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Toxicology 244 (2008) 1–12
Review
Molecular mechanisms triggered by mercury GianPaolo Guzzi b , Caterina A.M. La Porta a,∗ a
Department of Biomolecular Science and Biotechnology, University of Milan, Celoria 26, Milan, Italy b AIRMEB Italian Association for Metals and Biocompatibility Research, Italy Received 24 September 2007; accepted 2 November 2007
Abstract Mercury is an ubiquitous environmental toxin that causes a wide range of adverse health effects in humans. Three forms of mercury exist: elemental, inorganic and organic. Each of them has its own profile of toxicity. Exposure to mercury typically occurs by inhalation or ingestion. Mercury can be an indoor air pollutant, however industry emission remains the most important source of inhaled mercury. Furthermore, fresh water and ocean fish may contain large amounts of mercury and dental amalgam can be another important source of inorganic and mercury vapor. The present review discusses the current information on mercury toxicity and the distinct toxicologic profile of the three forms of mercury. The existing therapeutics, new therapeutics development or agents for treating mercury poisoning will also discussed. Since in general low levels of mercurial are tolerable, herein, we also discuss the defensive mechanisms developed by the cell to protect itself against mercury injury. This aspect may be useful to provide a biological protection against toxic effects exerted by mercury or by specific forms of mercury in view of a medicinal purposes. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Mercury; Toxicity
Contents 1.
2.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Methyl and ethyl mercury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Elemental mercury (Hg◦ ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Inorganic mercury compounds (I-Hg) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapeutic and agent treating mercury poisoning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. DMPS – Unithiol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. DMSA – Succimer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. d-Penicillamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. BAL – British anti Lewisite – 2,3-dimercaptopropanol - dimercaprol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. EDTA – Edetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Nonspecific supportive therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Corresponding author. Tel.: +39 0250314927; fax: +39 0250314932. E-mail address:
[email protected] (C.A.M. La Porta).
0300-483X/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.tox.2007.11.002
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3. 4. 5.
2.7. N-acetyl cysteine (NAC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.8. Selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.9. Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.10. Choline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Overviews of mercury chelating agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intracellular mechanisms of protection to mercury toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Overall comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Over the past century, there has been an increasing awareness throughout the world of the health and developmental risks associated with environmental exposure to toxic metals, such as lead (Pb), mercury (Hg), cadmium (Cd) and arsenic (As). The element Hg is classified as a heavy metal (at.wt.: 200.59) and exists in three species: elemental mercury (Hg0 ) known as metallic mercury, inorganic mercury compounds (I-Hg), primarily mercuric chloride, and organic mercury, primarily methyl mercury (MeHg). 1.1. Methyl and ethyl mercury Methyl mercury (MeHg)-contaminated foods, primarily fish, is the most common exposure to organic mercury in humans. The serious health consequences of MeHg exposure was dramatically illustrated in 1953, when an epidemic of MeHg poisoning occurred in humans from the consumption of fish in villages around Minamata Bay, Japan (Tsubaki and Irukayama, 1997). The resulting medical disorders associated with this epidemic became known as “Minamata disease”. A similar fish-mediated epidemic of MeHg poisoning occurred in riverside villages along the Agano river in Niigata, Japan in 1964–1965 (Tsubaki and Irukayama, 1997). Another sentinel outbreak of MeHg intoxication occurred in rural Iraq in 1971–1972 from seed grain treated with an Hg-based fungicide that was to be used for planting. More than 6500 individuals were hospitalized and 459 died from consumption of Hg-contaminated bread. In both Japan and Iraq disasters, which resulted from high-dose chronic and acute MeHg poisoning, respectively, there were many deaths and other effects, which included mental retardation, cerebral palsy, deafness, blindness, and dysarthria, especially in children exposed in utero. Although, epidemics are today uncommon, pervasive chronic low-level organic Hg exposure, primarily through the widespread consumption of fish, is a concern because there is evidence that low-level exposure is linked to subtle neurodevelopment disabilities. About
