RESUMO
Exposure to toxic elements in drinking water, such as arsenic (As) and fluoride (F), starts at gestation and has been associated with memory and learning deficits in children. Studies in which rodents underwent mechanistic single exposure to As or F showed that the neurotoxic effects are associated with their capacity to disrupt redox balance, mainly by diminishing glutathione (GSH) levels, altering glutamate disposal, and altering glutamate receptor expression, which disrupts synaptic transmission. Elevated levels of As and F are common in groundwater worldwide. To explore the neurotoxicity of chronic exposure to As and F in drinking water, pregnant CD-1 mice were exposed to 2 mg/L As (sodium arsenite) and 25 mg/L F (sodium fluoride) alone or in combination. The male litter continued to receive exposure up to 30 or 90 days after birth. The effects of chronic exposure on GSH levels, transsulfuration pathway enzymatic activity, expression of cysteine/cystine transporters, glutamate transporters, and ionotropic glutamate receptor subunits as well as behavioral performance in the object recognition memory task were assessed. Combined exposure resulted in a significant reduction in GSH levels in the cortex and hippocampus at different times, decreased transsulfuration pathway enzyme activity, as well as diminished xCT protein expression. Altered glutamate receptor expression in the cortex and hippocampus and decreased transaminase enzyme activity were observed. These molecular alterations were associated with memory impairment in the object recognition task, which relies on these brain regions.
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Arsênio , Água Potável , Gravidez , Feminino , Camundongos , Animais , Masculino , Fluoretos/toxicidade , Ácido Glutâmico/metabolismo , Arsênio/toxicidade , Receptores de Glutamato/metabolismo , Oxirredução , Encéfalo/metabolismo , Transtornos da Memória/induzido quimicamente , Glutationa/metabolismoRESUMO
Arsenic is a metalloid found in groundwater as a byproduct of soil/rock erosion and industrial and agricultural processes. This xenobiotic elicits its toxicity through different mechanisms, and it has been identified as a toxicant that affects virtually every organ or tissue in the body. In the central nervous system, exposure to arsenic can induce cognitive dysfunction. Furthermore, iAs has been linked to several neurological disorders, including neurodevelopmental alterations, and is considered a risk factor for neurodegenerative disorders. However, the exact mechanisms involved are still unclear. In this review, we aim to appraise the neurotoxic effects of arsenic and the molecular mechanisms involved. First, we discuss the epidemiological studies reporting on the effects of arsenic in intellectual and cognitive function during development as well as studies showing the correlation between arsenic exposure and altered cognition and mental health in adults. The neurotoxic effects of arsenic and the potential mechanisms associated with neurodegeneration are also reviewed including data from experimental models supporting epidemiological evidence of arsenic as a neurotoxicant. Next, we focused on recent literature regarding arsenic metabolism and the molecular mechanisms that begin to explain how arsenic damages the central nervous system including, oxidative stress, energy failure and mitochondrial dysfunction, epigenetics, alterations in neurotransmitter homeostasis and synaptic transmission, cell death pathways, and inflammation. Outlining the specific mechanisms by which arsenic alters the cell function is key to understand the neurotoxic effects that convey cognitive dysfunction, neurodevelopmental alterations, and neurodegenerative disorders.
Assuntos
Intoxicação por Arsênico/etiologia , Arsênio/toxicidade , Animais , Apoptose/efeitos dos fármacos , Intoxicação por Arsênico/genética , Autofagia/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Accumulating evidence indicates that homeostatic plasticity mechanisms dynamically adjust synaptic strength to promote stability that is crucial for memory storage. Our previous studies have shown that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of long-term potentiation (LTP) in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) in vivo. We have also reported that induction of LTP in the Bla-IC pathway modifies the CTA extinction. Memoryextinction involves the formation of a new associativememorythat inhibits a previously conditioned association. The aim of the present study was to analyze the effect of CTA extinction on the ability to induce subsequent LTP in the Bla-IC projection in vivo. Thus, 48â¯h after CTA extinction animals received high frequency stimulation in order to induce IC-LTP. Our results show that extinction training allows the induction but not the maintenance of IC-LTP. In addition, with the purpose of exploring part of the mechanisms involved in this process and since a body of evidence suggests that protein phosphatase calcineurin (CaN) is involved in the extinction of some behavioral tasks, we analyzed the participation of this phosphatase. The present results show that extinction training increases the CaN expression in the IC, as well as that the inhibition of this phosphatase reverts the effects of the CTA-extinction on the IC-LTP. These findings reveal that CTA extinction promotes a homeostatic regulation of subsequent IC synaptic plasticity maintenance through increases in CaN levels.
