RESUMEN
Lead (Pb), cadmium (Cd), and mercury (Hg) are environmentally toxic heavy metals that can be simultaneously detected at low levels in the blood of the general population. Although our previous studies have demonstrated neurodevelopmental toxicity upon co-exposure to these heavy metals at these low levels, the precise mechanisms remain largely unknown. Dendritic spines are the structural foundation of memory and undergo significant dynamic changes during development. This study focused on the dynamics of dendritic spines during brain development following Pb, Cd, and Hg co-exposure-induced memory impairment. First, the dynamic characteristics of dendritic spines in the prefrontal cortex were observed throughout the life cycle of normal rats. We observed that dendritic spines increased rapidly from birth to their peak value at weaning, followed by significant pruning and a decrease during adolescence. Dendritic spines tended to be stable until their loss in old age. Subsequently, a rat model of low-dose Pb, Cd, and Hg co-exposure from embryo to adolescence was established. The results showed that exposure to low doses of heavy metals equivalent to those detected in the blood of the general population impaired spatial memory and altered the dynamics of dendritic spine pruning from weaning to adolescence. Proteomic analysis of brain and blood samples suggested that differentially expressed proteins upon heavy metal exposure were enriched in dendritic spine-related cytoskeletal regulation and axon guidance signaling pathways and that cofilin was enriched in both of these pathways. Further experiments confirmed that heavy metal exposure altered actin cytoskeleton dynamics and disturbed the dendritic spine pruning-related LIM domain kinase 1-cofilin pathway in the rat prefrontal cortex. Our findings demonstrate that low-dose Pb, Cd, and Hg co-exposure may promote memory impairment by perturbing dendritic spine dynamics through dendritic spine pruning-related signaling pathways.
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Cadmio , Mercurio , Humanos , Adolescente , Animales , Ratas , Cadmio/toxicidad , Mercurio/toxicidad , Espinas Dendríticas , Plomo/toxicidad , Proteómica , Factores Despolimerizantes de la Actina , Encéfalo , Trastornos de la Memoria/inducido químicamenteRESUMEN
It is well known that exposure of double-stranded RNA (dsRNA) to intestine immediately induces villus damage with severe diarrhea, which is mediated by toll-like receptor 3 signaling activation. However, the role of intestinal stem cells (ISCs) remains obscure during the pathology. In the present study, polyinosinic-polycytidylic acid (poly[I:C]), mimicking viral dsRNA, was used to establish intestinal damage model. Mice were acutely and chronically exposed to poly(I:C), and ISCs in jejunum were analyzed. The results showed that the height of villus was shorter 48 hr after acute poly(I:C) exposure compared with that of controls, while chronic poly(I:C) treatment increased both villus height and crypt depth in jejunum compared with control animals. The numbers of ISCs in jejunum were significantly increased after acute and chronic poly(I:C) exposure. Poly (I:C)-stimulated ISCs have stronger capacities to differentiate into intestine endocrine cells. Mechanistically, poly(I:C) treatment increased expression of Stat1 and Axin2 in the intestinal crypt, which was along with increased expression of Myc, Bcl2, and ISC proliferation. These findings suggest that dsRNA exposure could induce ISC proliferation to ameliorate dsRNA-induced intestinal injury.
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Mucosa Intestinal/crecimiento & desarrollo , Poli I-C/farmacología , Proteínas Proto-Oncogénicas c-myc/genética , Células Madre/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Proteína Axina/genética , Proliferación Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Yeyuno/efectos de los fármacos , Yeyuno/crecimiento & desarrollo , Ratones , ARN Bicatenario/efectos de los fármacos , Factor de Transcripción STAT1/genética , Transducción de Señal , Receptor Toll-Like 3/genéticaRESUMEN
The benefit of chemotherapy as a constituent of transcatheter arterial chemoembolization (TACE) is still in debate. Recently we have developed arsenic trioxide nanoparticle prodrug (ATONP) as a new anticancer drug, but its systemic toxicity is a big issue. In this preclinical TACE study, ATONP emulsified in lipiodol behaved as drug-eluting bead manner. Sustained release of arsenic from ATONP within occluded tumor caused very low arsenic level in plasma, avoiding the "rushing out" effect as ATO did. Correspondingly, intratumoral arsenic accumulation and inorganic phosphate deprivation were simultaneously observed, and arsenic concentration was much higher as ATONP was transarterially administered than ATO, or intravenously injected. Tumor necrosis and apoptosis were remarkably more severe in ATONP group than ATO, but no significant hepatic and renal toxicity was perceived. In brief, ATONP alleviated arsenic toxicity and boosted the therapeutic effect of TACE via Pi-activated drug sustainable release.