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95% of MeHg ingested by fish is absorbed in the gastrointestinal tract, although the exact site of absorption is not known (US EPA, 1997, 2001; ATSDR, 1999). About 5% is found in the blood compartment and about 10% in brain. MeHg cross the placental barrier. Levels in cord blood slightly higher than levels in maternal blood. Levels in the foetal brain are about 5–7 times that in maternal blood (Cernichiari et al., 1995). MeHg is slowly metabolised to inorganic mercury mainly by microflora in the intestines, probably at a rate of about 1% of the body burden per day. Although, MeHg is the predominant form of mercury, during exposure to inorganic mercury slowly accumulates and resides for long periods in the central nervous system. It is believed to be in an inert form, probably insoluble mercury selenite (WHO, 1990). Urinary excretion of MeHg is negligible and undergoes extensive enterohepatic cycling. A fraction of the biliary mercury is converted by microflora to inorganic mercury. Thus, most of the MeHg is eliminated from body by demethylation and excretion of the inorganic form in the feces. MeHg is present in the body as water-soluble complexes mainly, if not exclusively, attached to the sulfur atom of thiol ligands. It enters the endothelial cells of the blood–brain barrier as a complex with l-cystein. The major toxic effects of MeHg are on the central nervous system. In adult the action of MeHg is characterised by a latent period between exposure and onset of symptoms depending of the dose and exposure period. The mechanism underlying this long latent period is still unknown. Paresthesia is the first symptom to appear at the lowest dose (Bakir et al., 1973). This may progress to cerebellar ataxia, dysarthria, constriction of the visual fields and loss of hearing. These signs and symptoms are caused by the loss of neuronal cells in specific anatomical regions of the brain. During development, McKeown-Eyssen and collaborators investigated the relationship of neurological and developmental deficits to MeHg exposure from contaminated fish in 234 Northern Quebec Cree Indian children aged 12–30 months (McKeown-Eyssen and Ruedy, 1983). The most prevalent neurological deficit was abnormal muscle tone or tendon reflexes which were
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significantly associated with MeHg exposure in the boys only. Clinical neurological outcomes of MeHg exposure were also investigated in a Peruvian population of 131 mother-child pairs in a fishing village in Mancora, Peru between 1981 and 1984 (Marsh et al., 1995; Myers et al., 2000). The population was exposed to MeHg apparently from regular consumption of marine fish. This study showed no relationships between MeHg exposure and neurological outcomes. The most frequently cited and informative large sample epidemiological studies of the developmental neurotoxicity of MeHg are the Seychelles Child Development study (Davidson et al., 1995, 1998; Myers et al., 1995a,b,c,d) and the Faroe Islands investigations (Grandjean et al., 1997, 1998, 1999). No relationship between MeHg exposure due to fish diet and development effects appeared from all these literature. Ethylmercury (EtHg) is an organic Hg compound and in form of thimerosal has been used as topical antiseptic and as a preservative in vaccines routinely given to children. Thimerosal contains 49.6% Hg by weight and is metabolized to EtHg and thiosalicylate. The normal dose of a pediatric vaccine contains about 12.5–25 mg of Hg per 0.5 ml. In some cases, when vaccines containing thimerosal have been given at their recommended doses, local hypersensitivity reaction has been observed (Ball et al., 2001). In July, 1999 a requested plans from vaccine manufacturers about removing thimerosal from vaccines and now, it has been removed from most vaccine in United States and in other European countries such as Italy but it is still used in some developing countries. In recent years has been concern that EtHg exposure may induce neuro-developmental disabilities such as language delay, attention deficit-hyperactivity disorder but especially autism spectrum disorder (Geier and Geier, 2005). The adverse effects of high dose EtHg are thought to be similar to those of high-dose MeHg (Ball et al., 2001; Halsey, 1999) but the effects of low dose EtHg are unclear. A recent review suggests that EtHg is less toxic neurologically than MeHg (Magos, 2001). Furthermore, in an experimental study, using cortical human neurons, thimerosal was found to change cell membrane permeability and induce DNA breaks and apoptosis at micromolar concentrations (Baskin et al., 2003). 1.2. Elemental mercury (Hg◦ ) Elemental mercury (Hg◦ ) is a naturally occurring metal that exists uniquely in liquid form at room temperature and quickly turns to vapor when heated. The natural sources of Hg◦ in the environment include the