Assuntos
Aprendizagem da Esquiva/fisiologia , Calcineurina/fisiologia , Córtex Cerebral/fisiologia , Extinção Psicológica/fisiologia , Potenciação de Longa Duração , Memória/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Masculino , Vias Neurais/fisiologia , Ratos Wistar , Paladar , Percepção GustatóriaRESUMO
Early life exposure to environmental pollutants and toxic chemicals has been linked to learning and behavioral alterations in children. iAs exposure is associated with different types neurological disorders such as memory and learning impairment. iAs is methylated in the brain by the arsenic III-methyltransferase in a process that requires glutathione (GSH). The xCT-antiporter cell membrane transporter participates in the influx of cystine for GSH synthesis in exchange for glutamate in a 1:1 ratio. In CD-1 mice gestationally exposed to 20 ppm of sodium arsenite in drinking water, we have previously observed up-regulation of xCT in the male mouse hippocampus which caused glutamatergic synapse alterations affecting learning and memory processes. Here, we used the same gestational iAs exposure model to investigate whether the up-regulation of xCT and down-regulation of GLT-1 transporters were associated with higher levels of extracellular glutamate and changes in the expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor, responsible for excitatory fast synaptic transmission. The induction of LTP in the perforant-dentate gyrus pathway (PP-DG) of the hippocampus was also studied, as well as learning and memory formation using the water maze test. Changes in GSH levels were also tested in the hippocampus of animals exposed to iAs. Results showed increased GSH synthesis (p < 0.05), associated with significantly higher extracellular glutamate levels in iAs exposed mice. Exposure was also significantly associated with AMPA subunits down-regulation, deficient LTP induction, and lower excitability of the PP-DG pathway. In addition, animals showed deficient learning and memory in the Morris Water Maze test.
Assuntos
Arsênio/toxicidade , Ácido Glutâmico/metabolismo , Hipocampo/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal , Receptores de Glutamato/metabolismo , Animais , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Feminino , Glutationa/metabolismo , Hipocampo/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Transtornos da Memória/etiologia , Camundongos Endogâmicos , Via Perfurante/efeitos dos fármacos , Gravidez , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismoRESUMO
The presence of arsenic (As) and fluoride (F-) in drinking water is of concern due to the enormous number of individuals exposed to this condition worldwide. Studies in cultured cells and animal models have shown that As- or F-induced hepatotoxicity is primarily associated with redox disturbance and altered mitochondrial homeostasis. To explore the hepatotoxic effects of chronic combined exposure to As and F- in drinking water, pregnant CD-1 mice were exposed to 2 mg/L As (sodium arsenite) and/or 25 mg/L F- (sodium fluoride). The male offspring continued the exposure treatment up to 30 (P30) or 90 (P90) postnatal days. GSH levels, cysteine synthesis enzyme activities, and cysteine transporter levels were investigated in liver homogenates, as well as the expression of biomarkers of ferroptosis and mitochondrial biogenesis-related proteins. Serum transaminase levels and Hematoxylin-Eosin and Masson trichrome-stained liver tissue slices were examined. Combined exposure at P30 significantly reduced GSH levels and the mitochondrial transcription factor A (TFAM) expression while increasing lipid peroxidation, free Fe 2+, p53 expression, and serum ALT activity. At P90, the upregulation of cysteine uptake and synthesis was associated with a recovery of GSH levels. Nevertheless, the downregulation of TFAM continued and was now associated with a downstream inhibition of the expression of MT-CO2 and reduced levels of mtDNA and fibrotic liver damage. Our experimental approach using human-relevant doses gives evidence of the increased risk for early liver damage associated with elevated levels of As and F- in the diet during intrauterine and postnatal period.