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Trióxido de Arsénico , Quimioembolización Terapéutica , Neoplasias Hepáticas Experimentales/terapia , Profármacos , Animales , Trióxido de Arsénico/farmacocinética , Trióxido de Arsénico/farmacología , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/farmacología , Aceite Etiodizado/química , Aceite Etiodizado/farmacocinética , Aceite Etiodizado/farmacología , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Profármacos/farmacocinética , Profármacos/farmacología , ConejosRESUMEN
Heavy metals such as lead (Pb), cadmium (Cd), and mercury (Hg) are representative neurotoxicological contaminants that can evoke cognitive dysfunctions. Low levels of these contaminants can be detected simultaneously in the human blood. In our previous study, behavioral performances were markedly impaired by exposure to these heavy metal mixtures (MM) at low levels. However, the aspects of cognitive functions involved are not well understood. Here, we further analyzed search strategies using a new algorithm named Morris water maze-unbiased strategy classification (MUST-C). Rat pups were co-exposed to low doses of Pb, Cd, and Hg during the embryonic and lactation stage. MM exposure at low doses, similar to those found in the general population, impaired search strategies even though their latency and path length were not affected in the Morris water maze task. MM-exposed rats preferred to use more directionless repetition strategies and less target orientation strategies than did vehicle-exposed animals in a dose-dependent manner. In addition, thionine staining and electron microscopy further revealed that MM exposure induced dose-dependent search strategy related place cell injures in the hippocampal CA1 and CA3 regions. These results demonstrate that the use of suboptimal search strategies underlies the early cognitive deficits in rats exposed to low doses of MM. The current study determined that search strategy analysis might be a novel sensitive assessment method for evaluating in the neurobehavioral toxicity.
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Disfunción Cognitiva/inducido químicamente , Contaminantes Ambientales/toxicidad , Metales Pesados/toxicidad , Animales , Cadmio/toxicidad , Cognición , Femenino , Hipocampo , Humanos , Hormonas Juveniles , Lactancia , Masculino , Mercurio/toxicidad , RatasRESUMEN
OBJECTIVES: A significant number of researches have evidenced that occupational lead (Pb) exposure increased risks of cardiovascular disease. However, evidences about the potential effects of Pb on the cardiac conduction system are sparse and inconclusive. Besides, ryanodine receptors (RyRs) induced dysfunction of cardiac excitation contraction coupling which is considered to be one of the mechanisms in cardiovascular diseases. Therefore, we examined the association between occupational Pb exposure and ECG conduction abnormalities, as well as RyRs in Pb-induced ECG abnormalities. METHODS: We investigated 529 Pb smelter workers, and measured blood lead (BPb), zinc protoporphyrin (ZPP), ECG outcomes and RyR expression levels. Based on BPb levels, the workers were divided into three groups: the BPb not elevated group, the BPb elevated group and the Pb poisoning group. Descriptive and multivariable analyses were performed. RESULTS: Compared with the BPb not elevated group, the Pb poisoning group had a higher incidence of high QRS voltage, and a lower level of RyR1 gene expression (p<0.05). Further unconditional multivariable logistic regression analyses showed that high QRS voltage was positively related to BPb (OR=1.045, 95% CI 1.014 to 1.078) and inversely associated with RyR1 expression (OR=0.042, 95% CI 0.002 to 0.980) after adjusting for potential confounders. In addition, multiple linear regression analyses showed that the QTc interval was positively associated with ZPP (ß=0.299, 95% CI 0.130 to 0.468) after adjusting for potential confounders. CONCLUSIONS: Our study provided evidences that occupational exposure to Pb may be associated with worse ECG outcomes (high QRS voltage), which might be related to decreased levels of RyR1.
