RESUMO
BACKGROUND: Studies with children exposed to methylmercury (MeHg) through fish consumption in the Brazilian Amazon region report that the high levels of hair Hg are associated with significant decreases in intelligence, memory, attention, and visuospatial processing. OBJECTIVE: To investigate the relationship between mercury exposure and neuropsychological functions in riverside communities of the Brazilian Amazon. METHOD: 263 participants aged 6 to 14 years old were assessed, from resettlement regions, near the Madeira river, Rondônia, Brazil. To assess the neuropsychological functions we used the following instruments: intelligence (WASI), working memory (Corsi Block-Tapping Task and Digit Span), verbal fluency (Word Generation - NEPSY II), inhibitory control (Inhibition Errors - NEPSY II), shifting (Trail Making Test) and manual motor dexterity (Grooved PegBoard Test). Socioeconomic status was obtained through household surveys. Total Hg levels were quantified hair samples (Total HgH) collected from the occipital region of the scalp and analyzed by Cold Vapor Atomic Absorption Spectrometry. RESULTS: The group in the upper quartile of Total HgH levels presented lower scores on the tasks that assessed estimated IQ, visuospatial working memory, semantic knowledge and phonological verbal fluency, when compared to the group in the lower quartile level. A regression analysis controlled for age, sex, and maternal education showed that for each increase of 10⯵g/g of Total HgH, there was a decrease around half standard deviation in Verbal IQ, estimated IQ scores, semantic knowledge, phonological verbal fluency and for verbal and visuospatial working memory. CONCLUSIONS: High concentrations of Total Hg in hair were associated with a lower performance in neuropsychological functions tests. The results show that environmental exposure to Hg is associated to children and adolescents' lower neuropsychological performance in the riverine and resettled areas of the Brazilian Amazon region.
Assuntos
Comportamento do Adolescente/efeitos dos fármacos , Desenvolvimento do Adolescente/efeitos dos fármacos , Comportamento Infantil/efeitos dos fármacos , Desenvolvimento Infantil/efeitos dos fármacos , Cabelo/química , Intoxicação do Sistema Nervoso por Mercúrio/etiologia , Mercúrio/efeitos adversos , Poluentes Químicos da Água/efeitos adversos , Adolescente , Fatores Etários , Brasil , Criança , Estudos Transversais , Exposição Ambiental/efeitos adversos , Feminino , Contaminação de Alimentos , Humanos , Masculino , Mercúrio/análise , Intoxicação do Sistema Nervoso por Mercúrio/diagnóstico , Intoxicação do Sistema Nervoso por Mercúrio/fisiopatologia , Testes Neuropsicológicos , Medição de Risco , Fatores de Risco , Alimentos Marinhos/efeitos adversos , Alimentos Marinhos/análise , Poluentes Químicos da Água/análiseRESUMO
Methylmercury (MeHg) is a highly neurotoxic environmental pollutant. Even though molecular mechanisms mediating MeHg toxicity are not completely understood, several lines of evidence indicate that the neurotoxic effects resultant from MeHg exposure represent a consequence of its pro-oxidative properties. In this regard, MeHg is a soft electrophile that preferentially interacts with (and oxidize) nucleophilic groups (mainly thiols and selenols) from biomolecules, including proteins and low-molecular-weight molecules. Such interaction contributes to the occurrence of oxidative stress and impaired function of several molecules [proteins (receptors, transporters, enzymes, structural proteins), lipids (i.e., membrane constituents and intracellular messengers), and nucleic acids (i.e., DNA)], culminating in neurotoxicity.In this chapter, an initial background on the general aspects regarding the neurotoxicology of MeHg, with a particular focus on its pro-oxidative properties and its interaction with nucleophilic thiol- and selenol-containing molecules, is provided. Even though experimental evidence indicates that symptoms (i.e., motor impairment) resultant from MeHg exposure are linked to its pro-oxidative properties, as well as to their molecular consequences (lipid peroxidation, disruption of glutamate and/or calcium homeostasis, etc.), data concerning the relationship between molecular parameters and behavioral impairment others that those related to the motor function (i.e., visual impairment, cognitive skills, etc.) are scarce. Thus, even though scientific research has provided a significant amount of knowledge concerning the mechanisms mediating MeHg-induced neurotoxicity in the last decades, the whole scenario is far from being completely understood, and further research in this area is well warranted.
