Metal chelators and neurotoxicity: lead, mercury, and arsenic.

This article reviews the clinical use of the metal chelators sodium 2,3-dimercapto-1-propanesulfonate (DMPS), meso-2,3-dimercaptosuccinic acid (DMSA), and calcium disodium edetate (CaEDTA, calcium EDTA) in overexposure and poisonings with salts of lead (Pb), mercury (Hg), and arsenic (As). DMSA has considerably lower toxicity than the classic heavy metal antagonist BAL (2,3-dimercaptopropanol) and is also less toxic than DMPS. Because of its adverse effects, CaEDTA should be replaced by DMSA as the antidote of choice in treating moderate Pb poisoning. Combination therapy with BAL and CaEDTA was previously recommended in cases of severe acute Pb poisoning with encephalopathy. We suggest that BAL in such cases acted as a shuttling Pb transporter from the intra- to the extracellular space. The present paper discusses if a combination of the extracellularly distributed DMSA with the ionophore, Monensin may provide a less toxic combination for Pb mobilization by increasing both the efflux of intracellularly deposited Pb and the urinary Pb excretion. Anyhow, oral therapy with DMSA should be continued with several intermittent courses. DMPS and DMSA are also promising antidotes in Hg poisoning, whereas DMPS seems to be a more efficient agent against As poisoning. However, new insight indicates that a combination of low-dosed BAL plus DMPS could be a preferred antidotal therapy to obtain mobilization of the intracerebral deposits into the circulation for subsequent rapid urinary excretion.

Selenium ameliorates mercuric chloride-induced brain damage through activating BDNF/TrKB/PI3K/AKT and inhibiting NF-κB signaling pathways.

Mercuric chloride (HgCl2), a heavy metal compound, causes neurotoxicity of animals and humans. Selenium (Se) antagonizes heavy metal-induced organ damage with the properties of anti-oxidation and anti-inflammation. Nevertheless, the molecular mechanism underlying the protective effects of sodium selenite (Na2SeO3) against HgCl2-induced neurotoxicity remains obscure. Therefore, the present study aimed to explore the protective mechanism of Na2SeO3 on HgCl2-induced brain damage in chickens. Morphological observations showed that Na2SeO3 alleviated HgCl2-induced brain tissues damage. The results also showed that Na2SeO3 decreased the protein expression of S100 calcium binding protein B (S100B), and increased the levels of nerve growth factors (NGF), doublecortin domain containing 2 (DCDC2), as well as neurotransmitter to reverse HgCl2-induced brain dysfunction. Further, Na2SeO3 attenuated HgCl2-induced oxidative stress by decreasing the level of malondialdehyde (MDA) and increasing the activities of total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC). Mechanistically, Na2SeO3 activated the brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase receptor type B (TrKB)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and suppressed the nuclear factor kappa B (NF-κB) signaling pathway to inhibit apoptosis and inflammation caused by HgCl2 exposure. In summary, Na2SeO3 ameliorated HgCl2-induced brain injury via inhibiting apoptosis and inflammation through activating BDNF/TrKB/PI3K/AKT and suppressing NF-κB pathways.

Hyperintense lesions in brain MRI after exposure to a mercuric chloride-containing skin whitening cream.

Exposure to inorganic mercury (Hg) is a serious problem presenting with a combination of neurological and psychiatric symptoms along with weight loss, pruritus, erythema, arterial hypertension, tachycardia, and renal tubular dysfunction. We report a 4-year-old girl with chronic intoxication of inorganic mercury secondary to the accidental use of an Hg2Cl2- and HgCl2-containing skin whitening cream (urine level of Hg, 41.1 µg/l; reference level, < 25 µg/l). Under treatment with dimercapto-1-propansulficacid, Hg level in the urine raised to 1,175.5 µg/l, neurological deterioration occurred, and brain magnetic resonance imaging (MRI) showed on fluid attenuated inversion recovery sequences new hyperintense lesions in the subcortical white matter. After 4 months, clinical signs and symptoms and brain MRI findings resolved. This is a first case of inorganic mercury poisoning showing hyperintense lesions in brain MRI and confirms earlier cases showing transient deterioration during chelation therapy. Although urinary excretion could be enhanced during chelation therapy, signs and symptoms of intoxication could be worsened.