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Intoxicación por Plomo/genética , Intoxicación por Plomo/fisiopatología , Plomo/sangre , Exposición Profesional , Canal Liberador de Calcio Receptor de Rianodina/genética , Adulto , Estudios Transversales , Electrocardiografía , Sistema de Conducción Cardíaco/fisiopatología , Humanos , Intoxicación por Plomo/sangre , Modelos Lineales , Modelos Logísticos , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/diagnóstico , Masculino , Análisis Multivariante , Protoporfirinas/sangre , Adulto JovenRESUMEN
Although the neurotoxic mechanism of lead (Pb2+) has been extensively studied, it is not well understood. The effects of Pb2+ on free cytosolic calcium (Ca2+) concentration and calcium-regulated events have been suggested to be major mechanisms in Pb2+ toxicity. Based on our previous findings that Pb2+ changes calcium release through ryanodine receptors (RyRs), the modulation of endoplasmic reticulum (ER) vesicular RyRs by Pb2+ was investigated further in the present study. The results of [3H]ryanodine binding assays showed that in the presence of a free Ca2+ concentration ([Ca2+]f) of 100µM, Pb2+ modulated the equilibrium of [3H]ryanodine binding to brain RyRs, with a U-type dose-response curve, where minimal binding was observed at a free Pb2+ concentration ([Pb2+]f) of 0.39µM. This modulation was also observed over a time course. Scatchard analysis indicated that both an increase in Kd and a possible decrease in Bmax were responsible for the decrease in binding induced by low [Pb2+]f. Moreover, the effects of Pb2+ on the function of ER RyRs in neurons might also be controlled by other RyR modulators. Whole-cell patch-clamp experiments revealed that dynamic calcium oscillations evoked by specific RyR agonists were depressed rapidly and reversibly by exposure to 10µM Pb2+. Our study indicates that RyRs are molecular targets of Pb2+, and this interaction disturbs Ca2+ signals and leads to neurotoxicity.
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Encéfalo/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , Plomo/toxicidad , Canal Liberador de Calcio Receptor de Rianodina/efectos de los fármacos , Animales , Calcio/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Retículo Endoplásmico/metabolismo , Ratas , Ratas Sprague-Dawley , Rianodina/metabolismoRESUMEN
Upregulation of histone acetylation plays a critical role in the dysregulation of transcription. It alters the structure of chromatin, which leads to the onset of cancer. Histone deacetylase inhibitors may therefore be a promising way to limit cancer progression. In this study, we examined the effects of droxinostat on the growth of HT-29 colon cancer cells. Our results show that droxinostat effectively inhibited cell growth and colony-forming ability by inducing cellular apoptosis and ROS production in HT-29 cells. Notably, the apoptotic inhibitor Z-VAD-FMK significantly decreased the levels of cellular apoptosis and the antioxidant γ-tocotrienol (GT3) significantly decreased ROS production induced by droxinostat treatment. Z-VAD-FMK and GT3 also partially reversed the negative growth effects of droxinstat on HT-29 cells. GT3 treatment decreased cellular apoptosis and increased colony-forming ability upon droxinostat administration. Z-VAD-FMK treatment also partially decreased droxinostat-induced ROS production. Our findings suggest that the effects of droxinostat on colon cancer cells are mediated by the induction of oxidative stress and apoptotic cell death.