Assuntos
Intoxicação do Sistema Nervoso por Mercúrio/metabolismo , Compostos de Metilmercúrio/intoxicação , Neurônios/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Metabolismo dos Lipídeos , Intoxicação do Sistema Nervoso por Mercúrio/fisiopatologia , Ácidos Nucleicos/metabolismo , Oxirredução , Compostos de Selênio/metabolismo , Compostos de Sulfidrila/metabolismo , Transmissão SinápticaRESUMO
The aims of this study were to evaluate whether chronic intoxication with mercury chloride (HgCl2), in a low concentration over a long time, can be deposited in the central nervous tissue and to determine if this exposure induces motor and cognitive impairments. Twenty animals were intoxicated for 45 days at a dose of 0.375 mg/kg/day. After this period, the animals underwent a battery of behavioral tests, in a sequence of open field, social recognition, elevated T maze and rotarod tests. They were then sacrificed, their brains collected and the motor cortex and hippocampus dissected for quantification of mercury deposited. This study demonstrates that long-term chronic HgCl2 intoxication in rats promotes functional damage. Exposure to HgCl2 induced anxiety-related responses, short- and long-term memory impairments and motor deficits. Additionally, HgCl2 accumulated in both the hippocampus and cortex of the brain with a higher affinity for the cortex.
Assuntos
Poluentes Ambientais/toxicidade , Memória/efeitos dos fármacos , Cloreto de Mercúrio/toxicidade , Intoxicação do Sistema Nervoso por Mercúrio/fisiopatologia , Atividade Motora/efeitos dos fármacos , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Intoxicação do Sistema Nervoso por Mercúrio/etiologia , Ratos , Ratos WistarRESUMO
Methylmercury (MeHg) is an environmental pollutant that biomagnifies throughout the aquatic food chain, thus representing a toxicological concern for humans subsiding on fish for their dietary intake. Although the developing brain is considered the critical target organ of MeHg toxicity, recent evidence indicates that the cardiovascular system may be the most sensitive in adults. However, data on the mechanisms mediating MeHg-induced cardiovascular toxicity are scarce. Based on the close relationship between cardiovascular disease and dyslipidemia, this study was designed to investigate the effects of long-term MeHg exposure on plasma lipid levels in mice, as well as their underlying mechanisms and potential relationships to MeHg-induced neurotoxicity. Our major finding was that long-term MeHg exposure induced dyslipidemia in rodents. Specifically, Swiss and C57BL/6 mice treated for 21 days with a drinking solution of MeHg (40 mg/l, ad libitum) diluted in tap water showed increased total and non-HDL plasma cholesterol levels. MeHg-induced hypercholesterolemia was also observed in low-density lipoprotein receptor knockout (LDLrâ»/â») mice, indicating that this effect was not related to decreased LDLr-mediated cholesterol transport from blood to other tissues. Although the hepatic synthesis of cholesterol was unchanged, significant signs of nephrotoxicity (glomerular shrinkage, tubular vacuolization, and changed urea levels) were observed in MeHg-exposed mice, indicating that the involvement of nephropathy in MeHg-induced lipid dyshomeostasis may not be ruled out. Notably, Probucol (a lipid-lowering drug) prevented the development of hypercholesterolemia when coadministered with MeHg. Finally, hypercholesterolemic LDLrâ»/â» mice were more susceptible to MeHg-induced cerebellar glial activation, suggesting that hypercholesterolemia in itself may pose a risk factor in MeHg-induced neurotoxicity. Overall, based on the strong and graded positive association between total as well as LDL cholesterol and risk of cardiovascular diseases, our data support the concept of MeHg-induced cardiovascular toxicity.