Fisetin impedes developmental methylmercury neurotoxicity via downregulating apoptotic signalling pathway and upregulating Rho GTPase signalling pathway in hippocampus of F1 generation rats.

Methyl mercury is a teratogenic and neurodevelopmental toxicant in the environment. MeHg affects several biological pathways critical for brain development. The present study validated the effect of Fisetin on developmental MeHg exposure induced alterations in mitochondrial apoptotic pathway and Rho GTPase mRNA expressions in hippocampus of F1 generation rats. Pregnant Wistar rats were grouped as Group I : administered with vehicle control, Group II: MeHg (1.5 mg/kg b.w), Group III: MeHg + Fisetin (10 mg/kg b.w), Group IV: MeHg + Fisetin (30 mg/kg b.w), Group V: MeHg + Fisetin (50 mg/kg b.w), Group VI: MeHg + Fisetin (70 mg/kg b.w), Group VII: Fisetin (30 mg/kg b.w) alone. Fisetin reduced mercury accumulation in offspring brain. In hippocampus, Fisetin preserved mitochondrial total thiol status, glutathione antioxidant system, mitochondrial metabolic integrity and respiratory chain activity. Fisetin ameliorated apoptotic signals by preventing Cytochrome c release, down regulating ERK 1/2 and Caspase 3 gene expression. Fisetin also upregulated mRNA expressions of RhoA/Rac1/Cdc42 in hippocampus. Predominant effect of Fisetin was to reduce mercury accumulation in offspring brain there by diminishing the toxic effect of MeHg. Hence we showed that, gestational intake of Fisetin (30 mg/kg b.w.) impedes developmental MeHg neurotoxicity by regulating mitochondrial apoptotic and Rho GTPase signalling molecules and by reducing the mercury accumulation in hippocampus of F1 generation rats.

Biomarkers of exposure and effect as indicators of the interference of selenomethionine on methylmercury toxicity.

The present study was conducted to clarify the interference of selenomethionine (SeMet) on methylmercury (MeHg) toxicity through the evaluation of changes in biomarkers of exposure and effect in rats exposed to MeHg and co-exposed to MeHg and SeMet. Male Wistar rats received two intraperitoneally (i.p.) administrations, either MeHg (1.5mg/kg body weight), SeMet alone (1mg/kg body weight) or combined MeHg and SeMet, followed by 3 weeks of rat urine collection and neurobehavioural assays. The effects of different administrations were investigated by the quantification of total mercury in kidney and brain, analysis of urinary porphyrins, determination of hepatic GSH and evaluation of motor activity functions (rearing and ambulation). MeHg exposure resulted in a significant increase of urinary porphyrins during the 3 weeks of rat urine collection, where as it caused a significant decrease in motor activity only at the first day after cessation of rat exposure. Additionally, SeMet co-exposure was able to normalize the porphyrins excretion, and a tendency to restore rat motor activity was observed, on the first day after cessation of exposure. Brain and kidney mercury levels increased significantly in rats exposed to MeHg; however, in co-exposed rats to SeMet no significant changes in Hg levels were found as compared to rats exposed to MeHg alone. Hence, the present study shows that urinary porphyrins are sensitive and persistent indicators of MeHg toxicity and demonstrates for the first time that SeMet reduces its formation. Finally, these results confirm that the mechanism of interaction between SeMet and MeHg cannot be explained by the reduction of Hg levels in target organs and suggestions are made to clarify the interference of SeMet on MeHg toxicity.

Mercury intoxication: lack of correlation between symptoms and levels.