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Apoptosis/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Estrés Oxidativo/efectos de los fármacos , Clorometilcetonas de Aminoácidos/farmacología , Neoplasias del Colon/metabolismo , Células HT29 , Humanos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg) are among the leading toxic agents detected in the environment, and they have also been detected simultaneously in blood, serum, and urine samples of the general population. Meanwhile early neurologic effects and multiple interactions of Pb, Cd, As, and Hg had been found in children from environmentally polluted area. However, the current studies of these four metals were mostly limited to the interactions between any two metals, whereas the interaction characteristics between any three and four metals were rarely studied. In our study, we firstly explored the characteristics of the neurotoxic interactions among these four elements in nerve cells with factorial designs. The results showed that Pb+Cd+As+Hg co-exposure had a synergistic neurotoxic effect that was more severe than that induced by any two or three metals, when their individual metals were at human environmental exposure (in the blood of U.S. population) relevant levels and below no observed adverse effect levels (NOAELs). Therefore, Pb+Cd+As+Hg co-exposure at human environmental exposure relevant levels were further selected to examine synaptic homeostasis as the cellular and molecular foundation of learning and memory. We reported for the first time that Pb+Cd+As+Hg co-exposure induced dose-dependent decreases of the dendritic lengths and branching, as well as spine density and mature phenotype in primary hippocampal neurons, and the stimulated neurite outgrowths in NGF-differentiated PC12 cells. And the above synaptic homeostasis disruption was associated with serum induced kinase (Snk)-spine associated Rap GTPase activating protein (SPAR) pathway. Our study suggests that human environmental Pb, Cd, As, and Hg co-exposure has the potential to evoke synergistic neurotoxicity even if their individual metals are below NOAELs, which reinforces the need to control and regulate potential sources of metal contamination.
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Arsénico/toxicidad , Cadmio/toxicidad , Plomo/toxicidad , Mercurio/toxicidad , Sinapsis/efectos de los fármacos , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Dendritas/efectos de los fármacos , Exposición a Riesgos Ambientales , Hipocampo , Homeostasis/efectos de los fármacos , Humanos , Neuronas/efectos de los fármacos , Síndromes de Neurotoxicidad/patología , RatasRESUMEN
BACKGROUND: Autism spectrum disorders (ASD) are hereditary, heterogeneous and biologically complex neurodevelopmental disorders. Individual studies on gene expression in ASD cannot provide clear consensus conclusions. Therefore, a systematic review to synthesize the current findings from brain tissues and a search tool to share the meta-analysis results are urgently needed. METHODS: Here, we conducted a meta-analysis of brain gene expression profiles in the current reported human ASD expression datasets (with 84 frozen male cortex samples, 17 female cortex samples, 32 cerebellum samples and 4 formalin fixed samples) and knock-out mouse ASD model expression datasets (with 80 collective brain samples). Then, we applied R language software and developed an interactive shared and updated database (dbMDEGA) displaying the results of meta-analysis of data from ASD studies regarding differentially expressed genes (DEGs) in the brain. RESULTS: This database, dbMDEGA ( https://dbmdega.shinyapps.io/dbMDEGA/ ), is a publicly available web-portal for manual annotation and visualization of DEGs in the brain from data from ASD studies. This database uniquely presents meta-analysis values and homologous forest plots of DEGs in brain tissues. Gene entries are annotated with meta-values, statistical values and forest plots of DEGs in brain samples. This database aims to provide searchable meta-analysis results based on the current reported brain gene expression datasets of ASD to help detect candidate genes underlying this disorder. CONCLUSION: This new analytical tool may provide valuable assistance in the discovery of DEGs and the elucidation of the molecular pathogenicity of ASD. This database model may be replicated to study other disorders.
