RESUMEN
PURPOSE: Malignant pleural mesothelioma (MPM) is a highly lethal cancer caused by exposure to asbestos. Currently, the diagnosis is a challenge, carried out by means of invasive methods of limited sensitivity. This is a case-control study to evaluate the individual and combined performance of minimally invasive biomarkers for the diagnosis of MPM. METHOD: A study of 166 incident cases of MPM and 378 population controls of Mestizo-Mexican ethnicity was conducted. Mesothelin, calretinin, and megakaryocyte potentiating factor (MPF) were quantified in plasma by ELISA. The samples were collected from 2011 to 2016. RESULTS: Based on ROC analysis and a preset specificity of 95%, the combination of the three biomarkers reached an AUC of 0.944 and a sensitivity of 82% in men. In women, an AUC of 0.937 and a sensitivity of 87% were reached. In nonconditional logistic regression models, the adjusted ORs in men were 7.92 (95% CI 3.02-20.78) for mesothelin, 20.44 (95% CI 8.90-46.94) for calretinin, and 4.37 (95% CI 1.60-11.94) for MPF. The ORs for women were 28.89 (95% CI 7.32-113.99), 17.89 (95% CI 3.93-81.49), and 2.77 (95% CI 0.47-16.21), respectively. CONCLUSIONS: To our knowledge, this is the first study evaluating a combination of mesothelin, calretinin, and MPF, and demonstrating a sex effect for calretinin. The biomarker panel showed a good performance in a Mestizo-Mexican population, with high sensitivity and specificity for the diagnosis of MPM.
Asunto(s)
Biomarcadores de Tumor/sangre , Calbindina 2/sangre , Proteínas Ligadas a GPI/sangre , Neoplasias Pulmonares/sangre , Mesotelioma/sangre , Neoplasias Pleurales/sangre , Anciano , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Incidencia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiología , Masculino , Mesotelina , Mesotelioma/diagnóstico , Mesotelioma/epidemiología , Mesotelioma Maligno , México/epidemiología , Persona de Mediana Edad , Neoplasias Pleurales/diagnóstico , Neoplasias Pleurales/epidemiología , Valor Predictivo de las Pruebas , Pronóstico , Medición de Riesgo , Factores de Riesgo , Factores SexualesRESUMEN
Background: Diagnosis of malignant pleural mesothelioma (MPM) remains a challenge, especially when resources in pathology are limited. The study aimed to evaluate cost-effective tumor markers to predict the probability of MPM in plasma samples in order to accelerate the diagnostic workup of the tissue of potential cases. Methods: We conducted a case-control study stratified by gender, which included 75 incident cases with MPM from three Mexican hospitals and 240 controls frequency-matched by age and year of blood drawing. Plasma samples were obtained to determine mesothelin, calretinin, and thrombomodulin using enzyme-linked immunosorbent assays (ELISAs). We estimated the performance of the markers based on the area under the curve (AUC) and predicted the probability of an MPM diagnosis of a potential case based on the marker concentrations. Results: Mesothelin and calretinin, but not thrombomodulin were significant predictors of a diagnosis of MPM with AUCs of 0.90 (95% CI: 0.85-0.95), 0.88 (95% CI: 0.82-0.94), and 0.51 (95% CI: 0.41-0.61) in males, respectively. For MPM diagnosis in men we estimated a true positive rate of 0.79 and a false positive rate of 0.11 for mesothelin. The corresponding figures for calretinin were 0.81 and 0.18, and for both markers combined 0.84 and 0.11, respectively. Conclusions: We developed prediction models based on plasma concentrations of mesothelin and calretinin to estimate the probability of an MPM diagnosis. Both markers showed a good performance and could be used to accelerate the diagnostic workup of tissue samples in Mexico.