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Tobacco smoke and air pollutants contain carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and tobacco specific nitrosamines (TSNA), that are substrates of metabolizing enzymes generating reactive metabolites that can bind to DNA. Variation in the activity of these enzymes may modify the extent to which these metabolites can interact with DNA. We compared the levels of bulky DNA adducts in blood leukocytes from 93 volunteers living in Mexico City with the presence of 13 single nucleotide polymorphisms (SNPs) in genes related to PAH and TSNA metabolism (AhR rs2044853, CYP1A1 rs1048943, CYP1A1 rs1048943, CYP1A1 rs1799814, EPHX1 rs1051740, EPHX1 rs2234922, GSTM1 null, GSTT1 null and GSTP1 rs947894), DNA repair (XRCC1 rs25487, ERCC2 rs13181 and MGMT rs12917) and cell cycle (TP53 rs1042522). (32)P-postlabeling analysis was used to quantify bulky DNA adduct formation. Genotyping was performed using PCR-RFLP. The mean levels of bulky DNA adducts were 8.51±3.66 adducts/10(8) nucleotides (nt) in smokers and 8.38±3.59 adducts/10(8) nt in non-smokers, being the difference not statistically significant. Without taking into account the smoking status, GSTM1 null individuals had a marginally significant lower adduct levels compared with GSTM1 volunteers (p=0.0433) and individuals heterozygous for MGMT Leu/Phe had a higher level of bulky adducts than those who were homozygous wild type (p=0.0170). A multiple regression analysis model showed a significant association between the GSTM1 (deletion) and MGMT rs12917 (Phe/Phe) haplotype and the formation of DNA adducts in smokers (R(2)=0.2401, p=0.0215). The presence of these variants conferred a greater risk for higher adduct levels in this Mexican population.
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Adutos de DNA/sangue , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glutationa Transferase/genética , Haplótipos , Leucócitos/química , Proteínas Supressoras de Tumor/genética , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Environmental geochemical and health studies were carried out in urban areas of Villa de la Paz, S.L.P. (Mexico), where mining activities have been developed for more of 200 years, leading to the pollution of surface soil by arsenic and heavy metals (Pb, Cd, Cu, Zn). The analysis of urban soils to determine total and bioaccessibility concentrations of As and Pb, demonstrated a combined contribution of the natural and anthropogenic concentrations in the site, at levels higher than the environmental guideline values that provoke a human health risk. Contour soil mapping confirmed that historical mine waste deposits without environmental control measures, are the main source of pollution soil by As and Pb in the site. Exposure (Pb in blood and As in urine) and effect (micronucleated exfoliated cells assay) biological monitoring were then carried out in the childhood population of the site and in a control site. The exposure biological monitoring demonstrated that at least 20-30 % of children presented Pb and As exposure values higher than the national and international maximum intervention values. The effect biomonitoring by MEC assay confirmed that there is a genotoxic damage in local childhood population that could be associated with the arsenic exposure in the site.
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Arsênio/química , Exposição Ambiental/efeitos adversos , Chumbo/química , Poluentes do Solo/toxicidade , Criança , Pré-Escolar , Monitoramento Ambiental/métodos , Humanos , México , Testes para Micronúcleos , Mineração , Medição de Risco , Poluentes do Solo/química , Saúde da População UrbanaRESUMO
BACKGROUND: Few epidemiologic studies have focused on the specific source of ambient air pollution and adverse health effects in early life. Here, we investigated whether air pollutants from different emission sources were associated with decreased birth anthropometry parameters and increased DNA adduct formation in mother-child pairs residing in the Mexico City Metropolitan Area (MCMA). METHODS: This cross-sectional study included 190 pregnant women recruited during their last trimester of pregnancy from two hospitals at MCMA, and a Modeling Emissions Inventory (MEI) to calculate exposure to ambient air pollutants from different emissions sources (area, point, mobile, and natural) for two geographical buffers 250 and 750 m radii around the participants households. RESULTS: Contaminants were positively correlated with umbilical cord blood (UCB) adducts, but not with maternal blood (MB) adducts. PM10 emissions (area and point sources, overall emissions), PM2.5 (point sources), volatile organic compounds (VOC), total organic compounds (TOC) from point sources were positively correlated with UCB adducts. Air pollutants emitted from natural sources were correlated with a decrease in MB and UCB adducts. PM10 and PM2.5 were correlated (p < 0.05) with a decrease in birth weight (BW), birth length (BL) and gestational age at term (GA). In multivariate analyses adjusted for potential confounders, PM10 was associated with an increase in UCB adducts. PM10 and PM2.5 from overall emissions were associated with a decrease in BW, BL and GA at term. IMPACT: Results suggested higher susceptibility of newborns compared to mothers to damage related to ambient air pollution. PMs are associated with birth anthropometry parameters and DNA damage in adjusted models, highlighting the need for more strict regulation of PM emissions.