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Trastorno del Espectro Autista/genética , Bases de Datos Genéticas , Transcriptoma , Animales , Cerebelo , Corteza Cerebral/metabolismo , Femenino , Humanos , Masculino , RatonesRESUMEN
OBJECTIVE: To explore the effect of long-term lead exposure on brain iron in aged rats. METHODS: SPF female and male Sprague-Dawley rats were respectively randomly divided into three groups: control, low lead-exposed, high lead-exposed. Lead-exposed female rats drank 0.8g/L or 1.5g/L lead acetate solutions through pregnancy until weaning and then the pups received 0.3g/L or 0.9g/L lead acetate solution depending on their group. Control group rats drank deionized water throughout the experiment. At the postnatal 18 months, one pup for per group was given an ultra structural detection of hippocampus, and the other male pups were measured the lead and iron concentration of blood and brain by GE MR 3.0T MR scanner and ICP-AES. RESULTS: In comparing with control group, the lead concentrations of blood and brain in lead-exposed groups were significantly higher, and the iron contents of brain and cortex, hippocampus, thalamus were significantly higher in 0.9g/L lead-exposed group. Also, it was highly positively correlated between blood lead and iron of blood, cortex, hippocampus, thalamus, respectively. With the dose of lead-exposed increased, cytoplasm, nucleus, mitochondrial structure and synaptic structure had suffered vary degrees of damage from ultra structural detection of hippocampus, it could be observed early neuronal apoptosis. CONCLUSION: Lead induced neurodegenerative diseases might be related to iron overload which caused by lead exposure.
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Química Encefálica , Encéfalo/patología , Exposición a Riesgos Ambientales/efectos adversos , Hierro/análisis , Plomo/toxicidad , Envejecimiento , Animales , Femenino , Hipocampo/patología , Imagen por Resonancia Magnética , Masculino , Enfermedades Neurodegenerativas/inducido químicamente , Ratas , Ratas Sprague-DawleyRESUMEN
Contaminated water and food are the main sources of lead, cadmium, and mercury in the human body. Long-term and low-level ingestion of these toxic heavy metals may affect brain development and cognition. However, the neurotoxic effects of exposure to lead, cadmium, and mercury mixture (Pb + Cd + Hg) at different stages of brain development are rarely elucidated. In this study, different doses of low-level Pb + Cd + Hg were administered to Sprague-Dawley rats via drinking water during the critical stage of brain development, late stage, and after maturation, respectively. Our findings showed that Pb + Cd + Hg exposure decreased the density of memory- and learning-related dendritic spines in the hippocampus during the critical period of brain development, resulting in hippocampus-dependent spatial memory deficits. Only the density of learning-related dendritic spines was reduced during the late phase of brain development and a higher-dose of Pb + Cd + Hg exposure was required, which led to hippocampus-independent spatial memory abnormalities. Exposure to Pb + Cd + Hg after brain maturation revealed no significant change in dendritic spines or cognitive function. Further molecular analysis indicated that morphological and functional changes caused by Pb + Cd + Hg exposure during the critical phase were associated with PSD95 and GluA1 dysregulation. Collectively, the effects of Pb + Cd + Hg on cognition varied depending on the brain development stages.
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Mercurio , Metales Pesados , Ratas , Animales , Humanos , Cadmio/toxicidad , Cadmio/análisis , Plomo/toxicidad , Plomo/análisis , Ratas Sprague-Dawley , Mercurio/toxicidad , Mercurio/análisis , Cognición , HipocampoRESUMEN
In the real world, humans are exposed to multiple metal(loid)s (designated hereafter metals) that contain essential metals as well as toxic metals. Exposure to the metal mixture was assumed to be associated with renal function impairment; however, there is no consensus on available studies. Therefore, we here explored the association between multiple metals exposure and indicators of renal function in the general population from southeastern China. A total of 11 metals with 6 human essential metals and 5 toxic metals were determined in the selected 720 subjects. In addition, serum uric acid (SUA), serum creatinine (SCR), and the estimated glomerular filtration rate (eGFR) were measured or calculated as indicators of renal function. Using multiple flexible statistical models of generalized linear model, elastic net regression, and Bayesian kernel machine regression, the joint as well as the individual effect of metals within the mixture, and the interactions between metals were explored. When exposed to the metal mixture, the statistically non-significantly increased SUA, the significantly increased SCR, and the significantly declined eGFR were observed. In addition, the declined renal function may be primarily attributed to lead (Pb), arsenic (As), and nickel (Ni) exposure. Finally, interactions, such as the synergistic effect between Pb and Mo on SUA, whereas the antagonistic effect between Ni and Cd on SCR and eGFR were identified. Our finding suggests that combined exposure to multiple metals would impair renal function. Therefore, reducing exposure to toxic heavy metals of Pb, As, and Cd and limiting exposure to the human essential metal of Ni would protect renal function.