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release of Hg gases from volcanic eruptions and the erosion of ores that contain Hg. Sources of Hg◦ exposure from human enterprise include industrial fossil fuel emission, topical medicines, cathartics, dental amalgam, thermometers, sphygmomanometer, barometers, incandescent lights, batteries, medical waste incineration, and Hg-based substances used in ritualistic practices. Elemental Hg is more hazardous to humans in the vaporized state. Most early clinical reports of Hg◦ intoxication typically involved adults with occupational exposure to Hg vapors or dust (Malm, 1998; Ratcliffe et al., 1996; Sweet and Zelikoff, 2001). Exposure to toxic Hg◦ vapors may be acute or chronic, occupational or residential. Both acute or chronic Hg◦ exposure may induce a broad sequels of reactions or symptoms, including cough, dyspnea, fever, tremors, malaise, axonal sensor motor polyneuropathy, gingivitis, delusions, hallucinations and mercurial erythrism, a syndrome that includes excitability, loss of memory, insomnia, extreme shyness and neurocognitive disorders (Vroom and Greer, 1972; WHO, 1991). More that 80% of Hg◦ vapor is absorbed by the lungs. Oxidized Hg◦ is accumulated in the brain, liver and cortex of the kidney. The biotransformation of highly lipid-soluble Hg vapor to mercuric Hg in the brain may lead to an accumulation of Hg2+ in the cortex and cerebellum, producing impairment of the CNS. Hg◦ is eliminated through urine and faecal excretion but a low amount through exhalation, sweat and saliva. Several studies over the past 30 years have demonstrated that amalgam filling releases mercury vapor into the oral cavity. Mouth breathing carries the vapor to the lung where it is absorbed and distributed to tissues. Excessive chewing such as occurs when smokers try to stop smoking by using nicotine-containing chewing gum may lead to urine levels in excess of 20 microHg/g creatinine, thereby approaching occupational health safe limits (Sallsten et al., 1996). 1.3. Inorganic mercury compounds (I-Hg) Inorganic Hg (I-Hg) compounds (mercury salts) are also a significant source of Hg intoxication in some countries. Inorganic Hg have been used for many years in numerous products, including various medications, germicidal soaps, teething powders, and skin creams. Many of these Hg-based products are still in use today (Goldman and Shannon, 2001). Some skin cream contains as much as 6–10% mercurial chloride or calomel. For many years, mercurial chloride calomel was used in infant teething powders, worm drugs, and as an analgesic. Inorganic mercurial preparations may induce
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fatigue, insomnia, weight loss, paresthesia of the feet and hands, erythema, pruritus, excessive perspiration and hyper salivation, progressive weakness in the extremities, renal tubular dysfunction, and neuropsychiatry disorders (Dyall-Smith and Scurry, 1990; Weldon et al., 2000). Mercurial mercury such as calomer, a bivalent inorganic mercury salt added to teething powder, was reported to give immunoallergic reaction (Clarkson, 2002). Acrodynia was also reported in babies who were in contact with diapers treated with phenyl mercury, which is an organic form of mercury (Clarkson, 2002). Inorganic mercury exposure may induce another immunotoxic response from the immune system, especially in children: the Kawasaki disease. Individuals affected by this disease have the following symptoms: fever, photophobia, pharyngitis, oral lesions, fissured lips, skin rashes, shedding of the skin on the palms and soles, peripheral extremity changes, tachycardia, and lymphoid tissues involvement. Infants and children have a higher absorption rate of inorganic mercury with respect to adults (Walsh, 1982; Goyer and Clarkson, 2001). Also, patients with Kawasaki syndrome have shown higher levels of mercury in urine compared to controls. 2. Therapeutic and agent treating mercury poisoning In this section, we review the properties of mercury mobilizing and chelating agents and we discuss what is known about the possibility to remove mercury from the accumulated metal in tissues. Chelating agents are primarily sulfhydril-containing compounds such as mono- or dithiol molecules. At the molecular level, the chelation process appears as an inevitable tug of war between the chelating agents and the competing biological ligands (Andersen and Molecular, 2002). In the past 50 years there has been substantial progress in understanding, developing and clinical application of chelating agents used to treat acute and chronic mercury poisonings in humans. Particularly, considerable time and efforts have been made with regard to the capacity of mobilizing and removing the mercury from organs and tissues after exposure to inorganic mercury salts and mercury vapor (Baum, 1999). Of these drugs developed as chelating agents and tentatively used as specific chelators with respect to mercury we listed: DMPS – DMSA – d-penicillamine – BAL – EDTA. Concept of synergy between the various antidotes has been considered even though is much controversial. It
Fig. 1. The structure of DMPS, the current most effective chelator of mercury in case of mercury poisoning.