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The transsulfuration pathway (TSP) is a metabolic pathway involving sulfur transfer from homocysteine to cysteine. Transsulfuration pathway leads to many sulfur metabolites, principally glutathione, H2S, taurine, and cysteine. Key enzymes of the TSP, such as cystathionine ß-synthase and cystathionine γ-lyase, are essential regulators at multiple levels in this pathway. TSP metabolites are implicated in many physiological processes in the central nervous system and other tissues. TSP is important in controlling sulfur balance and optimal cellular functions such as glutathione synthesis. Alterations in the TSP and related pathways (transmethylation and remethylation) are altered in several neurodegenerative diseases, including Parkinson's disease, suggesting their participation in the pathophysiology and progression of these diseases. In Parkinson's disease many cellular processes are comprised mainly those that regulate redox homeostasis, inflammation, reticulum endoplasmic stress, mitochondrial function, oxidative stress, and sulfur content metabolites of TSP are involved in these damage processes. Current research on the transsulfuration pathway in Parkinson's disease has primarily focused on the synthesis and function of certain metabolites, particularly glutathione. However, our understanding of the regulation of other metabolites of the transsulfuration pathway, as well as their relationships with other metabolites, and their synthesis regulation in Parkinson´s disease remain limited. Thus, this paper highlights the importance of studying the molecular dynamics in different metabolites and enzymes that affect the transsulfuration in Parkinson's disease.
Assuntos
Cisteína , Doença de Parkinson , Humanos , Cisteína/metabolismo , Enxofre/metabolismo , Cistationina beta-Sintase/metabolismo , Glutationa/metabolismoRESUMO
Organisms have metabolic pathways responsible for eliminating endogenous and exogenous toxicants. Generally, we associate the liver par excellence as the organ in charge of detoxifying the body; however, this process occurs in all tissues, including the brain. Due to the presence of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), the Central Nervous System (CNS) is considered a partially isolated organ, but similar to other organs, the CNS possess xenobiotic transporters and metabolic pathways associated with the elimination of xenobiotic agents. In this review, we describe the different systems related to the detoxification of xenobiotics in the CNS, providing examples in which their association with neurodegenerative processes is suspected. The CNS detoxifying systems include carrier-mediated, active efflux and receptor-mediated transport, and detoxifying systems that include phase I and phase II enzymes, as well as those enzymes in charge of neutralizing compounds such as electrophilic agents, reactive oxygen species (ROS), and free radicals, which are products of the bioactivation of xenobiotics. Moreover, we discuss the differential expression of these systems in different regions of the CNS, showing the different detoxifying needs and the composition of each region in terms of the cell type, neurotransmitter content, and the accumulation of xenobiotics and/or reactive compounds.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Xenobióticos/metabolismo , Xenobióticos/toxicidade , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Biotransformação/efeitos dos fármacos , Biotransformação/fisiologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Humanos , Redes e Vias Metabólicas/fisiologiaRESUMO
Human exposure to inorganic arsenic (iAs) has been associated with cancer and serious injury to various internal organs, as well as peripheral neuropathy, endocrine disruption and diverse effects in the central nervous system (CNS). Using rodent models, it is possible to demonstrate As accumulation in the brain that leads to defects in operant learning, behavioral changes, and affect pituitary gonadotrophins. iAs biomethylation in the CNS is a significant process, yielding products that are more reactive and toxic than the parent compound. Mice received 2.5, 5, and 10 mg/kg/day sodium arsenite orally for 9 days. We investigated the distribution of iAs and its metabolites as well as the mRNA and protein expression of arsenic (III) methyltransferase (AS3MT), which encodes the key enzyme in iAs metabolism, in the cerebral cortex, hippocampus, striatum, mesencephalon, thalamus, cerebellum, hypothalamus, pons, medulla oblongata, and pituitary of mouse brain. Our findings show that methylated As metabolites are present in all brain regions studied suggesting that AS3MT is ubiquitously expressed in the brain and it is not inducible by dose of arsenite. There is also a dose-related accumulation of As species in all brain regions, with the highest accumulation observed in the pituitary. The higher distribution of arsenicals in pituitary can help to explain the neuroendocrine effects associated with iAs exposure.