Assuntos
Doenças Cardiovasculares/induzido quimicamente , Hipercolesterolemia/induzido quimicamente , Intoxicação do Sistema Nervoso por Mercúrio/etiologia , Compostos de Metilmercúrio/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Anticolesterolemiantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Biomarcadores/sangue , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cerebelo/fisiopatologia , Colesterol/sangue , LDL-Colesterol/sangue , Glutationa Peroxidase/metabolismo , Hipercolesterolemia/sangue , Hipercolesterolemia/genética , Hipercolesterolemia/prevenção & controle , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Intoxicação do Sistema Nervoso por Mercúrio/patologia , Intoxicação do Sistema Nervoso por Mercúrio/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Probucol/farmacologia , Receptores de LDL/deficiência , Receptores de LDL/genética , Fatores de Tempo , Ureia/sangueRESUMO
Adult zebrafish were treated acutely with methylmercury (1.0 or 5.0 µg g(-1), i.p.) and, 24h after treatment, were tested in two behavioral models of anxiety, the novel tank and the light/dark preference tests. At the smaller dose, methylmercury produced a marked anxiogenic profile in both tests, while the greater dose produced hyperlocomotion in the novel tank test. These effects were accompanied by a decrease in extracellular levels of serotonin, and an increase in extracellular levels of tryptamine-4,5-dione, a partially oxidized metabolite of serotonin. A marked increase in the formation of malondialdehyde, a marker of oxidative stress, accompanied these parameters. It is suggested that methylmercury-induced oxidative stress produced mitochondrial dysfunction and originated tryptamine-4,5-dione, which could have further inhibited tryptophan hydroxylase. These results underscore the importance of assessing acute, low-level neurobehavioral effects of methylmercury.
Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Mercúrio/fisiopatologia , Compostos de Metilmercúrio/toxicidade , Serotonina/metabolismo , Peixe-Zebra/metabolismo , Animais , Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Frações Subcelulares/metabolismo , Peixe-Zebra/fisiologiaRESUMO
The present studies were conducted to changes arising from mercury poisoning in the central nervous system (CNS), with a focus on determining the receptors and neurotransmitters involved. Currently, little is known regarding the neurological basis of the cardiopulmonary effects of mercury poisoning. We evaluated changes in systolic arterial pressure (SAP), diastolic arterial pressure (DAP), respiratory rate (RR) and heart rate (HR) following a 5 µl intracisternal (i.c) injection of mercuric chloride (HgCl(2)) and the participation of the autonomic nervous system in these responses. 58 animals were utilized and distributed randomly into 10 groups and administered a 5 µL intracisternal injection of 0.68 µg/kg HgCl(2) (n=7), 1.2 µg/kg HgCl(2) (n=7), 2.4 µg/kg HgCl(2) (n=7), 60 µg/kg HgCl(2) (n=7), 120 µg/kg HgCl(2) (n=3), saline (control) (n=7), 60 µg/kg HgCl(2) plus prazosin (n=6), saline plus prazosin (n=6), 60 µg/kg HgCl(2) plus metilatropina (n=4) or saline plus metilatropina (n=4)HgCl(2). Anesthesia was induced with halothane and maintained as needed with urethane (1.2 g/kg) administered intravenously (i.v.) through a cannula placed in the left femoral vein. The left femoral artery was also cannulated to record systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and heart rate (HR). A tracheotomy was performed to record respiratory rate. Animals were placed in a stereotaxic frame, and the cisterna magna was exposed. After a stabilization period, solutions (saline or HgCl(2)) were injected i.c., and cardiopulmonary responses were recorded for 50 min. Involvement of the autonomic nervous system was assessed through the i.v. injection of hexamethonium (20 mg/kg), prazosin (1 mg/kg) and methylatropine (1 mg/kg) 10 min before the i.c. injection of HgCl(2) or saline. Treatment with 0.68, 1.2, 2.4 µg/kg HgCl(2) or saline did not modify basal cardiorespiratory parameters, whereas the 120 µg/kg dose induced acute toxicity, provoking respiratory arrest and death. The administration of 60 µg/kg HgCl(2), however, induced significant increases (p<0.05) in SAP at the 30°, 40° and 50° min, timepoints and DAP at the 5°, 10°, 20°, 30°, 40° and 50° timepoints. RR was significantly decreased at the 5°, 10°, 20°, 40° and 50° min timepoints; however, there was no change in HR. Hexamethonium administration, which causes non-specific inhibition of the autonomic nervous system, abolished the observed cardiorespiratory effects. Similarly, prazosin, a α(1)-adrenoceptor blocker that specifically inhibits sympathetic nervous system function, abolished HgCl(2) induced increases in SAP and DAP without affecting HR and RR. Methylatropine (1 mg/Kg), a parasympathetic nervous system inhibitor, exacerbated the effects of HgCl(2) and caused slow-onset respiratory depression, culminating in respiratory arrest and death. Our results demonstrate that increases in SAP and DAP induced by the i.c. injection of mercuric chloride are mediated by activation of the sympathetic nervous system.
Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Cisterna Magna/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Frequência Cardíaca/efeitos dos fármacos , Cloreto de Mercúrio/toxicidade , Intoxicação do Sistema Nervoso por Mercúrio/etiologia , Taxa Respiratória/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Análise de Variância , Animais , Sistema Nervoso Autônomo/fisiopatologia , Cisterna Magna/fisiopatologia , Relação Dose-Resposta a Droga , Poluentes Ambientais/administração & dosagem , Masculino , Cloreto de Mercúrio/administração & dosagem , Intoxicação do Sistema Nervoso por Mercúrio/fisiopatologia , Intoxicação do Sistema Nervoso por Mercúrio/prevenção & controle , Microinjeções , Antagonistas Nicotínicos/administração & dosagem , Parassimpatolíticos/administração & dosagem , Ratos , Ratos Wistar , Fatores de TempoRESUMO
This study examined the effects of inorganic mercury exposure on behavioral and biochemical parameters and investigated the possible preventive effects of zinc on the alterations induced by mercury. Pups were exposed from 3rd to 7th postnatal day to ZnCl2 (27 mg/kg/day, s.c.) and subsequently to HgCl2 (5 doses of 5 mg/kg/day, s.c.). Each litter contained two rats for each treatment. The rats were submitted to behavioral task and litters were killed at 13 or 33 days old for acetylcholinesterase activity assays and for the determination of metal levels. Based on the results obtained from 13-day-old rats, they were divided in two groups of litters that were defined at the end of the experimental period (33 days) as less sensitive rats to mercury and more sensitive rats to mercury in accordance with the recovery of body weight until day 33. The mercury exposure caused accumulation of this metal in cerebrum and cerebellum in all mercury treated rats, and inhibited the cerebellum acetylcholinesterase activity from 13-day-old rats. Besides, the mercury-animals of the most sensitive litters to mercury presented impairment in motor function and muscular strength verified in the beaker test, as well as a reduction of the locomotor and exploratory activities in the open field task. Zinc partially prevented all the alterations induced by mercury exposure and reduced the mercury level accumulated in cerebrum and cerebellum. This study confirms the preventive effect of zinc on behavioral alterations induced by mercury in young rats and demonstrates that the mercury behavioral effects are present even for a long time after the end of the exposure.
Assuntos
Acetilcolinesterase/metabolismo , Cloretos/uso terapêutico , Cloreto de Mercúrio/intoxicação , Intoxicação do Sistema Nervoso por Mercúrio/prevenção & controle , Atividade Motora/efeitos dos fármacos , Compostos de Zinco/uso terapêutico , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Cerebelo/química , Cerebelo/efeitos dos fármacos , Cerebelo/enzimologia , Cérebro/química , Cérebro/efeitos dos fármacos , Cérebro/enzimologia , Cloreto de Mercúrio/análise , Intoxicação do Sistema Nervoso por Mercúrio/patologia , Intoxicação do Sistema Nervoso por Mercúrio/fisiopatologia , Ratos , Ratos WistarRESUMO
This study examined the exclusive contribution of methylmercury (MeHg) exposure through maternal milk on biochemical parameters related to the thiol status (glutathione (GSH) levels, glutathione peroxidase (GPx) and glutathione reductase (GR) activities) in the cerebellums of suckling mice. The same biochemical parameters were also evaluated in the cerebellums of mothers, which were submitted to a direct oral exposure to MeHg (10 mg/L in drinking water). With regard to the relationship between cerebellar function and motor activity, the presence of signs of motor impairment was also evaluated in the offspring exposed to MeHg during lactation. After the treatment (at weaning period), the pups lactationally exposed to MeHg showed increased levels of mercury in the cerebellum compared to pups in the control group and a significant impairment in the motor performance in the rotarod apparatus. In addition, these pups showed decreased levels of GSH in the cerebellum compared to pups in the control group. In dams, MeHg significantly increased the levels of cerebellar GSH and the activities of cerebellar GR. However, this was not observed in pups. This study indicates that (1) the exposure of lactating mice to MeHg causes significant impairments in motor performance in the offspring which may be related to a decrease in the cerebellar thiol status and (2) the increased GSH levels and GR activity, observed only in the cerebellums of MeHg-exposed dams, could represent compensatory pathophysiologic responses to the oxidative effects of MeHg toward endogenous GSH.