is important to emphasize that a good chelator is usually water soluble, while lipophilic chelators may have a redistribution effect of the mercury to the target organs (Baum, 1999). 2.1. DMPS – Unithiol The water-soluble sodium salt of 2,3-dimercapto-1propane sulfonic acid (acronym DMPS) (Fig. 1) has been considered by the World Health Organization Expert committee as the first-line drug for ascertained inorganic mercury acute and chronic poisoning (Campbell et al., 1986; WHO, 1991). The chemical formula of this dithiol is C3 H7 O3 S3 Na, akin to BAL from which it is derived. The DMPS may be administered both orally and by intravenous (iv) continuous infusion. In experimental models, DMPS has been suggested as a useful drug to prevent fatal damage in fetus associated with methyl mercury exposure during pregnancy. This chelating agent was also able to protect the pregnant mice against methyl mercury exposure (Domingo, 1995). An underlying mechanism that underpins chelation activity of inorganic mercury is that DMPS molecules are conveyed to kidney’s functional unit, the nephrons, on the organic anion acid system (Zalups, 1993; Goyer and Clarkson, 2001). Penetration of DMPS into the kidney cells allows mobilization of mercury accumulated in renal tissues. Once chelated with DMPS, mercury is filtered into urine, which represents the most important route of elimination after mobilization. Considerable clinical and experimental evidence suggests that DMPS is capable of removing a substantial amount of mercuric mercury deposited in human tissues. After DMPS administration, the measurement of total mercury in urine provides an early elimination of the metal peaking within six hours. This ground breaking study was performed by Aposhian et al. (1992), when for the first time, he correlated the levels of urine total mercury with the number of dental amalgam surfaces in a dental team (Aposhian et al., 1992). The findings provided by these data imply that mercury dental amalgams are the most important source of inorganic and mercury vapor for the general population and the concentrations of mercury in urine post-chelation challenge testing with DMPS reflect the current body burden
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of mercury (Aposhian et al., 1992; Echeverria et al., 1998). DMPS is also able to induce an increased excretion of mercury in urine among individuals who have an extensive industrial exposure to metallic mercury A (Andersen and Molecular, 2002). In these cases, the concentrations of urinary mercury are influenced by the accumulated long-term body burden. The uptake of mercuric mercury in intestinal tract is importantly reduced by the chelation with both DMPS and DMSA. In this way, even the local toxicity of the metal should be remarkably reduced (Nielsen and Andersen, 1991; Andersen and Molecular, 2002). Importantly, data from animal studies have shown that DMPS does not redistribute the mercury to the brain subsequent to the following exposure to mercury chloride (Planas-Bohne, 1981; Nielsen and Andersen, 1991; Aposhian et al., 1992). Despite the acknowledged mercury-mobilizing proprieties in various human clinical studies, DMPS administrated in mercury poisoned animal model has failed to remove the mercury from tissues (Aposhian et al., 2003). These findings made it clear that neither DMPS nor DMSA have showed to be effective in post exposure treatment of mercury vapor in animal model, demonstrating thus that the use of current chelating agents did not reduce the inorganic mercury burden from the most important target organ: the brain. In view of the practical implications, it is interesting to note that contrary to what was thought even glutathione (GSH), N-acetyl cysteine (NAC), vitamin C (as sodium ascorbate) and lipoic acid were unable to reduce the concentrations in kidney and brain (Aposhian et al., 2003). The rate of removal of mercuric mercury from the renal burden in rats is considered to be higher greater superior with DMPS compared to DMSA (Buchet and Lauwerys, 1989; Aposhian et al., 1992). DMPS chelation challenge has been proposed in clinical settings to evaluate the mercury body burden from dental amalgams. However, this purpose is in contrast to the findings of other reports. These investigators have found that there was no significant difference in both blood and urine total mercury levels in group of subjects with or without dental amalgam fillings after intravenous injection of DMPS (Vamnes et al., 2003). 2.2. DMSA – Succimer Also termed ‘succimer’, the meso-2,3-dimercaptosuccinic acid isomer (acronym DMSA) displays capability to diminish blood lead concentration. Its chemical formula is C4 H6 O4 S2 (Fig. 2).
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Fig. 2. Structural formula of DMSA, a useful chelator in case of mercury intoxication.