Assuntos
Arsênio/toxicidade , Encéfalo/efeitos dos fármacos , Metiltransferases/metabolismo , Animais , Arsênio/farmacocinética , Arsenitos/farmacocinética , Arsenitos/toxicidade , Encéfalo/metabolismo , Expressão Gênica/efeitos dos fármacos , Masculino , Metiltransferases/genética , Camundongos , Compostos de Sódio/farmacocinética , Compostos de Sódio/toxicidadeRESUMO
Mice exposed to sodium arsenite show a dose-related accumulation of inorganic arsenic (iAs) and its methylated metabolites in the liver. While the accumulation of iAs forms increased linearly with dose in liver cells, a different pattern was observed in other tissues such as the brain and lung, as well as in the peripheral nerves of the rat. As such, trivalent iAs enters the cells, using aquaglyceroporin transporters to modulate cell arsenic accumulation and cytotoxicity. We investigated here if the dose-related accumulation of arsenic in the liver was related to the expression of aquaglyceroporin 9 (AQP9) in the same organ. CD1 male mice were treated with different concentrations (0, 2.5, 5 or 10mg/kg/day) of sodium arsenite during 1, 3 or 9 days. A significant dose-related, up-regulation of AQP9 mRNA and protein was observed and which was verified by immunohistochemistry in liver sections using specific antibodies. The increased transcription of AQP9 has been observed in fasting and diabetic rats, suggesting that this channel could play a role in the diabetogenic effect of arsenic.
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Aquagliceroporinas/metabolismo , Aquaporinas/metabolismo , Arsenitos/toxicidade , Fígado/efeitos dos fármacos , Compostos de Sódio/toxicidade , Animais , Arsenitos/administração & dosagem , Arsenitos/metabolismo , Relação Dose-Resposta a Droga , Glicerol/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Compostos de Sódio/administração & dosagem , Compostos de Sódio/metabolismo , Ureia/metabolismoRESUMO
Exposure to toxic metals and metalloids is an important cause of preventable diseases worldwide. Inorganic arsenic (iAs) affects several organs and tissues, causing neurobehavioral alterations in the central nervous system (CNS) that might lead to neurodegeneration. In this work, we wanted to explore the time- and dose-related changes on glutathione (GSH) levels in several regions of the CNS, such as the cortex, striatum, hippocampus, and cerebellum, to identify the initial cellular changes associated to GSH depletion due to iAs exposure. Mice received a single intraperitoneal injection containing 5 or 14 mg/kg sodium arsenite. Animals were killed at 2, 6, and 24 h. Significant depletion of GSH levels was observed in the cortex at 2 and 6 h, while on the striatum, hippocampus, or cerebellum regions, no significant changes were observed. GSH depletion in the cortex was associated with the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa B (NFκB) pathways, which led to the upregulation of xCT, excitatory amino acid carrier 1 (EAAC1), glutamate/aspartate transporter (GLAST), and glial glutamate transporter 1 (GLT-1), and the activation of the transsulfuration pathways, which led to the overproduction of H2S in the cortex and increased levels of GSH in the cortex and cerebellum at 24 h. In the cortex, the N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B were also altered at 24 h. These early effects were not homogeneous among different brain regions and indicate early neurotoxic alterations in the cortex and cerebellum.