Asunto(s)
Biomarcadores de Tumor/análisis , Calbindina 2/sangre , Proteínas Ligadas a GPI/sangre , Mesotelioma/diagnóstico , Neoplasias Pleurales/diagnóstico , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Neoplasias Pulmonares , Masculino , Mesotelina , Mesotelioma/sangre , México , Persona de Mediana Edad , Neoplasias Pleurales/sangreRESUMEN
Two pyrethroids, permethrin and allethrin, are often combined for large-scale use in public health programs to control vector-borne diseases. In this study, the genotoxic potential of a commercial formulation of permethrin and allethrin was examined using cultured human peripheral blood lymphocytes (PBL). Genotoxicity was evaluated using the cytokinesis-block micronucleus cytome (CBMN cyt) assay by measuring the frequency of micronuclei (MN), nuclear division index (NDI), formation of nucleoplasmic bridges (NPB) and nuclear buds (NBUD), as well as apoptotic and necrotic cells. Human PBL were treated with different concentrations of a permethrin/allethrin mixture (1/0.01, 5/0.07, and 10/0.14 µg/ml) for 24 or 36 h. The highest concentration (10/0.14 µg/ml) of permethrin/allethrin mixture significantly increased MN frequency and percent apoptotic cells after incubations for 24 or 36 h. The NDI was markedly decreased in response to treatment with 5/0.07 or 10/0.14 µg/ml permethrin/allethrin for both 24 and 36 h. Exposure to the permethrin/allethrin mixture did not significantly alter formation of NBUD, NPB, or percent necrotic cells. The MN frequency was significantly correlated with the number of apoptotic and necrotic cells but inversely correlated with NDI. Data demonstrated that a mixture of permethrin and allethrin induced concentration- and time-dependent cytotoxic and genotoxic damage to human PBL in vitro.
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Aletrinas/toxicidad , Daño del ADN/efectos de los fármacos , Linfocitos/efectos de los fármacos , Permetrina/toxicidad , Apoptosis/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citocinesis/efectos de los fármacos , Humanos , Pruebas de Micronúcleos , Mutágenos/toxicidad , Necrosis/inducido químicamente , Necrosis/patologíaRESUMEN
This study aims to portray the complex diversity of the Mexican Mestizo population, which represents 98.8% of the entire population of Mexico. We compiled extended haplotype data of the Y chromosome from populations in the Central Valley of Mexico (CVM), which we compared with other Mestizo and parental (Amerindian, European, and African) populations. A complex ancestral relationship was found in the CVM population, suggesting cosmopolitan origins. Nevertheless, the most preeminent lineages point toward a European ancestry, where the R1b lineage was most frequent. In addition, important frequencies of Amerindian lineages were also found in the Mestizo sample studied. Interestingly, the Amerindian ancestry showed a remarkable substructure, which was represented by the two main founding lineages: QL54 (× M3) and M3. However, even within each lineage a high diversity was found despite the small number of sample bearers of these lineages. Further, we detected important genetic differences between the CVM populations and the Mexican Mestizo populations from the north and south. This result points to the fact that Mestizo populations present different ancestral proportions, which are related to the demographic events that gave origin to each population. Finally, we provide additional forensic statistical parameters that are useful in the interpretation of genetic analysis where autosomal loci are limited. Our findings illustrate the complex genetic background of the Mexican Mestizo population and reinforce the need to encompass more geographic regions to generate more robust data for forensic applications.
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Cromosomas Humanos Y/genética , Indígenas Norteamericanos/genética , Filogenia , Población Negra , Frecuencia de los Genes , Variación Genética/genética , Genética de Población , Haplotipos/genética , Humanos , México/epidemiología , Población BlancaRESUMEN
DDT, a persistent organic pollutant, remains affecting human health worldwide. DDT and its most persistent metabolite (p,p'-DDE) negatively affect the immune response regulation and mechanisms involved in protecting against pathogens Such metabolite decreases the capability to limit intracellular growth of Mycobacterium microti and yeast. However, the effect on unstimulated (M0) and anti-inflammatory macrophages (M2) has been evaluated scanty. Herein, we evaluated the impact of p,p'-DDE at environmentally relevant concentrations (0.125, 1.25, 2.5, and 5 µg/mL) on bone marrow-derived macrophages stimulated with IFNγ+LPS to M1 or with IL-4 +IL-13 to M2. Thus we study whether the p,p'-DDE induces M0 to a specific phenotype or modulates activation of the macrophage phenotypes and explains, at least partly, the reported effects of p,p'-DDE on the M1 function. The p,p'-DDE did not affect the cell viability of M0 or the macrophage phenotypes. In M1, the p,p'-DDE decreased NOâ¢- production and IL-1ß secretion, but increasing cellular ROS and mitochondrial O2â¢-, but did not alter iNOS, TNF-α, MHCII, and CD86 protein expression nor affect M2 markers arginase activity, TGF-ß1, and CD206; p,p'-DDE, did not affect marker expression in M0 or M2, supporting that its effects on M1 parameters are not dependent on M0 nor M2 modulation. The decreasing of NOâ¢- production by the p,p'-DDE without altering iNOS levels, Arginase activity, or TNF-α, but increasing cellular ROS and mitochondrial O2 suggests that p,p'-DDE interferes with the iNOS function but not with its transcription. The p,p'-DDE decreasing of IL-1ß secretion, without any effect on TNF-α, suggest that an alteration of specific targets involved in IL-1ß secretion may be affected and related to ROS induction. The p,p'-DDE effect on iNOS function and the IL-1ß secretion process, as the NLRP3 activation, deserves further study.