It has been considered a safe and nontoxic chelating agent for lead poisoning and approved by the Food and Drug Administration since 1991. Previous studies in this area have shown that the DMSA has a notable specificity to lead in humans. In addition, a clinical trial has evidenced that this antidote is able to induce a shortterm reduction of blood levels in children exposed to lead, but there was no evidence of it being beneficial on health outcome (Rischitelli et al., 2006). Even during pregnancy, in animal models, subcutaneous treatment with DMSA may prevent embryo lethality as well as embryo- and fetotoxicity (Domingo, 1995). Pregnant mice which had received high dosage of DMSA for various days had a decreased number of dead fetuses. When DMSA dosage was diminished and given only one time, there was evidence of reduced skeletal defects and cleft palate (Domingo, 1995). In an experiment on animal model, DMSA seemed to have the ability to diminish the methyl mercury levels in the brain (Aaseth and Frieheim, 1978). In humans, mercury is mobilized by DMSA and this occurs primarily in kidneys (Zalups, 1993). The advantages of DMSA, like DMPS, are that they both are easily administrated and have useful effects on the body burden of mercury retained in tissues. With regard to the mercury deposited in brain tissues, DMSA does not cross the blood–brain barrier in animals and humans studies (Aaseth et al., 1995). Recently, in an observational case-control study in adult patients with motor neuron disease, Louwerse et al. (1995) detected no differences in urine mercury levels between case and controls subjects after oral administration of 20 mg/Kg of DMSA. Likewise, these results are similar to those reported by Frumkin et al. (2001). The authors conclude that DMSA chelation challenge lacks usefulness in subjects who have been occupationally exposed to mercury. Indeed, there was no substantial variation among measured total mercury levels in urine of exposed subjects compared to the controls after chelation challenge testing with DMSA (Frumkin et al., 2001). Finally, to prevent potential neurotoxic effects, DMSA has been used to treat children who had overexposure to metallic mercury.
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Fig. 3. d-penicillamine: the chemical structure.
In this report by Forman et al. (2000) there was no evidence of any adverse events to this chelating agent, which showed to be indicated in pediatric post exposure prophylaxis of metallic mercury among acute-overexposed children. 2.3. d-Penicillamine As monthiol sulfhydrilic antidote (,,-dimetilcysteine) the d-penicillamine has a high affinity for mercury, owing to the presence of sulfur molecules. Given its ability to chelate copper, d-penicillamine has also been used to treat the Wilson’s disease. Penicillamine has a preventive effect on developmental toxicity. In animal models, if injected parenterally few hours after oral administration of methyl mercury chloride in pregnant rats, it was able to prevent morphologic changes in the fetal brain (Aposhian et al., 1992). Penicillamine, and its derivate N-acetyl-dl-penicillamine, have been shown to reduce the blood methyl mercury levels among persons poisoned with methyl mercury (Clarkson et al., 1981). Despite its clinically significant effects during removal of metals such as lead, mercury, and iron, there may be potential adverse outcome. Pediatrically, it has been reported that penicillamine was unable to help in two cases of acrodynia due to mercury poisoning (Karagol et al., 1998) (see Fig. 3).
effects against organic mercury compounds (Goyer and Clarkson, 2001). Even if more rarely, it is still used in some clinical circumstances of mercury poisoning (Torres-Alanis et al., 2000; Koyun et al., 2004). In studies involving animal models, BAL did not protect maternal and fetal toxicity against exposure to methyl mercury chloride (Domingo, 1995). Over the past 30–40 years, it has been utilized to selectively remove inorganic mercury from the kidneys. This chelator is not able to remove the organic forms of mercury from the tissues. Moreover, there is a mercury rise in mouse brain when animals are exposed to almost all forms of mercury (Berlin and Ullberg, 1963; Aaseth and Frieheim, 1978; Goyer and Clarkson, 2001). In humans, BAL-related adverse events may be clinically significant, accounting for nearly 55% of patients treated (Aposhian et al., 1995). Reports of side effects include skin rashes, fever, vomiting, hyperhydrosis, high blood pressure and heart-rate abnormalities, headache, and muscoskeletal pains. BAL has an important clinical limitation. In fact, BAL injections are a painful and stressful procedure, particularly for children and involve the injection of a local anesthetic (see Fig. 4). 2.5. EDTA – Edetate
2.4. BAL – British anti Lewisite – 2,3-dimercaptopropanol - dimercaprol
Etilendiammintetraacetic acid (acronym as EDTA). Chemical compound formula is C10 H12 N2 O8–4 . Clinically, it is used as calcium EDTA, which is the calcium disodium salt of EDTA. For individuals who have mercury exposure history, EDTA does not reduce the burden of mercury in human tissues (Goyer and Clarkson, 2001; Guldager et al., 1996). An important inherent limitation for using EDTA in chelation and elimination of mercury accumulated in organs is that EDTA is unable to enter in the cells.