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In aerobic organisms, oxygen is essential for efficient energy production but paradoxically, produces chronic toxic stress in cells. Diverse protective systems must exist to enable adaptation to oxidative environments. Oxidative stress (OS) results when production of reactive oxidative species (ROS) exceeds the capacity of cellular antioxidant defenses to remove these toxic species. Epidemiological and clinical studies have linked environmental factors such as diet and lifestyle to cancer, diabetes, atherosclerosis, and neurodegenerative disorders. All of these conditions, as well as the aging process, are associated with OS due to elevation of ROS or insufficient ROS detoxification. Many environmental pollutants engage signaling pathways that are activated in response to OS. The same sequences of events are also associated with the etiology and early pathology of many chronic diseases. Investigations of oxidative responses in different in vivo models suggest that, in complex organisms such as mammals, organs and tissues contain distinct antioxidant systems, and this may form the basis for differential susceptibility to environmental toxic agents Thus, understanding the pathways leading to the induction of antioxidant responses will enable development of strategies to protect against oxidative damage. We shall review evidence of organ-specific antioxidant responses elicited by environmental pollutants in humans and animal models.
Assuntos
Antioxidantes/fisiologia , Citoproteção/fisiologia , Meio Ambiente , Enzimas/fisiologia , Estresse Oxidativo/fisiologia , Animais , Antioxidantes/metabolismo , Citoproteção/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Enzimas/genética , Enzimas/metabolismo , Humanos , Metais/toxicidade , Modelos Biológicos , Estresse Oxidativo/genética , Praguicidas/toxicidade , Radiação Ionizante , Espécies Reativas de Oxigênio/metabolismo , Raios UltravioletaRESUMO
Glutathione (GSH) is the most abundant intracellular antioxidant. GSH depletion leads to oxidative stress and neuronal damage in the central nervous system (CNS). In mice, the acute systemic inhibition of GSH synthesis by L-buthionine-S-R-sulfoximine (BSO) triggers a protective response and a subsequent increase in the CNS GSH content. This response might be modulated by a peripheral increment of circulating nerve growth factor (NGF). NGF is an important activator of antioxidant pathways mediated by tropomyosin-related kinase receptor A (TrkA). Here, we report that peripheral administration of BSO increased plasma NGF levels. Additionally, BSO increased NGF levels and activated the NGF/TrkA/Akt pathway in striatal neurons. Moreover, the response in the striatum included an increased transcription of nrf2, gclm, lat1, eaac1, and xct, all of which are involved in antioxidant responses, and L-cys/L-cys2 and glutamate transporters. Using antibody against NGF confirmed that peripheral NGF activated the NGF/TrkA/Akt/Nrf2 pathway in the striatum and subsequently increased the transcription of gclm, nrf2, lat1, eaac1, and xct. These results provide evidence that the reduction of peripheral GSH pools increases peripheral NGF circulation that orchestrates a neuroprotective response in the CNS, at least in the striatum, through the NGF/TrkA/Akt/Nrf2 pathway.
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Studies associate particulate matter (PM) exposure with pulmonary, cardiovascular, and neurologic diseases. Elevated levels of coarse (PM10) and fine (PM2.5) PM have been reported in the Mexico City metropolitan area during the last two decades. There is limited information if these conditions affect newborns. We associated maternal exposure to PM reported by the monitoring stations considering the place of residence of each participant with the presence of genotoxic damage (cytome analysis) in maternal and umbilical cord blood (UCB) lymphocytes. Eighty-four healthy women in their last quarter of pregnancy met the inclusion criteria. Each volunteer exposure was estimated according to the average PM2.5 and PM10 levels during the last month of gestation. The micronuclei (MN) frequencies in UCB lymphocyte cultures ranged between 0 and 9. They also showed lower cell proliferation indexes than their mothers. There was a strong correlation between the maternal and the UCB MN frequency (ρ = 0.3767, P = 0.0002). Multiple regression analysis including PM10 and PM2.5 levels, maternal age, and occupation, showed a significant and positive association between UCB MN frequency and PM2.5. A statistically significant increase in the MN frequency in both maternal and UCB lymphocytes was observed in samples obtained during the dry season (higher PM levels) as compared with the MN frequency in blood samples obtained during the rainy season (lower PM levels). These results suggest that PM, mainly PM2.5 , can cross the placenta causing DNA damage in fetal cells which may increase the potential for diseases during childhood or adult life. Environ. Mol. Mutagen. 60:421-427, 2019. © 2019 Wiley Periodicals, Inc.