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Diclorodifenil Dicloroetileno , Macrófagos , Animales , Humanos , Ratones , Arginasa/genética , Arginasa/metabolismo , Arginasa/farmacología , DDT/metabolismo , DDT/farmacología , Diclorodifenil Dicloroetileno/toxicidad , Diclorodifenil Dicloroetileno/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos BALB C , Fenotipo , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Immunization with neurally derived peptides (INDP) boosts the action of an autoreactive immune response that has been shown to induce neuroprotection in several neurodegenerative diseases, especially after spinal cord (SC) injury. This strategy provides an environment that promotes neuronal survival and tissue preservation. The mechanisms by which this autoreactive response exerts its protective effects is not totally understood at the moment. A recent study showed that INDP reduces lipid peroxidation. Lipid peroxidation is a neurodegenerative phenomenon caused by the increased production of reactive nitrogen species such as nitric oxide (NO). It is possible that INDP could be interfering with NO production. To test this hypothesis, we examined the effect of INDP on the amount of NO produced by glial cells when cocultured with autoreactive T cells. We also evaluated the amount of NO and the expression of the inducible form of nitric oxide synthase (iNOS) at the injury site of SC-injured animals. The neural-derived peptides A91 and Cop-1 were used to immunize mice and rats with SC injury. In vitro studies showed that INDP significantly reduces the production of NO by glial cells. This observation was substantiated by in vivo experiments demonstrating that INDP decreases the amount of NO and iNOS gene expression at the site of injury. The present study provides substantial evidence on the inhibitory effect of INDP on NO production, helpingour understanding of the mechanisms through which protective autoimmunity promotes neuroprotection.
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Proteína Básica de Mielina/farmacología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico/metabolismo , Péptidos/farmacología , Traumatismos de la Médula Espinal/metabolismo , Médula Espinal/metabolismo , Animales , Proliferación Celular , Acetato de Glatiramer , Inmunización , Ratones , Ratones Endogámicos BALB C , Ratas , Ratas Endogámicas F344 , Médula Espinal/inmunología , Traumatismos de la Médula Espinal/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Since Mexican mestizos are an admixed population, it is necessary to determine the effects that the substructure of the population has on genetic and forensic parameters. With this aim, a study was performed with 15 STR loci (CODIS plus D2S1338 and D19S433) on 1,640 unrelated Mexican mestizos. We determine allele and genotypic frequencies observing departure from Hardy-Weinberg expectation (12 out of 15 loci, with an excess of homozygotes, Fis > 0), as well as pairs of loci in an apparent linkage disequilibrium (13 of 92 loci). We conducted a test for genetic population stratification, the results show that the Mexican mestizo population is substructured into three subgroups, which are in HW and linkage equilibrium. The combination of the 15 loci in the whole population has high forensic efficiency with the capacity to genetically discriminate one individual in one quintillion (1/10(18)). Our data potentially validates the use of these 15 STR loci to establish forensic identity and parentage testing for legal purposes, and offers a powerful tool for genetic variation analysis. However, given that the population is stratified, we highly recommend applying a correction with the inbreeding coefficient in calculations of paternity and forensic studies to avoid erroneous assumptions.