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Arsénico , Metales Pesados , Humanos , Estudios Transversales , Cadmio , Teorema de Bayes , Plomo , Ácido Úrico , Níquel , Intoxicación por Metales Pesados , Riñón/fisiología , ChinaRESUMEN
Exposure to essential and toxic metals occurs simultaneously as a mixture in real-life. However, there is no consensus regarding the effects of co-exposure to multiple metal(loid)s (designated hereafter metals) on blood lipid levels. Thus, blood concentrations of six human essential metals and five toxic metals in 720 general populations from southeastern China were simultaneously determined as a measure of exposure. In addition, quantile g-computation, Bayesian kernel machine regression, elastic net regression, and generalized linear model were used to investigate both the joint and individual effects of exposure to this metal mixture on human blood lipid levels. The significant positive joint effect of exposure to this metal mixture on serum total cholesterol (TC) levels, rather than on serum triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, Castelli risk index I, Castelli risk index II, atherogenic coefficient, and non-HDL-C levels, was found. In addition, the positive effect may be primarily driven by selenium (Se), lead (Pb), and mercury (Hg) exposure. In addition, on the effect of TC levels, the synergistic effect between Pb and Hg and the antagonistic effect between Se and Pb were identified. Our finding suggests that combined exposure to this metal mixture may affect human blood lipid levels. Therefore, reducing exposure to heavy metals, such as Pb and Hg, should be a priority for the general population. In addition, Se supplementation should also be considered with caution.
RESUMEN
Humans are commonly exposed to the representative neurotoxic heavy metals lead (Pb), cadmium (Cd), and mercury (Hg). These three substances can be detected simultaneously in the blood of the general population. We have previously shown that a low-dose mixture of these heavy metals induces rat learning and memory impairment at human exposure levels, but the pathogenic mechanism is still unclear. LIM kinase 1 (LIMK1) plays a critical role in orchestrating synaptic plasticity during brain function and dysfunction. Hence, we investigated the role of LIMK1 activity in low-dose heavy metal mixture-induced neurobehavioral deficits and structural synaptic plasticity disorders. Our results showed that heavy metal mixture exposure altered rat fear responses and spatial learning at general population exposure levels and that these alterations were accompanied by downregulation of LIMK1 phosphorylation and structural synaptic plasticity dysfunction in rat hippocampal tissues and cultured hippocampal neurons. In addition, upregulation of LIMK1 phosphorylation attenuated heavy metal mixture-induced structural synaptic plasticity, dendritic actin dynamics, and cofilin phosphorylation damage. The potent LIMK1 inhibitor BMS-5 yielded similar results induced by heavy metal mixture exposure and aggravated these impairments. Our findings demonstrate that LIMK1 plays a crucial role in neurobehavioral deficits induced by low-dose heavy metal mixture exposure by suppressing structural synaptic plasticity.