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Poluentes Atmosféricos/toxicidade , Sangue Fetal/citologia , Linfócitos/citologia , Troca Materno-Fetal/fisiologia , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Material Particulado/toxicidade , Adulto , Poluição do Ar/análise , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Feminino , Humanos , Recém-Nascido , Masculino , Exposição Materna , México , GravidezRESUMO
Mexico City's Metropolitan Area (MCMA) includes Mexico City and 60 municipalities of the neighbor states. Inhabitants are exposed to emissions from over five million vehicles and stationary sources of air pollutants such as particulate matter (PM) and ozone. MCMA PM contains elemental carbon and organic carbon (OC). OCs include polycyclic aromatic hydrocarbons (PAHs), many of which induce mutagenic and carcinogenic DNA adducts. Gestational exposure to air pollution has been associated with increased risk of intrauterine growth restriction, preterm birth or low birth weight risk, and PAH-DNA adducts. These effects also depend on the presence of risk alleles. We investigated the presence of bulky PAH-DNA adducts, plasma 8-iso-PGF2α (8-iso-prostaglandin F2α ) and risk allele variants in neonates cord blood and their non-smoking mothers' leucocytes from families that were living in a highly polluted area during 2014-2015. The presence of adducts was significantly associated with both PM2.5 and PM10 levels, mainly during the last trimester of gestation in both neonates and mothers, while the last month of pregnancy was significant for the association between ozone levels and maternal plasma 8-iso-PGF2α . Fetal CYP1B1*3 risk allele was associated with increased adduct levels in neonates while the presence of the maternal allele significantly reduced the levels of fetal adducts. Maternal NQO1*2 was associated with lower maternal levels of adducts. Our findings suggest the need to reduce actual PM limits in MCMA. We did not observe a clear association between PM and/or adduct levels and neonate weight, length, body mass index, Apgar or Capurro score. Environ. Mol. Mutagen. 60:428-442, 2019. © 2019 Wiley Periodicals, Inc.
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Adutos de DNA/análise , Exposição Materna , Troca Materno-Fetal/fisiologia , Ozônio/toxicidade , Material Particulado/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/análise , Efeitos Tardios da Exposição Pré-Natal/patologia , Adulto , Poluição do Ar/análise , Citocromo P-450 CYP1B1/genética , Adutos de DNA/genética , Feminino , Sangue Fetal/química , Humanos , Recém-Nascido , Isoprostanos/sangue , México , NAD(P)H Desidrogenase (Quinona)/genética , Gravidez , Emissões de Veículos/análise , Adulto JovemRESUMO
SIGNIFICANCE: Essential metals such as copper, iron, manganese, and zinc play a role as cofactors in the activity of a wide range of processes involved in cellular homeostasis and survival, as well as during organ and tissue development. Throughout our life span, humans are also exposed to xenobiotic metals from natural and anthropogenic sources, including aluminum, arsenic, cadmium, lead, and mercury. It is well recognized that alterations in the homeostasis of essential metals and an increased environmental/occupational exposure to xenobiotic metals are linked to several neurological disorders, including neurodegeneration and neurodevelopmental alterations. Recent Advances: The redox activity of essential metals is key for neuronal homeostasis and brain function. Alterations in redox homeostasis and signaling are central to the pathological consequences of dysfunctional metal ion homeostasis and increased exposure to xenobiotic metals. Both redox-active and redox-inactive metals trigger oxidative stress and damage in the central nervous system, and the exact mechanisms involved are starting to become delineated. CRITICAL ISSUES: In this review, we aim to appraise the role of essential metals in determining the redox balance in the brain and the mechanisms by which alterations in the homeostasis of essential metals and exposure to xenobiotic metals disturb the cellular redox balance and signaling. We focus on recent literature regarding their transport, metabolism, and mechanisms of toxicity in neural systems. FUTURE DIRECTIONS: Delineating the specific mechanisms by which metals alter redox homeostasis is key to understand the pathological processes that convey chronic neuronal dysfunction in neurodegenerative and neurodevelopmental disorders. Antioxid. Redox Signal. 28, 1669-1703.