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Población Negra/genética , Indígenas Norteamericanos/genética , Repeticiones de Microsatélite , Población Blanca/genética , Genética Forense , Frecuencia de los Genes , Sitios Genéticos , Pruebas Genéticas , Genotipo , Humanos , Desequilibrio de Ligamiento , México , Modelos Genéticos , Modelos Estadísticos , PaternidadRESUMEN
The exposure to air pollutants causes significant damage to health, and inefficient cooking and heating practices produce high levels of household air pollution, including a wide range of health-damaging pollutants such as fine particles, carbon monoxide and PAHs. The exposure to PAHs has been associated with the development of neoplastic processes, asthma, genotoxicity, altered neurodevelopment and inflammation. The effects on the induction of proinflammatory cytokines are attributed to the activation of AhR. However, the molecular mechanisms by which the PAHs produce proinflammatory effects are unknown. This study was performed on a group of 41 Mexican women from two rural communities who had stoves inside their houses, used wood as biomass fuel, and, thus, were vulnerable. According to the urinary 1-OHP concentration, the samples were stratified into two groups for determination of the levels of TNF-α, AhR, CYP1B1, miR-125b and miR-155 expression. Our results showed that the CYP1B1, TNF-α, miR-125b and miR-155 expression levels were not statistically different between women with the lowest and highest levels of 1-OHP. Interestingly, high levels of PAHs promoted augmented expression of AhR, which is a protein involved in the modulation of inflammatory pathways in vivo, suggesting that cell signaling of AhR may be implicated in several pathogenesis processes.
RESUMEN
Exposure to lead (Pb) and mercury (Hg) remains a world public health problem, particularly for young children in developing countries. In Mexico, the main sources of exposure to Pb and Hg are wastes from human activities that increase the natural sources of these metals. Pb and Hg are highly toxic during development and maturation periods of the central nervous system (CNS); these effects are associated with the risk for neurodegenerative diseases. Mexico has numerous exposure sources to Pb and Hg; nevertheless, information on exposure in children is limited, particularly for Hg. Therefore, we conducted a review of the studies performed in children exposed to Pb and Hg. Data presented support that an important proportion of Mexican children have Pb levels above values associated with dangerous effects. On the other hand, studies on Hg-exposure are scarce, so we need more studies to estimate the magnitude of the problem and to determine exposure levels in Mexican children. Available data support the urgent need for coordinated actions among researchers, and health and environmental government authorities to implement education and nutritional campaigns, as well as to decrease exposure and effects of Pb and Hg. In addition, there must be a priority for the implementation of educational campaigns directed to the general population, but with emphasis in parents, education staff and health care providers to decrease both the risk of exposure of children to Pb and Hg and the effects of the exposure to these metals.
Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Exposición a Riesgos Ambientales , Intoxicación por Plomo , Intoxicación por Mercurio , Niño , Preescolar , Humanos , MéxicoRESUMEN
Lead (Pb) is a ubiquitous toxic metal that decreases resistance to infections, in which the macrophages have an essential role. Pb adverse effects on nitric oxide (NO-) production and variable effects on inflammatory cytokines in activated macrophages have been reported, but no effects have been reported in anti-inflammatory macrophages. We studied Pb (0.03-6 µg/dL equivalent to 0.014-2.89 µM) effects on the function of bone marrow-derived macrophages (BMDM) induced to either inflammatory or anti-inflammatory phenotypes, with LPS + IFNγ or IL-4+IL-13, respectively, and whether these effects are related. Pb did not induce cytotoxicity at any concentration in both macrophage phenotypes. In inflammatory BMDM, Pb (6 µg/dL) inhibited NO- production without affecting inducible nitric oxide synthase (iNOS) levels or basal arginase activity. At 3 and 6 µg/dL, Pb enhanced the major histocompatibility complex class II (MHC II) membrane expression but did not modify CD86 expression, TNFα, or IL-1ß production and secretion. In anti-inflammatory BMDM, Pb did not alter arginase activity, but at 3 and 6 µg/dL, increased TGF-ß1 and mannose receptor expression. Results showed that environmentally relevant concentrations of Pb alter functional outcomes or phenotypic markers of anti-inflammatory for the first time. The Pb effects on the inflammatory macrophages are not dependent on negative feedback resulting from the Pb effect on the anti-inflammatory phenotype. The Pb affected only some molecules or specific pathways related to both phenotypes. These effects could be related to Pb effects on immune defense against intracellular pathogens and allergy susceptibility.
