Methylmercury blood-brain barrier

Kerper LE, Ballatori N, Clarkson TW. 1992. Methylmercury transport across the blood-brain barrier by an amino acid carrier. Am J Physiol 262 R761-R765. 

Most cases of mercury poisoning led to handicap, chronic disease, or death. The most frequent symptoms include numbness of limbs, lips and tongue, speech abnormalities, limb function disorders, visual acuity disorders, deafness, and muscular atrophy. Insomnia, hyperactivity, and coma have also been reported. Methylmercury penetrates the blood-brain barrier and causes central nervous system injuries. Mercury also has a teratogenic effect, leading to congenital abnormalities or congenital Minamata disease. 

Nervous System. The nervous system is also a common target of toxic metals particularly, organic metal compounds (see Chapter 16). For example, methylmercury, because it is lipid soluble, readily crosses the blood-brain barrier and enters the nervous system. By contrast, inorganic mercury compounds, which are more water soluble, are less likely to enter the nervous system and are primarily nephrotoxicants. Likewise organic lead compounds are mainly neurotoxicants, whereas the first site of inorganic lead is enzyme inhibition (e.g., enzymes involved in heme synthesis). 

With respect to distribution in the body, the methylmercury species behave more like mercury metal, Hg(0), than inorganic mercury(II), Hg2+. Like elemental mercury, methylmercury compounds traverse the blood-brain barrier and affect the central nervous system. However, the psychopatho-logical effects of methylmercury compounds (laughing, crying, impaired intellectual abilities) are different from those of elemental mercury (irritability, shyness). 

The definition of neurotoxicity also indicates a potential difference between the developing and the mature nervous system, to underscore the fact that developmental neurotoxicity is an important aspect of neurotoxicology. Most known human neurotoxicants are indeed developmental neurotoxicants.4 In most, but not all cases, the developing nervous system is more sensitive to adverse effects than the adult nervous system, as indicated, for example, by the most deleterious effects of ethanol, methylmercury, or lead when exposure occurs in utero or during childhood. Furthermore, the blood-brain barrier (BBB), which protects the mature nervous system from the entry of a number of substances, appears to be poorly developed at birth and during the first few years of life.6... 

The existence of the blood-brain barrier does not preclude the passage of chemicals into the brain. As is the case with all other cellular membranes in the body, lipid-soluble nonionized chemicals enter the brain by passive diffusion. Anesthetics, ethanol, and CNS depressants, for instance, rapidly diffuse into the brain in a matter of a few seconds or minutes. They also exit the brain rapidly when the concentration gradient between blood and brain is reversed. Elemental mercury, methylmercury, and tetraethyl lead are examples of lipid-soluble forms of metals that easily enter the brain, while the ionized, much less lipid-soluble inorganic salts of mercury and lead penetrate only poorly. 

Methylmercury is rapidly and nearly completely absorbed from the gastrointestinal tract 90-100% absorption is estimated. Methylmercury is somewhat lipophilic, allowing it to pass through lipid membranes of cells and facilitating its distribution to all tissues, and it binds readily to proteins. Methylmercury binds to amino acids in fish muscle tissue. The highest methylmercury levels in humans generally are found in the kidneys. Methylmercury in the body is considered to be relatively stable and is only slowly transformed to other forms of mercury. Methylmercury readily crosses the placental and blood/brain barriers. Its estimated half-life in the human body ranges from 44 to 80 days. Excretion of methylmercury is via the feces, urine, and breast milk. Methylmercury is also distributed to human hair and to the fur and feathers of wildlife measurement of mercury in hair and these other tissues has served as a useful biomonitor of contamination levels. 

Thiomerosal is metabolized to ethylmercury and thiosalicylate. Toxicologists have assumed that ethylmercury poisoning is similar to the toxicity of me-thylmercury. Flowever, ethylmercury cannot bypass the blood-brain barrier as easily as methylmercury. The entry of methylmercury into the brain relies on an active transport system. Ethylmercury on the other hand is a larger molecule and cannot use this system. Furthermore, it is more rapidly decomposed. Because of these limitations, when the same dose of both mercurial compounds is administered, the concentrations of methylmercury are greater in the brain when compared to ethylmercury. Due to the limited entry of the latter into the brain, this compound is more likely to cause damage to the spinal cord, myocardium and skeletal muscle. 

