Riederer P, Connor JR, and Crichton RR (2004) Iron, brain ageing and neurodegenerative disorders. Nature Reviews Neuroscience 5: 863873. Zucca FA, Giaveri G, Gallorini M, et al. (2004) The neuromelanin of human substantia nigra: Physiological and pathological aspects. Pigment Cell Research 17: 610617.

Mercury
C G Goetz, Rush University Medical Center, Chicago, IL, USA
2010 Elsevier Ltd. All rights reserved.

Glossary
Mercury An element that in organic and inorganic forms can be toxic to the nervous system. Neurasthenia A neurological condition marked most prominently by fatigue and lassitude. Many other symptoms may accompany these feelings including headache and other, often vaguely localized pains. Tremor A to-and-fro movement around a joint.

Mercury Compounds and the Nervous System

Human mercurial intoxication results from exposure to the metal, to its inorganic salts, to organic

mercury-containing compounds that are degraded to the inorganic metal. Another form of mercurialism, with different chemical and clinical manifestations, results from intoxication with alkyl compounds, particularly methyl and ethyl mercury. Inorganic mercury poisoning occurs as an industrial disease during paper manufacture, in the preparation of chlorine, and as a result of exposure to certain other chemical processes. Historically, mercurialism was associated with the hat manufacturing industry, because mercuric nitrate was used for processing felt. Acute poisoning has also followed the use of mercuric chloride as a local antiseptic, the excessive use of calomel as a diuretic, and following merthiolate ear irrigations. Dental amalgams release small amounts of mercury, available data do not indicate that this exposure represents a significant clinical risk of neurological intoxication. The chief atmospheric source of mercury pollution is through the burning of coal and other fossil fuels. Metallic

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mercury volatilizes at room temperature and condenses on skin and respiratory membranes. It is absorbed from the skin and the gastrointestinal and respiratory tracts. Elemental, nonionized mercury is transported in the blood, bound to plasma proteins and hemoglobin. Inorganic mercury has remarkable affinity for the kidney; as a result, symptoms of intoxication relate predominately to that organ. Brain uptake varies, depending on chemical form, but under appropriate conditions, the brain incorporates mercury rapidly. Once incorporated into the nervous system, mercury is very slowly eliminated.

Toxic Mechanisms
Serum concentrations are unreliable indicators of inorganic mercury toxicity, but toxic symptoms are usually present when concentrations exceed 500 mg l1. Blood concentrations below 100 mg l1 are considered to be safe. Urinary excretion is similarly an untrustworthy measure of toxicity. Inorganic mercury produces its toxic effects by altering membranes, particularly through combination with sulfur-containing bonds. Mercury inhibits energy metabolism by interacting with several enzyme systems that contain sulfur and by effects on chemicals including lipoic acid, coenzyme A, and pantetheine. Unlike lead, however, mercury forms complexes with amino groups of proteins.

Clinical Syndromes of Intoxication

Acute poisoning does not cause movement disorders but is associated with neurological signs that include emotional irritability, weakness in the lower limbs, psychosis with delirium, hallucinations, and locomotor hyperactivity when weakness does not occur. The chronic form of mercurialism is more common and occurs in industries that use mercury in low doses. The onset of illness may be subtle with postural and kinetic tremor, accompanied by weakness of the limbs and often a progressive personality change. The presence of tremor has been frequently associated with exposure to mercury, but tremor intensity and frequency had not been definitely correlated with current urinary levels of mercury. Other involuntary movements are described but have been poorly characterized in the literature. Muscle cramps and convulsions may develop. Occasionally a clinical picture resembling Parkinsons disease with slowness, gait difficulty, rigidity, and tremor develops, but in a large casecontrol study, no association between chronic mercury exposure and Parkinsons disease was found. Personality changes that can accompany or precede the motor phenomena include fatigue, apathy, and insomnia, often termed historically as mercurial

neurasthenia. These symptoms may be interrupted or accompanied by periods of excitability and irritability, as typified in Lewis Carrolls Mad Hatter. The hyperirritability can be associated with violent behaviors, with some descriptions of assaultive and homicidal aggression. Ataxia and gait instability has also been described in the context of chronic mercury exposure, and this syndrome can be associated with additional signs that include vertigo, nystagmus, blurred vision, narrowing of the visual fields, optic neuritis and atrophy of the optic nerve, and peripheral neuropathy. In children, far more often than in adults, chronic inorganic mercurialism is associated with acrodynia, but this syndrome involves generalized irritability and dysautonomia and has no associated movement disorder. Organic mercury readily enters the brain from the blood, and brain turnover is slow. In chronic exposure, $10% of the body burden localizes in the brain. With acute intoxication, less than 3% is degraded into inorganic brain mercury, but this rate may change with chronic exposure. Specifically, inorganic mercury levels may account for 82100% of brain mercury after organic mercury exposure if the autopsy is done several years after exposure. Once biotransformation to inorganic mercury occurs, excretion rates are extremely low since inorganic mercury cannot leave the brain easily. Anatomic changes in the brain involve especially the primary visual cortex and cerebellum followed by the putamen and frontal/parietal lobes. Peripheral nerves are also damaged. Because organic mercury is converted to inorganic metal, the intoxication syndrome seen after organic mercury exposure largely mimics the signs seen with inorganic exposure. Alkyl mercury poisoning has followed the ingestion of contaminated sea food or exposure to alkyl mercury used in seed grain as an antifungal additive. Massive intoxication occurred in individuals living in the vicinity of Minamata Bay, Japan, as a result of ingestion of fish and shellfish containing methyl mercury. After effluent containing inorganic mercury from an adjacent chemical plant was deposited in sea water, mercury was methylated by microorganisms in the sediment, and methyl mercury so formed was incorporated into the protein of fish and shellfish. Alkyl mercury remains bound to protein for long periods as the half-life is several years. The intoxication occurred after humans consumed contaminated sea food. In 1972, another catastrophic epidemic of methyl mercury poisoning occurred in Iraq. Over 6000 patients were hospitalized for treatment, and 459 known fatalities occurred, principally as a result of eating homemade bread prepared from seed treated with a methyl mercury fungicide. At the cellular level, alkyl mercury compounds share many of the biochemical effects of their inorganic counterparts and form complexes with sulfhydryl radicals. The bloodbrain barrier provides little impediment to the crossing of alkyl mercurials.