The incidence of mercury intoxication has decreased considerably because of stricter public health regulations. However, it has not been completely eliminated and should be considered in a child with unexplained tachycardia, hypertension, mood changes, weight loss, and acrodynia. Mercury intoxication can be difficult to differentiate from pheochromocytoma and Kawasaki's disease. Here, the authors report the case of an 8-year-old boy with history of mercury exposure, signs and symptoms suggestive of mercury intoxication, and good response to chelation therapy, but with only mild increase in urinary mercury levels. This case highlights the fact that urinary mercury levels do not necessarily correlate with the severity of clinical signs and symptoms of mercury intoxication.

Chemical Speciation of Selenium and Mercury as Determinant of Their Neurotoxicity.

The antagonism of mercury toxicity by selenium has been well documented. Mercury is a toxic metal, widespread in the environment. The main target organs (kidneys, lungs, or brain) of mercury vary depending on its chemical forms (inorganic or organic). Selenium is a semimetal essential to mammalian life as part of the amino acid selenocysteine, which is required to the synthesis of the selenoproteins. This chapter has the aim of disclosing the role of selenide or hydrogen selenide (Se-2 or HSe-) as central metabolite of selenium and as an important antidote of the electrophilic mercury forms (particularly, Hg2+ and MeHg). Emphasis will be centered on the neurotoxicity of electrophile forms of mercury and selenium. The controversial participation of electrophile mercury and selenium forms in the development of some neurodegenerative disease will be briefly presented. The potential pharmacological use of organoseleno compounds (Ebselen and diphenyl diselenide) in the treatment of mercury poisoning will be considered. The central role of thiol (-SH) and selenol (-SeH) groups as the generic targets of electrophile mercury forms and the need of new in silico tools to guide the future biological researches will be commented.

Co-consumption of selenium and vitamin E altered the reproductive and developmental toxicity of methylmercury in rats.

Methylmercury (MeHg), an environmental contaminant primarily found in fish and seafood, may pose long-term health risks to pregnant women and their developing children. The objective of this study was to determine whether co-consumption of nutritional supplements would alter the effects of MeHg on reproductive and developmental toxicity using a rodent model. Adult female rats were fed a diet containing additional selenium (1 ppm), additional vitamin E (225 IU/kg) or a combination of the two for 4 weeks before oral dosing of MeHg (1.25 mg/kg/day). Treatment with MeHg and dietary supplementation continued throughout pregnancy after which the dams were allowed to deliver their offspring. In addition to routine evaluations including periodic body weight measurements and daily clinical signs observations, dams and pups were evaluated for auditory startle habituation and pups were evaluated for developmental landmarks and reflexology. The dams and offspring were euthanized approximately 4 weeks after birth of the offspring. Results indicated that treatment with MeHg caused adverse effects on both reproduction of the dams and decreased progeny survival. However, the dams showed significant improvement in body weight gain during lactation and average auditory startle response time when the diet was enriched with both selenium and vitamin E. The combination of both vitamin E and Se also resulted in a significant increase in post-natal survival when compared to MeHg-treated group. There was no nutrient effect on the MeHg toxicity shown in offspring physical landmarks, performance in reflex tests and assessment of simple auricular startle response. Also, accelerated development as indicated by earlier opening in the pups of the supplemental diet groups was observed. These results suggest that antioxidant nutrients in the diet may alter MeHg reproductive and developmental toxicity. The underlying and human health implications warrant further investigations.

Gestational exposure to methylmercury and n-3 fatty acids: effects on high- and low-rate operant behavior in adulthood.