Asunto(s)
Mediadores de Inflamación/metabolismo , Plomo/toxicidad , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Fenotipo , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Plomo/administración & dosificación , Ratones , Ratones Endogámicos BALB CRESUMEN
Arsenic (As) exposure has been associated with alterations in the immune system, studies in experimental models and adults have shown that these effects involve macrophage function; however, limited information is available on what type of effects could be induced in children. The aim of this study was to evaluate effects of As exposure, through the association of inorganic As (iAs) and its metabolites [monomethylated arsenic (MMA) and dimethylated arsenic (DMA)] with basal levels of nitric oxide (NO(-)) and superoxide anion (O(2)(-)), in peripheral blood mononuclear cells (PBMC) and monocytes, and NO(-) and O(2)(-) produced by activated monocytes. Hence, a cross-sectional study was conducted in 87 children (6-10 years old) who had been environmentally exposed to As through drinking water. Levels of urinary As species (iAs, MMA and DMA) were determined by hydride generation atomic absorption spectrometry, total As (tAs) represents the sum of iAs and its species; tAs urine levels ranged from 12.3 to 1411 microg/g creatinine. Using multiple linear regression models, iAs presented a positive and statistical association with basal NO(-) in PBMC (beta=0.0048, p=0.049) and monocytes (beta=0.0044, p=0.044), while basal O(2)(-) had a significant positive association with DMA (beta=0.0025, p=0.046). In activated monocytes, O(2)(-) showed a statistical and positive association with iAs (beta=0.0108, p=0.023), MMA (beta=0.0066, p=0.022), DMA (beta=0.0018, p=0.015), and tAs (beta=0.0013, p=0.015). We conclude that As exposure in the studied children was positively associated with basal levels of NO(-) and O(2)(-) in PBMC and monocytes, suggesting that As induces oxidative stress in circulating blood cells. Additionally, this study showed a positive association of O(2)(-) production with iAs and its metabolites in stimulated monocytes, supporting previous data that suggests that these cells, and particularly the O(2)(-) activation pathway, are relevant targets for As toxicity.
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Arsénico/toxicidad , Exposición a Riesgos Ambientales/efectos adversos , Leucocitos Mononucleares/efectos de los fármacos , Óxido Nítrico/biosíntesis , Superóxidos/metabolismo , Contaminantes Químicos del Agua/toxicidad , Arsénico/farmacocinética , Niño , Estudios Transversales , Femenino , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Metilación , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Contaminantes Químicos del Agua/farmacocinéticaRESUMEN
Arsenic is an endocrine disruptor that promotes breast cancer (BCa) development. Estrogen synthesis, through aromatase activation, is essential for BCa promotion and progression through activating the G-coupled estrogen receptor 1 (GPER1), regulating rapid nongenomic effects involved in cell proliferation and migration of BCa cells. Herein, was studied the role of aromatase activation and the GPER1 pathway on sodium arsenite-induced promotion and progression of MDA-MB-231 and MDA-MB-453 BCa cell lines. Our results demonstrated that 0.1 µM of sodium arsenite induces cell proliferation, migration, invasion, and stimulates aromatase activity of BCa cell lines MDA-MB-231, MDA-MB-453, MCF-7, but not in a nontumorigenic breast epithelial cell line (MCF-12A). Using letrozole (an aromatase inhibitor) and G-15 (a GPER1-selective antagonist), we demonstrated that sodium arsenite-induced proliferation and migration is mediated by induction of aromatase enzyme and, at least in part, by GPER1 activation in MDA-MB-231 and MDA-MB-453 cells. Sodium arsenite induced phosphorylation of Src that participated in sodium arsenite-induced aromatase activity, and -cell proliferation of MDA-MB-231 cell line. Overall, data suggests that sodium arsenite induces a positive-feedback loop, resulting in the promotion and progression of BCa cells, through induction of aromatase activity, E2 production, GPER1 stimulation, and Src activation.
Asunto(s)
Aromatasa/metabolismo , Arsenitos/toxicidad , Neoplasias de la Mama/enzimología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Activadores de Enzimas/toxicidad , Compuestos de Sodio/toxicidad , Neoplasias de la Mama/patología , Activación Enzimática , Estradiol/metabolismo , Femenino , Humanos , Células MCF-7 , Invasividad Neoplásica , Fosforilación , Receptores de Estrógenos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Familia-src Quinasas/metabolismoRESUMEN
The impact of pregnancy hypertension in the offspring endothelia remains unknown. We evaluated the transcriptional expression of four genes that participate in the process of endothelial dysfunction using umbilical vein endothelial cell cultures (HUVEC) from healthy pregnant women (PW) and those with hypertensive disorders (HD). The cytochrome P450 1A1 (CYP1A1), gluthathione S-transferase subtype T1 (GSTT1), interleukin 6 (IL-6) and 8 (IL-8) mRNA and IL-6 protein levels were assessed. IL-6 and IL-8 transcripts were significantly reduced in HUVEC obtained from HD women. Our results suggest that a hypertensive environment in utero modifies the transcriptional expression of key inflammatory molecules in the newborn.