The British anti Lewisite (acronym BAL) has been developed as specific antidote for cases of arsenical poisoning due to Lewisite gas exposure. It is an organic dithiol and its chemical formula is C3 H8 OS2 . Interestingly, BAL has been considered the first effective cure for mercury salt (e.g.; mercuric chloride), demonstrating that the outcome of inorganic mercury intoxication was improved after BAL administration. The use of BAL for the treatment of individuals with mercury intoxication is able to remove inorganic mercury from kidneys. There was no evidence of favorable
Fig. 4. Chemical formula of BAL first molecule used in mercury poisoning.
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It is necessary to use this molecule by intravenous route owing to that EDTA is adsorbed in very tiny quantities (less than 5%) (Aposhian et al., 1995; Goyer and Clarkson, 2001; Blanusa et al., 2005). Lead intoxication responds at the best to the calcium EDTA given parenterally, in fact, it is considered to be the treatment of choice of lead poisoning (Aposhian et al., 1995; Blanusa et al., 2005). However, as the affinity of EDTA for mercury is low, there is no evidence that calcium disodium EDTA is able to remove mercury from human tissues (Aposhian et al., 2003). In animal models, EDTA is teratogenic if administrated perorally, accounting for the zinc severe depletion after EDTA therapy. Although, calcium disodium EDTA is nonselective for mercury ions and data argue against the routine administration of EDTA in individuals with exposure to mercury, as it renders the subjects vulnerable due to chelation of vital trace elements but, still, many practitioners use this chelator for mercury chelation.
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treatment with NAC compared with unexposed controls (Watson et al., 2004). Data on embryo- and fetus toxicity are contrasting (Domingo, 1995). 2.8. Selenium Selenium, an essential trace element for human beings, is structurally incorporated into selenoproteins (selenomethionine and selenocysteine) and plays a key role as antioxidant. It constitutes the glutathione peroxidase, which protects the cells from being to damage by radical and oxidative stress (Rooney, 2007). In addition, selenium is an efficient catalyst involved in the production of the thyroid hormone. However, it also acts as toxic element in appropriate quantities. Among other mineral micronutrients, selenium has probably the major role in the relationship between mercury and its toxicity in human tissues. Currently, it seems to protect against mercury toxicity, leading to some health benefit.
2.6. Nonspecific supportive therapy
2.9. Vitamin E
Apart from chelating agents, a number of molecules have been proposed as secondary supportive therapy. Despite the lack of studies supporting the use of these secondary remedies for mercury detoxification, they are the most frequently prescribed drugs in patients with symptoms allegedly originated by mercurial exposure, dental amalgams, and in case of autism spectrum disorder linked to mercury (Aposhian et al., 2003). Here, we summarize below some of the common drugs recommended as nonspecific therapy to treat acute or chronic mercurial exposure.
Vitamin E is a lipid-soluble vitamin and occurs in various isomers in nature. Known as a potent antioxidant, it protects the cell from free radical injuries. In a case reported by Nierenberg et al. (1998) there was a fatal dimethylmercury exposure. During the treatment with DMSA (succimer), vitamin E was administrated against the oxidative injury induced associated with dimethylmercury poisoning.
2.7. N-acetyl cysteine (NAC)
There is evidence that the administration of choline – when given during prenatal period – seems to protect against neurotoxic effects caused by N-methyl-daspartic acid (NMDA) antagonists (Clarkson and Strain, 2003). Although, the effects of choline are still under investigation, it might serve as a useful novel substance to counteract the effects of methyl mercury chronic body burden.