Tissue distribution of phenylmercury is initially similar to methylmercury. One week after administration, the distribution pattern resembles that seen after administration of inorganic compounds (Nordberg 1976). Once in the blood, phenylmercury distributes to a greater extent into the red blood cells than the plasma. Phenylmercury also predominantly distributes to the liver (Berlin 1963). It is less permeable to the placental and blood-brain barriers than methylmercury (Yamaguchi and Nunotani 1974). Phenylmercury also accumulates in the fur of rats but to a lesser extent than detected with methylmercury exposure (Gage 1964). 

The compartments and barriers to methylmercury transport in the tissue compartments and placenta are shown in Figure 2-6. The cell membrane is assumed to be the barrier for methylmercury transport for all tissues except the brain and placenta. The barrier to methylmercury transport to the brain is the endothelial cell wall of the cerebral vascular system (the blood-brain barrier). The placenta is modeled as four compartments, with separate transfer constants for placental barrier and placental tissue transport. There is a tissue compartment for both the maternal and fetal sides of the placenta. 

Mercury is unusual in its ability to induce delayed neurological effects. This is especially prevalent with exposure to alkyl mercury compounds. In such cases, the onset of adverse effects may be delayed for months after the initial exposure. The delayed effects of methyl- and dimethylmercury reported in human poisonings are thought, in part, to result from binding to red blood cells, and subsequent slow release. Methylmercury also forms a complex in plasma with the amino acid cysteine, which is structurally similar to the essential amino acid methionine (Aschner and Clarkson 1988). Clarkson (1995) proposed that methylmercury can cross the blood-brain barrier "disguised" as an amino acid via a carrier-mediated system (i.e., transport is not solely the result of methylmercury s lipid solubility). 

Yasutake A, Adachi T, Hirayama K, et al. 1991a. Integrity of the blood-brain barrier system against methylmercury acute toxicity. Eisei Kagaku 37(5) 355-362. 

Today the predominant if not the sole source of methylmercury is derived from the methylation of inorganic mercury in aquatic sediments and soils. Methylmercury is well absorbed from the diet and distributes within a few days to all tissues in the body. It is present in the body as water-soluble complexes mainly, if not exclusively, attached to the sulfur atom of thiol ligands, and crosses the blood—brain barrier without hindrance, entering the endothelial cells of the blood—brain barrier as a complex with L-cysteine. The principal target tissue of MeHg is the brain, and its major toxic effects are on the central nervous system. Whereas adult poisoning affects the visual cortex and the cerebellum, in neonatal infants the outcome can be much more serious, ranging in its effects from cerebral palsy to developmental retardation. 

The most insidious mercury toxin is methylmercury, which accumulates in various organs and is able to cross both the placental and blood-brain barriers to harm the fetus (Craig, 1986 Fergusson, 1990). 

More recently, 2,3-dimercaptosuccinic acid 11.25) has been introduced because it has the following advantages over dimercaprol it is active orally, penetrates the blood—brain barrier, and actually removes methylmercury ion from the brain (Aaseth and Friedheim, 1978). This ion is often consumed, by whole communities, from dressed seed or from fish exposed to mercury-containing industrial waste. Another orally active analogue, undergoing trials, is 2,3-dimercaptopropane-1 -sulfonic acid. 

Methylmercury transport across the blood-brain barrier appears to be mediated by the large neutral amino acid transport system (system L) on the luminal surface of brain capillary endothelial cells (Kerper et al. 1992). Previous in vivo studies had shown that the amino acid, L-cysteine, accelerates methylmercury uptake into brain in vivo, but the mechanism was not identified. Because the methylmercury-L-cysteine complex has close struc-... 

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Uptake of lead and reaction of brain capillaries. Arch. Neurol, 31, 382-389 Hargreaves, R. J., Moorhouse, S. R., Gangolli, S. D. and Pelling, D. (1986) The effects of methylmercury on glucose transport, glucose metabolism and blood flow in the central nervous system of the rat. In Suckling, A. ]., Rumsby, M. G. and Bradbury, M. W. B. (eds). The Blood-Brain Barrier in Health and Disease (Chichester Ellis Horwood)... 

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