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Endotelio Vascular/fisiopatología , Hipertensión/metabolismo , Complicaciones Cardiovasculares del Embarazo/metabolismo , Adulto , Estudios de Casos y Controles , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Femenino , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Preeclampsia/metabolismo , Embarazo , Transcripción Genética , Venas Umbilicales/citología , Adulto JovenRESUMEN
Methylmercury (MeHg) is an environmental neurotoxicant that inhibits neuronal migration. This process requires several cyclic steps involving the formation of membrane protrusions (lamellipodia and filopodia) and focal adhesion turnover. FAK and Src are critical proteins that regulate both processes. The FAK-Src complex promotes the activation of Rac1 and Cdc42, two GTPases involved in the remodeling of the actin cytoskeletal network. Here, we studied the effect of MeHg (1, 10, 100, 500 and 1000nM) on cell migration, the formation of cell protrusions, focal adhesion location and the activation of FAK, Src, Rac1 and Cdc42 using the SH-SY5Y neuroblastoma cell line stimulated with PDGF-BB (PDGF). The data show that MeHg (1-500nM) inhibited PDGF-stimulated cell migration. In PDGF-stimulated cells, MeHg (100-1000nM) decreased protrusions and increased the size of the p-FAKY397 clusters. MeHg also inhibited PDGF-induced FAK and Src activation and, at 100nM, MeHg inhibited the activation of Rac1 and Cdc42. Altogether, the findings show that low concentrations of MeHg inhibit SH-SY5Y cell migration by disrupting the activation and disassembly of FAK. This negatively affects the activation of Src, Rac1 and Cdc42, all of which are critical proteins for the regulation of cell movement. These effects could be related to the MeHg-mediated inhibition of PDGF-induced formation of lamellipodia and filopodia, focal adhesion disassembly and PDGF-induced movement.
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Movimiento Celular/efectos de los fármacos , Quinasa 1 de Adhesión Focal/metabolismo , Compuestos de Metilmercurio/farmacología , Neuroblastoma/metabolismo , Factor de Crecimiento Derivado de Plaquetas/farmacología , Proteína de Unión al GTP cdc42/antagonistas & inhibidores , Proteína de Unión al GTP rac1/antagonistas & inhibidores , Familia-src Quinasas/antagonistas & inhibidores , Línea Celular Tumoral , Humanos , Neuroblastoma/enzimología , Neuroblastoma/patología , Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Proteína de Unión al GTP cdc42/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Familia-src Quinasas/metabolismoRESUMEN
Exposure of several human populations to arsenic has been associated with a high incidence of detrimental dermatological and carcinogenic effects. To date, studies examining the immunotoxic effects of arsenic in humans, and specifically in children, are lacking. Therefore, we evaluated several parameters of immunological status in a group of children exposed to arsenic through their drinking water. Peripheral blood mononuclear cells (PBMCs) of 90 children (6 to 10 years old) were collected. Proportions of lymphocyte subpopulations, PBMC mitogenic proliferative response, and urinary arsenic levels were evaluated. Increased urine arsenic levels were associated with a reduced proliferative response to phytohemaglutinin (PHA) stimulation (P=0.005), CD4 subpopulation proportion (P=0.092), CD4/CD8 ratio (P=0.056), and IL-2 secretion levels (P=0.003). Increased arsenic exposure was also associated with an increase in GM-CSF secretion by mononucleated cells (P=0.000). We did not observe changes in CD8, B, or NK cell proportions, nor did we observe changes in the secretion of IL-4, IL-10, or IFN-gamma by PHA-activated PBMCs. These data indicate that arsenic exposure could alter the activation processes of T cells, such that an immunosuppression status that favors opportunistic infections and carcinogenesis is produced together with increased GM-CSF secretion that may be associated with chronic inflammation.