According to the US Poison Control Center database, the monothiol N-acetyl cisteine (NAC) is the most common specific antidote used in emergency, both orally and parenterally (Watson et al., 2004). It is a cysteine-containing drug, which regenerates the glutathione substrate. The latter is involved and depleted in the process of detoxification. Unfortunately, as previously noted, a research in animal has suggested that post-exposure treatment with NAC among young rats exposed to mercury vapor failed to reduce the levels of mercury both in brain and in kidneys. Furthermore, there was evidence of an increased level of mercury in the brain associated to the post-exposure
2.10. Choline
3. Overviews of mercury chelating agents The treatment of mercury-induced toxicity is a critical point in medicine. Acute mercury poisoning may lead to potentially life-threatening events (Watson et al., 2004; Clarkson et al., 2003). In case of acute mercury
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intoxication, DMPS and DMSA appear to be superior in the improvement in patients’ conditions after exposed to mercury compounds. These two relatively new chelating agents such as DMPS and DMSA have both an evidence of superiority with regards to penicillamine and BAL in the treatment of human’s mercury poisoning in adults and children. Given caveats about the lack of reducing mercury in the brain after therapy with both DMPS and DMSA, there is a clear evidence that these chelating agents are unable to remove mercury within nervous system as well as they did not improve outcome in neurological patients who had been exposed to mercury (Sandborgh Englund et al., 1994; Louwerse et al., 1995; Aposhian et al., 2003). However, given the large quantities of mercury mobilizing and transporting to kidneys, there may be severe and long-standing adverse effects. We still have an unclear picture regarding the potential long-term adverse events triggered by mobilizing and chelating mercury agents. Specifically, it would be important to identify whether patients who had underwent treatments with chelating agents owing to acute or chronic exposure to mercury would be affected by auto immune diseases. Another possible difference in the clinical response to the mercury antidotes is the intra-individual variation in response to the amounts of mercury mobilized. We therefore suggest evaluating the impact of chelation therapy for mercury exposure with any chelating agents for immunotoxicity, which may develop over time. There is another important implication that it is important to point out. Even though DMPS and DMSA are proved superior to other chelators as mercury-mobilizing agents, clinicians are often forced to choose less effective therapy for their patients (e.g.; BAL, d-penicillamine) because of the unavailability of the DMPS and DMSA in many countries worldwide. Furthermore, it should be made clear that although chelating agents as DMPS and/or DMSA which may lead to a brisk clinical improvement in patients with mercury intoxication, however, these chelators might redistribute mercury in an action-at-distance in other tissues, especially in nervous tissues (Ewan and Pamphlett, 1996). Of note, in absence of published data on human distribution of chelating agents through the placental barrier, the use of chelators during the pregnancy should be avoided for safety reasons. In summary, in acute exposure, the best strategy available for reducing the mercury blood levels after mercury overexposure and/or overt poisoning consists of a timely use of DMPS and/or DMSA, preventing the mercury dis-
position in specific target organs such as kidneys and brain and within the body. 4. Intracellular mechanisms of protection to mercury toxicity Generally, human exposure to mercury results in neurologic and kidney disorders. As discussed above, the first indication of the special susceptibility of the developing brain to prenatal exposure to methyl mercury came from anecdotal reports from Minamata that mothers with mild symptoms gave birth to offspring with severe brain damage. The Iraq outbreak confirmed that severe brain damage occur from high prenatal exposure. A milder syndrome was also identified in the Iraq outbreak (Marsh et al., 1987). Children apparently normal nevertheless had a history of delayed achievement of developmental milestones and, on examination, exhibited neurologic abnormalities such as brisk tendon reflexes. An important question remains to understand the molecular mechanisms triggered by mercury and in particular why methyl mercury exhorts its toxic effects preferentially on the central nervous system. Lipid solubility of mercury compounds promotes accumulation in lipid-rich compartments such as the brain. In particular, chronic exposure to the lipid-soluble forms of Hg◦ (elemental mercury) and methylmercury perturb neuromotor, behavioural and cognitive functions (Shafer and Atchinson, 1991; Pekel et al., 1993; Atchison and Hare, 1994; Leonhardt et al., 1996a,b). Kidney is the critical organ following the ingestion of mercury salts (Jonnalagadda and Rao, 1993). Recently, inorganic mercury was demonstrated to affect the differentiative pathway of neural stem cells (Cedrola et al., 2003). On the other hand, a paper showed that mercuric chloride as well as methylmercury inhibits lymphocyte functions including proliferation, expression of cell activation markers on cell surface and cytokine production, inducing the cells to apoptosis. A key event in the induction of apoptosis is the depletion of all thiol reserves, which predisposes cell to ROS damage and at the same time, activates death-signalling pathways (Shanker and Aschner, 2003). In this connection, cytochrome c was shown to leak from the mitochondria upon organic mercury exposure (thimerosal), followed by caspase nine cleavage, caspase three activation, deleterious effects on the cytoarchitecture and initiation of mitochondrialmediated apoptosis (Humphrey et al., 2005). Recently, thimerosal was also demonstrated recently to induce apoptosis and G2-M phase arrest in human leukaemia cells (Woo et al., 2006). Because mercury has a high affinity for thiol (sulfydryl (SH)) groups, the thiol-