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Mercurio , Metales Pesados , Humanos , Ratas , Animales , Metales Pesados/toxicidad , Hipocampo/patología , Mercurio/toxicidad , Cadmio/toxicidad , Plasticidad Neuronal , Quinasas LimRESUMEN
Environmental exposure to heavy metal mixture of lead (Pb), cadmium (Cd), and mercury (Hg) would induce hazardous health effects. However, there is a paucity of data on how exposure to heavy metal mixture alters the metabolic dynamics of individual metals. Considering that the dose plays a key role in determining the toxicity of heavy metals, we performed a factorial design with three heavy metals (Pb, Cd, and Hg) at low exposure levels. Female rats were exposed to Pb, Cd, and (or) Hg from successful mating until pup weaning. Their concentrations in maternal blood, breast milk, and postnatal day 0 (PND0) and PND21 offspring blood and whole brain were measured. Using ANOVA analysis, Pearson correlation, and structural equation model, we demonstrated the complex interactions among heavy metals during their absorption, mother-offspring transport, and target organ accumulation. Among all the explored samples, almost all the highest Pb, Cd, and Hg levels were observed in their respective single heavy metal exposure groups. In addition, Hg was found could antagonize the transport of Pb or Cd, when they cross the placental barrier and blood-brain barriers (BBB). However, the effect of Hg no longer presented when they are absorbed through the digestive system. The antagonistic effect of Pb on Cd was observed when they cross the placental barrier. In addition, Cd was also found to compete the transport pathway of Pb when they cross the BBB after birth. Compared to Pb and Hg, we found that the transport efficiency of Cd in the digestive system was lower, whereas the chelation of Cd by the placental barrier was better. This preliminary information may help researchers to explore the mechanism underlying the hazardous effects of heavy metal mixture exposure, or for regulatory agencies to revise guidelines for heavy metal exposure.
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Mercurio , Metales Pesados , Femenino , Embarazo , Ratas , Animales , Cadmio/toxicidad , Plomo/toxicidad , Mercurio/toxicidad , Placenta , Metales Pesados/toxicidad , LactanciaRESUMEN
The heavy metals lead (Pb), cadmium (Cd), and mercury (Hg) that cause neurocognitive impairment have been extensively studied. These elements typically do not exist alone in the environment; they are often found with other heavy metals and can enter the body through various routes, thereby impacting health. Our previous research showed that low Pb, Cd, and Hg levels cause neurobehavioral impairments in weaning and adult rats. However, little is known about the biomarkers and mechanisms underlying Pb, Cd, and Hg mixture-induced neurological impairments. A combined analysis of metabolomic and proteomic data may reveal heavy metal-induced alterations in metabolic and protein profiles, thereby improving our understanding of the molecular mechanisms underlying heavy metal-induced neurological impairments. Therefore, brain tissue and serum samples were collected from rats exposed to a Pb, Cd, and Hg mixture for proteomic and metabolomic analyses, respectively. The analysis revealed 363 differential proteins in the brain and 206 metabolites in serum uniquely altered in the Pb, Cd, and Hg mixture exposure group, compared to those of the control group. The main metabolic impacted pathways were unsaturated fatty acids biosynthesis, linoleic acid metabolism, phenylalanine metabolism, and tryptophan metabolism. We further identified that the levels of arachidonic acid (C20:4 n-3) and, adrenic acid (C22:4 n-3) were elevated and that kynurenic acid (KA) and quinolinic acid (QA) levels and the KA/QA ratio, were decreased in the group exposed to the Pb, Cd, and Hg mixture. A joint analysis of the proteome and metabolome showed that significantly altered proteins such as LPCAT3, SLC7A11, ASCL4, and KYAT1 may participate in the neurological impairments induced by the heavy metal mixture. Overall, we hypothesize that the dysregulation of ferroptosis and kynurenine pathways is associated with neurological damage due to chronic exposure to a heavy metal mixture.