Fish in the diet is the major source of methylmercury (MeHg) exposure, but eating fish also provides important nutrients. Many fish species contain essential long chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), an omega-3 (or n-3) fatty acid, that is important for neural development and function. To examine interactions between MeHg and n-3 fatty acids, female Long-Evans rats were exposed, in utero, to 0, 0.5, or 5 ppm MeHg via drinking water, approximating exposures of 0, 40, and 400 mug/kg/day. They also received pre- and postnatal exposure to a diet containing either fish oil or coconut oil, creating a 2 (Diet)x3 (MeHg) full factorial design, with 6-8 rats per cell. The diets were high or marginal, respectively, in n-3 fatty acids but approximately equal in n-6 fatty acids. No exposure-related effects on developmental milestones or growth were noted. Behavior was evaluated using a series of rapidly increasing fixed ratio (FR) schedules of sucrose reinforcement; 1, 5, 25 and 75 lever presses were required for sucrose delivery, with three sessions provided at each requirement. This phase was followed by four sessions of a differential-reinforcement-of-low-rate-behavior (DRL) schedule, in which presses preceded by 10 s (or more) without a press were reinforced. Subsequently, several progressive ratio (PR) schedules that increased response requirements throughout a single session by a rate of 5%, 10%, or 20% were imposed. Rats exposed during gestation to MeHg had significantly higher response rates than controls under the large FR schedules, during the first session of DRL, and the PR 5% schedule, but neither fish oil nor coconut oil modified MeHg's effects. This finding is consistent with hypotheses that developmental MeHg exposure produced perseverative responding or altered the sensitivity of behavior to its reinforcing consequences and that certain reinforcement contingencies can unmask MeHg's effects.

[Vilon effect on consequences of repeated radioactive and mercuric impact in small doses].

The purpose of the study was to determine the efficacy of vilon administration in rats after reiterated exposure to ecotoxicants (mercury in concentration near to maximum allowable one and gamma-radiation in small dose). In 24 hours after repeated radioactive and mercuric impact (RMI) and for 30 consecutive days the animals reported lymphopenia. At the same time the indices of DNA leucocytes content and structure did not differ from the parameters of intact animals, this could evidence the development of adaptation reactions. Vilon administration led to the normalization of the lymphocytes number by the 30th day after repeated irradiation (contrary to the radioactive- chemical control), while the number of granulocytes in the test group was higher than that in the intact control group. Study of the survival rate in rats revealed that Vilon reduced morbidity of rats in the course of 15 months after RMI.

[Chronic occupational metallic mercurialism]. / Mercuralismo metálico crônico ocupacional.

This is a review on current knowledge of chronic occupational mercurialism syndrome. Major scientific studies and reviews on clinical manifestation and physiopathology of mercury poisoning were evaluated. The search was complemented using Medline and Lilacs data. Erethism or neuropsychological syndrome, characterized by irritability, personality change, loss of self-confidence, depression, delirium, insomnia, apathy, loss of memory, headaches, general pain, and tremors, is seen after exposure to metallic mercury. Hypertension, renal disturbances, allergies and immunological conditions are also common. Mercury is found in many different work processes: industries, gold mining, and dentistry. As prevention measures are not often adopted there is an increasing risk of mercury poisoning. The disease has been under diagnosed even though 16 clinical forms of mercury poisoning are described by Brazilian regulations. Clinical diagnosis is important, especially because abnormalities in the central nervous, renal and immunological systems can be detected using current medical technology, helping to develop the knowledge and control measures for mercurialism.

Commentary on the abuse of metal chelation therapy in patients with autism spectrum disorders.

Approximately half a million patients with autism spectrum disorders are subjected to chelation therapy in the US annually. The overwhelming majority of such cases are chelated for non-accepted medical indications. These patients may seek evaluation when a urine sample is assayed after the administration of a chelating agent and the values obtained have been improperly compared to references ranges for non-chelated urines, causing falsely elevated results. Legitimate practitioners confronted with such data must decide, preferably in consultation with the patient or their guardian(s), whether to do further testing using legitimate methodology or to simply dismiss the results of the improper testing. Bayesian principles tell us that further testing is likely to yield results within normal reference ranges. However, under some circumstances, it is useful to do such testing in order to demonstrate that there is no need for chelation therapy. Unnecessary chelation therapy is expensive, can cause significant acute adverse effects, and may be associated with long-term consequences.