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containing antioxidant, glutathione (GSH), provides the major intracellular defence against mercury-induced neurotoxicity (James et al., 2005). According to these data, Sarafian suggested that the selective vulnerability of cells in the nervous system arise from a “critical absence of inherent protective mechanisms” (Sarafian et al., 1996). Cellular defences are obviously decisive in determining the toxic outcome and defense mechanism. Thiol compounds play a key role (Miura et al., 1994) and resistant cells were demonstrated to have higher levels of the thiol-containing peptide glutathione (Miura et al., 1994). Glutathione, in fact, plays an important role in the excretion of methyl mercury. Furthermore, the thiol-rich family of proteins, known generically as metallothioneins, plays a protective role for instance in kidney damage from inorganic mercury (Satoh et al., 1997). Accordingly, recently, metallothioneine-null mice showed more severe lung damage than normal mice after exposure to mercury vapor (Yoshida et al., 1999). Another potential important target in particular of methylmercury activity is the family of membraneanchored zinc-metalloproteases known as ADAMs (a dissintegrin and metalloprotease). ADAMs required for normal neural development (Fambrough and Goodman, 1996; Pan and Rubin, 1997; Rooke et al., 1996). ADAMs acts as “sheddases” by cleaving and realising the extracellular domains of a number of signalling receptors and ligands (Seals and Courtneidge, 2003). ADAM proteases are synthesized as pro-enzymes, which can be activated by organomercurials such as p-aminophenylmercuric acetate (APMA) (Fig. 5) (Bland et al., 2003; Sanderson et al., 2005). High affinity interaction of mercury with a conserved cysteine residue in the propeptide of ADAMs displaces the propetide, exposing the active site of the zinc-metalloprotease domain (Fig. 5) (Galazka et al., 1996; Van Wart and Birkedal-Hansen, 1990). A recent paper suggested that an increase in ADAM activity would influence the signalling activity of cell surface receptors (Bland and Rand, 2006). They demonstrated that Notch signalling, a pathway highly conserved that influences cell fate decision, proliferation, migra-
Fig. 5. Structure of ADAM.
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tion and neurite outgrowth during neural development (Artavanis-Tsakonas et al., 1999), are substrates for ADAM proteases and the resulting cleavage is an integral step in activation of these receptors. By knockdown of Notch protein expression, Bland et al. (2003) demonstrated that methyl mercury activate E(sp1) target genes. Interestingly, the methylmercury-induced activation of Notch is partially attenuated by the potent metalloprotease inhibitor GM60001 (Bland and Rand, 2006). Therefore, all these data support the hypothesis that methylmercury exerts some of its toxic effects through altering protease activity leading to alter signal activity of Notch receptors. 5. Overall comments Mercury is a ubiquitous components used for many purposes. Methyl mercury from fresh- and saline-water fish and mercury vapor from dental amalgams are the most important sources of mercury in the general population. Both methyl mercury and mercury vapor are highly reactive and neurotoxicant species, interacting mainly with thiol-based-proteins (-SH) in the human body. Currently, in various industrialized countries and in human population with much more poor healthy condition such as Africa, India, South America, burden of mercury can be near the safety limits. As shown by this review, the drugs used in case of mercury toxicity are insufficient and most of them act as specifically. Therefore, the investigation in the defensive mechanisms exerted by the cells to protect them from mercury toxicity is, in our opinion, a new way to identify a new and efficacy way to mercury toxicity. In particular, both metallothioneins and glutathione appear to have a strong relation with inorganic mercury and organic mercury cytotoxicity, respectively, and the protective detoxifying mechanisms in humans. References Aaseth, J., Frieheim, E.A., 1978. Treatment of methyl mercury poisoning in mice with 2,3-dimercaptosuccinic acid and other complexing thiols. Acta Pharmacol. Toxicol. 42, 248–252. Aaseth, J., Jacobsen, D., Andersen, O., Wickstrom, E., 1995. Treatment of mercury and lead poisonings with dimercaptosuccinic acid and sodium dimercaptopropanesulfonate. A Rev. Anal. 120, 853–854. Andersen, O., Molecular, A.J., 2002. Mechanisms of in vivo metal chelation: implications for clinical treatment of metal intoxications. Environ. Health Perspect. 110 (Suppl 5), 887–890. Aposhian, H.V., Bruce, D.C., Alter, W., Dart, R.C., Hurlbut, K.M., Aposhian, M.M., 1992. Urinary mercury after administration of 2,3-dimercaptopropane-1-sulfonic acid: correlation with dental amalgam score. FASEB J. 6, 2472–2476. Aposhian, H.V., Maiorino, R.M., Gonzalez-Ramirez, D., ZunigaCharles, M., Xu, Z., Hurlbut, K.M., et al., 1995. Mobilization of
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