Assuntos
Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Glutationa/metabolismo , Compostos de Metilmercúrio/toxicidade , Atividade Motora/efeitos dos fármacos , Animais , Animais Lactentes , Cerebelo/enzimologia , Feminino , Lactação , Masculino , Intoxicação do Sistema Nervoso por Mercúrio/metabolismo , Intoxicação do Sistema Nervoso por Mercúrio/fisiopatologia , Camundongos , Atividade Motora/fisiologia , Gravidez , Distribuição AleatóriaRESUMO
The nervous system can be damaged when the population is exposed to methyl mercury (MeHg) by ingesting fish, and children deserve special attention due to their increased susceptibility as compared to adults. A comparative cross-sectional study was performed in order to investigate the use of a battery of neurological development tests in two groups of 209 riverine children from 3 to 7 years old: a group exposed to moderate levels of MeHg (n = 75) and a control group (n = 134). The study included a questionnaire, the collection of scalp hair samples for determination of total mercury concentration, and performance on a test for evaluating neurological function in children. Riverine children presented higher exposure to MeHg (mean hair Hg = 5.37 +/- 3.35 microg x g(-1)) in comparison to the control group (mean Hg = 2.08 +/- 1.37 microg x g(-1)). Both groups showed a high proportion of children with what was considered "non-normal" performance, suggesting that the results could not be related to mercury exposure and that this type of test presented limitations for use with river-dwelling Amazon communities.
Assuntos
Desenvolvimento Infantil/efeitos dos fármacos , Exposição Ambiental , Intoxicação do Sistema Nervoso por Mercúrio/diagnóstico , Compostos de Metilmercúrio/toxicidade , Exame Neurológico , Adulto , Brasil , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Criança , Desenvolvimento Infantil/fisiologia , Pré-Escolar , Estudos Transversais , Feminino , Contaminação de Alimentos , Cabelo/química , Humanos , Masculino , Intoxicação do Sistema Nervoso por Mercúrio/fisiopatologia , Compostos de Metilmercúrio/análise , Couro Cabeludo/químicaRESUMO
INTRODUCTION AND AIMS: Mercury is a metal that is widely used in hundreds of applications nowadays. This metal has proved to be extremely toxic in humans, especially for the central nervous system, both in cases of exposure from everyday applications (e.g. dental fillings) and from environmental exposure. Unfortunately, most of the research carried out on this metal is relatively recent and many questions remain unanswered. The aim of this work is to review all the knowledge we have at the present time about the mechanisms of action of this metal. DEVELOPMENT: To do so, we discuss the latest scientific findings about the toxic processes that are activated, as well as its effects on the cellular cytoskeleton, its genotoxicity or the production of compounds that have been linked to neurodegeneration. CONCLUSIONS: Its prolonged period of latency, ambiguous symptoms and the activation of generalised toxic mechanisms call for urgent efforts to be made in basic research to help determine as clearly as possible the way this metal acts in the body. This knowledge will provide us not only with the way to obtain therapies but also with the hope of developing biomarkers that make it possible to carry out early and reliable diagnoses of the damage done and of individual susceptibility.