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Intoxicación por Arsénico/inmunología , Arsénico/toxicidad , Citocinas/metabolismo , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/metabolismo , Arsénico/administración & dosificación , Arsénico/orina , Intoxicación por Arsénico/patología , Niño , Estudios Transversales , Femenino , Humanos , Masculino , México , Subgrupos de Linfocitos T/citología , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/orinaRESUMEN
Nonmelanoma skin cancer (NMSC) is the most frequent type of cancer in humans. Exposure to UV radiation is a major risk factor for NMSC, and oxidative DNA damage, caused either by UV radiation itself or by other agents, may be involved in its induction. Increased sensitivity to oxidative damage and an altered DNA repair capacity (DRC) increase the risk of many types of cancer; however, sensitivity to oxidizing agents has not been evaluated for NMSC, and results regarding DRC in NMSC are inconclusive. In the present study, we evaluated DNA damage and repair in leukocytes from 41 NMSC patients and 45 controls. The Comet assay was used to measure basal and H(2)O(2)-induced DNA damage, as well as the DRC, while the cytokinesis-block micronucleus assay was used to measure the basal level of chromosome damage. Although basal DNA damage was higher for the controls than for the patients, this finding was mainly due to sampling more controls in the summer, which was associated with longer comet tails. In contrast, H(2)O(2)-induced DNA damage was significantly higher in cases than in controls, and this parameter was not influenced by the season of the year. The DRC for the H(2)O(2)-induced damage was similar for cases and controls and unrelated to seasonality. Finally, the frequency of binucleated lymphocytes with micronuclei was similar for cases and controls. The results of this study indicate that NMSC patients are distinguished from controls by an increased sensitivity to oxidative DNA damage.
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Daño del ADN , Reparación del ADN , Micronúcleos con Defecto Cromosómico , Mutágenos/toxicidad , Neoplasias Cutáneas/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Peróxido de Hidrógeno/toxicidad , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Masculino , Micronúcleos con Defecto Cromosómico/efectos de los fármacos , Micronúcleos con Defecto Cromosómico/efectos de la radiación , Pruebas de Micronúcleos , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Estaciones del Año , Neoplasias Cutáneas/sangre , Rayos Ultravioleta/efectos adversosRESUMEN
Few studies have assessed the effects of developmental methylmercury (MeHg) exposure on learning and memory at different ages. The possibility of the amelioration or worsening of the effects has not been sufficiently investigated. This study aimed to assess whether low-dose MeHg exposure in utero and during suckling induces differential disturbances in learning and memory of periadolescent and young adult rats. Four experimental groups of pregnant Sprague-Dawley rats were orally exposed to MeHg or vehicle from gestational day 5 to weaning: (1) control (vehicle), (2) 250 µg/kg/day MeHg, (3) 500 µg/kg/day MeHg, and (4) vehicle, and treated on the test day with MK-801 (0.15 mg/kg i.p.), an antagonist of the N-methyl D-aspartate receptor. The effects were evaluated in male offspring through the open field test, object recognition test, Morris water maze, and conditioned taste aversion. For each test and stage assessed, different groups of animals were used. MeHg exposure, in a dose-dependent manner, disrupted exploratory behaviour, recognition memory, spatial learning, and acquisition of aversive memories in periadolescent rats, but alterations were not observed in littermates tested in young adulthood. These results suggest that developmental low-dose exposure to MeHg induces age-dependent detrimental effects. The relevance of decreasing exposure to MeHg in humans remains to be determined.
Asunto(s)
Aprendizaje/efectos de los fármacos , Memoria/efectos de los fármacos , Compuestos de Metilmercurio/toxicidad , Factores de Edad , Animales , Femenino , Humanos , Aprendizaje/fisiología , Masculino , Memoria/fisiología , Embarazo , RatasRESUMEN
Dichlorodiphenyldichloroethylene (p,p'-DDE), the most persistent metabolite of dichlorodiphenyltrichloroethane (DDT), is still present in the human population. Both are present in the bone marrow of patients with bone marrow disorders, but thus far there are no studies that assess the capability of p,p'-DDE to affect myeloid cells. The aim of this study was to determine the effect of p,p'-DDE on promyelocytic cell differentiation and intracellular pathways related to this event. p,p'-DDE induced morphological changes compatible with promyelocytic differentiation in a concentration-dependent manner. The p,p'-DDE effect on [Ca2+]i, C/EBPß protein levels, PKCα and p38 activation, and the role of oxidative stress or PLA2 was assayed. Exposure to 1.9 µg/mL of p,p'-DDE increased [Ca2+]i, PKCα, p38, and C/EBPß protein levels; the increase of nuclear C/EBPß protein was dependent on p38. PKCα phosphorylation was dependent on PLA2 and p,p'-DDE-induced oxidative stress. p38 phosphorylation induced by p,p'-DDE was dependent on PLA2, PKC activation, and oxidative stress. These effects of p,p'-DDE at concentrations found in human bone marrow may induce alterations in immature myeloid cells and could affect their cellular homeostasis. In order to establish the risk from exposure to p,p'-DDE on the development of bone marrow disorders in humans, these effects deserve further study.