Assuntos
Encéfalo/metabolismo , Homeostase , Estresse Oxidativo , Transdução de Sinais , Oligoelementos/metabolismo , Xenobióticos/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Humanos , Íons/efeitos adversos , Íons/metabolismo , Oxirredução , Oligoelementos/efeitos adversosRESUMO
Glutathione (GSH) is an essential component of intracellular antioxidant systems that plays a primordial role in the protection of cells against oxidative stress, maintaining redox homeostasis and xenobiotic detoxification. GSH synthesis in the brain is limited by the availability of cysteine and glutamate. Cystine, the disulfide form of cysteine is transported into endothelial cells of the blood-brain barrier (BBB) and astrocytes via the system xc-, which is composed of xCT and the heavy chain of 4F2 cell surface antigen (4F2hc). Cystine is reduced inside the cells and the L-type amino acid transporter 1 (LAT1) transports cysteine from the endothelial cells into the brain, cysteine is transported into the neurons through the excitatory amino acid transporter 3 (EAAT3), also known as excitatory amino acid carrier 1 (EAAC1). The mechanistic/mammalian target of rapamycin (mTOR) and neurotrophins can activate signaling pathways that modulate amino acid transporters for GSH synthesis. The present study found that systemic L-buthionine-S-R-sulfoximine (BSO) administration selectively altered GSH homeostasis and EAAT3 levels in the mice cerebellum. Intraperitoneal treatment of mice with 6â¯mmol/kg of BSO depleted GSH and GSSG in the liver at 2â¯h of treatment. The cerebellum, but not other brain regions, exhibited a redox response. The mTOR and the neuronal growth factor (NGF)/tropomyosin receptor kinase A (TrkA) signaling pathways were activated and lead to an increase in the protein levels of the EAAT3 transporter, which was linked to an increase in the GSH/GSSG ratio and GSH concentration in the cerebellum at 0.5 and 2â¯h, respectively. Therefore, the cerebellum responds to peripheral GSH depletion via activation of the mTOR and NGF/TrkA pathways, which increase the transport of cysteine for GSH synthesis.
Assuntos
Butionina Sulfoximina/administração & dosagem , Cerebelo/metabolismo , Glutationa/metabolismo , Homeostase/fisiologia , Fator de Crescimento Neural/metabolismo , Receptor trkA/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Cerebelo/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Glutationa/antagonistas & inibidores , Homeostase/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Mexico is included in the list of countries with concurrent arsenic and fluoride contamination in drinking water. Most of the studies have been carried out in the adult population and very few in the child population. Urinary arsenic and urinary fluoride levels have been accepted as good biomarkers of exposure dose. The Biomonitoring Equivalents (BE) values are useful tools for health assessment using human biomonitoring data in relation to the exposure guidance values, but BE information for children is limited. METHODS: We conducted a systematic review of the reported levels of arsenic and fluoride in drinking water, urinary quantification of speciated arsenic (inorganic arsenic and its methylated metabolites), and urinary fluoride levels in child populations. For BE values, urinary arsenic and fluoride concentrations reported in Mexican child populations were revised discussing the influence of factors such as diet, use of dental products, sex, and metabolism. RESULTS: Approximately 0.5 and 6 million Mexican children up to 14 years of age drink water with arsenic levels over 10 µg/L and fluoride over 1.5 mg/L, respectively. Moreover, 40% of localities with arsenic levels higher than 10 µg/L also present concurrent fluoride exposure higher than 1.5 mgF/L. BE values based in urinary arsenic of 15 µg/L and urinary fluoride of 1.2 mg/L for the environmentally exposed child population are suggested. CONCLUSIONS: An actual risk map of Mexican children exposed to high levels of arsenic, fluoride, and both arsenic and fluoride in drinking water was generated. Mexican normativity for maximum contaminant level for arsenic and fluoride in drinking water should be adjusted and enforced to preserve health. BE should be used in child populations to investigate exposure.