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The primary neurological syndrome of this form of intoxication involves neuropathy, visual field defects, and blindness, many patients demonstrate evidence of cerebellar involvement, with unsteady gait, slurred speech, and poor coordination. Less frequent movement disorders include resting or postural tremor, chorea, athetosis, myoclonus, and rigidity. Prominent behavioral problems include labile affect, mental deterioration, comatose states, and even akinetic mutism.

potentially adverse systemic effects. Spironolactone has also been employed in the experimental treatment of inorganic mercury poisoning. The protective effect appears to be related to increasing stool excretion through a yet unknown mechanism.

Prognosis
Most patients with severe mercury poisoning die within a few weeks of symptom onset, and those who survive have major neurological disability. In those with mild or moderate neurological symptoms, especially children and young adults, improvement may occur within the first 6 months. Examples have also been reported of ataxic, bedridden individuals who regained the ability to walk, and some children who were totally blind regained vision.
See also: Ataxia; Athetosis; Chorea; Tremor.

Diagnosis
It is difficult to diagnose mercury toxicity from laboratory data because of variability of blood and urine measurements. While measurements in blood and hair are less variable than those in urine, these do not accurately reflect the degree of mercury toxicity. In urine, levels higher than 35 mg g1 creatinine are considered elevated. Hair samples must be collected according to specific protocols. For example, head samples must be taken close to the scalp and then washed to remove contaminants such as hair dyes or hair treatments. The advantage of hair samples is that they provide exposure information for the past year. Pubic hair has the advantage of being more likely free of mercury-containing surface contaminants. Subclinical slowing of finger tap speed has been detected in subjects with regular high fish consumption and levels of urinary organic and inorganic mercury that were higher than controls, but still far lower than the levels cited above.

Further Reading
Albers JW, Kallenbach LR, and Fine LJ (1988) Neurological abnormalities associated with remote occupational elemental mercury exposure. Annals of Neurology 24: 651659. Carta P, Flore C, Alinovi R, and Ibba A (2003) Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through fish consumption. Neurotoxicology 24: 617623. Davis LE, Kornfeld M, Mooney HS, and Fieldler KJ (1994) Methyl mercury poisoning: Long-term clinical, radiological, toxicologic, and pathologic studies of an affected family. Annals of Neurology 35: 680688. ` s C, Beuter A, Richer F, and Poitras K (2005) Neuromotor Despre functions in Inuit preschool children exposed to Pb, PCBs and Hg. Neurotoxicology and Teratology 27: 245257. Goetz CG and Washburn KR (1999) Metals and neurotoxicology. In: Blain PG and Harris JB (eds.) Medical Neurotoxicology, pp. 181200. London: Arnold. Gorell JM, Johnson CC, Rybicki BA, and Peterson EL (1999) Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinsons disease. Neurotoxicology 20: 239247. Iwata T, Sakamoto M, Feng X, Yoshida M, and Liu XJ (2007) Effects of mercury vapor exposure on neuromotor function in Chinese minors and smelters. International Archives of Occupational and Environmental Health 80: 381387. Kazantzis G (2002) Mercury exposure and early effects: An overview. Medicina del Lavoro 93: 139147. Sharma DC (1987) Biochemical basis of the toxicity of mercury. Medical Hypotheses 23(3): 259263. Wastensson G, Lamoureux D, Sallsten G, and Beuter A (2006) Quantitative tremor assessment in workers with current low exposure to mercury vapor. Neurotoxicology and Teratology 28: 681693.

Treatment
For treatment, mercury-binding compounds augment excretion of the metal in intoxicated patients regardless of the type of mercury exposure. The agents employed include D-penicillamine, n-acetyl-DL-penicillamine, and thiol resins. Dimer-caprol (BAL) is no longer utilized, because it increased the cerebral mercury concentrations in animals experimentally receiving the methyl form. Administration of chelating agents results in only irregular removal of mercury from the body. When chelating agents are administered, mercury concentrations of blood increase for 13 days, presumably as a result of rapid mobilization from the tissues and a slower rate of urinary and fecal excretion. After this period, blood concentrations decline. Thiol resins are not absorbed from the gastrointestinal tract, so they can be administered orally to bind mercury in bile and other fluids within the intestine. Fecal excretion is then enhanced by preventing reabsorption of methyl mercury so that redistribution of mercury in the body will not occur. Because thiol resins cannot reenter the body, they have no

Relevant Websites
www.movementdisorders.org Movement Disorder Society.