Asunto(s)
Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Diclorodifenil Dicloroetileno/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Células Mieloides/efectos de los fármacos , Proteína Quinasa C-alfa/metabolismo , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Calcio/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular , Células HL-60 , Humanos , Células Mieloides/metabolismo , Estrés Oxidativo/efectos de los fármacosRESUMEN
BACKGROUND: Lead and cadmium exposure may promote atherosclerosis, although the cardiovascular effects of chronic low-dose exposure are largely unknown. The objective of the present study was to evaluate the association between blood levels of lead and cadmium and peripheral arterial disease. METHODS AND RESULTS: We analyzed data from 2125 participants who were > or =40 years of age in the 1999 to 2000 National Health and Nutrition Examination Survey (NHANES). Peripheral arterial disease was defined as an ankle brachial index <0.9 in at least 1 leg. Lead and cadmium levels were measured by atomic absorption spectrometry. After adjustment for demographic and cardiovascular risk factors, the ORs of peripheral arterial disease comparing quartiles 2 to 4 of lead with the lowest quartile were 1.63 (95% CI, 0.51 to 5.15), 1.92 (95% CI, 0.62 to 9.47), and 2.88 (95% CI, 0.87 to 9.47), respectively (P for trend=0.02). The corresponding ORs for cadmium were 1.07 (95% CI, 0.44 to 2.60), 1.30 (95% CI, 0.69 to 2.44), and 2.82 (95% CI, 1.36 to 5.85), respectively (P for trend=0.01). The OR of peripheral arterial disease for current smokers compared with never smokers was 4.13. Adjustment for lead reduced this OR to 3.38, and adjustment for cadmium reduced it to 1.84. CONCLUSIONS: Blood lead and cadmium, at levels well below current safety standards, were associated with an increased prevalence of peripheral arterial disease in the general US population. Cadmium may partially mediate the effect of smoking on peripheral arterial disease.
Asunto(s)
Cadmio/sangre , Plomo/sangre , Enfermedades Vasculares Periféricas/epidemiología , Fumar/epidemiología , Adulto , Anciano , Consumo de Bebidas Alcohólicas/epidemiología , Tobillo , Presión Sanguínea , Arteria Braquial , Proteína C-Reactiva/análisis , Estudios de Cohortes , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Enfermedades Vasculares Periféricas/sangre , Riesgo , Muestreo , Estados Unidos/epidemiologíaRESUMEN
Exposure to metals may promote atherosclerosis. Blood cadmium and lead were associated with peripheral arterial disease (PAD) in the 1999-2000 National Health and Nutrition Examination Survey (NHANES). In the present study we evaluated the association between urinary levels of cadmium, lead, barium, cobalt, cesium, molybdenum, antimony, thallium, and tungsten with PAD in a cross-sectional analysis of 790 participants > or =40 years of age in NHANES 1999-2000. PAD was defined as a blood pressure ankle brachial index < 0.9 in at least one leg. Metals were measured in casual (spot) urine specimens by inductively coupled plasma-mass spectrometry. After multivariable adjustment, subjects with PAD had 36% higher levels of cadmium in urine and 49% higher levels of tungsten compared with noncases. The adjusted odds ratio for PAD comparing the 75th to the 25th percentile of the cadmium distribution was 3.05 [95% confidence interval (CI), 0.97 to 9.58]; that for tungsten was 2.25 (95% CI, 0.97 to 5.24). PAD risk increased sharply at low levels of antimony and remained elevated beyond 0.1 microg/L. PAD was not associated with other metals. In conclusion, urinary cadmium, tungsten, and possibly antimony were associated with PAD in a representative sample of the U.S. population. For cadmium, these results strengthen previous findings using blood cadmium as a biomarker, and they support its role in atherosclerosis. For tungsten and antimony, these results need to be interpreted cautiously in the context of an exploratory analysis but deserve further study. Other metals in urine were not associated with PAD at the levels found in the general population.