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Mercurio , Metales Pesados , Ratas , Animales , Cadmio/toxicidad , Proteómica , Plomo/toxicidad , Metales Pesados/toxicidad , Mercurio/toxicidad , EncéfaloRESUMEN
OBJECTIVE: To study the effects of methionine and choline on the expression levels of CaMKII and CREB mRNA and proteins in hippocampus of rats exposed to lead. METHODS: Male SD rats were divided into five groups. (1) control group, (2) group exposed to lead+2 by drinking water with 0.40 g/L lead acetate, (3) group exposed to methionine and choline (1:1, 400 mg/kg), (4) group exposed to 0.40 g/L lead acetate plus methionine and choline (1:1, 100 mg/kg), (5) group exposed to 0.40 g/L lead acetate plus methionine and choline (1:1, 400 mg/kg). In 8 weeks after exposure, all rats were killed. Then CREB mRNA and CaMK II mRNA expression levels in hippocampus were detected by real-time PCR, CREB and CaMK II protein expression levels in hippocampus were measured by western blot assay. RESULTS: The expression levels (0.743 ± 0.185 and 0.729 ± 0.199) of CaMKII mRNA and CREB mRNA in the hippocampus of lead group were significantly lower than those (0.950 ± 0.238 and 0.901 ± 0.232) of control group (P < 0.05), also the expression levels (0.271 ± 0.045 and 0.212 ± 0.058) of CREB protein and pCREB protein in the hippocampus of lead group were significantly lower than those (0.319 ± 0.058 and 0.506 ± 0.125) of control group (P < 0.05). The expression levels (1.014 ± 0.210 and 1.126 ± 0.379) of CaMKII mRNA and the expression levels (1.029 ± 0.335 and 0.932 ± 0.251) of CREB mRNA in the hippocampus of 2 groups exposed to lead acetate plus methionine and choline were significantly higher than those of lead group (P < 0.05). The expression levels (0.407 ± 0.951 and 0.563 ± 0.178) of CREB protein and pCREB protein in the hippocampus of group exposed to lead acetate plus 400 mg/kg methionine and choline were significantly higher than those of lead group (P < 0.05). CONCLUSION: Methionine and choline could decrease the inhibition effects of lead on the expression of CaMKII and CREB mRNA or CREB and pCREB proteins in the hippocampus of rats.
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Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Colina/farmacología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Hipocampo/efectos de los fármacos , Plomo/toxicidad , Metionina/farmacología , Animales , Hipocampo/metabolismo , Masculino , ARN Mensajero/genética , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: Ischemic stroke (IS) with subsequent cerebrocardiac syndrome (CCS) has a poor prognosis. We aimed to investigate electrocardiogram (ECG) changes after IS with artificial intelligence (AI). METHODS: We collected ECGs from a healthy population and patients with IS, and then analyzed participant demographics and ECG parameters to identify abnormal features in post-IS ECGs. Next, we trained the convolutional neural network (CNN), random forest (RF) and support vector machine (SVM) models to automatically detect the changes in the ECGs; Additionally, We compared the CNN scores of good prognosis (mRS ≤ 2) and poor prognosis (mRS > 2) to assess the prognostic value of CNN model. Finally, we used gradient class activation map (Grad-CAM) to localize the key abnormalities. RESULTS: Among the 3506 ECGs of the IS patients, 2764 ECGs (78.84%) led to an abnormal diagnosis. Then we divided ECGs in the primary cohort into three groups, normal ECGs (N-Ns), abnormal ECGs after the first ischemic stroke (A-ISs), and normal ECGs after the first ischemic stroke (N-ISs). Basic demographic and ECG parameter analyses showed that heart rate, QT interval, and P-R interval were significantly different between 673 N-ISs and 3546 N-Ns (p < 0.05). The CNN has the best performance among the three models in distinguishing A-ISs and N-Ns (AUC: 0.88, 95%CI = 0.86-0.90). The prediction scores of the A-ISs and N-ISs obtained from the all three models are statistically different from the N-Ns (p < 0.001). Futhermore, the CNN scores of the two groups (mRS > 2 and mRS ≤ 2) were significantly different (p < 0.05). Finally, Grad-CAM revealed that the V4 lead may harbor the highest probability of abnormality. CONCLUSION: Our study showed that a high proportion of post-IS ECGs harbored abnormal changes. Our CNN model can systematically assess anomalies in and prognosticate post-IS ECGs.
Asunto(s)
Inteligencia Artificial , Accidente Cerebrovascular Isquémico , Humanos , Accidente Cerebrovascular Isquémico/diagnóstico , Redes Neurales de la Computación , Electrocardiografía , Arritmias CardíacasRESUMEN
OBJECTIVE: To investigate the distribution characteristics and influencing factors of mental workload of teachers in primary schools. METHODS: National Aeronautics and Space Administration-Task Load Index (NASA-TLX) was used to assess the mental workload levels for 397 teachers of primary schools in a city. RESULTS: The mental workload (64.34+10.56) of female teachers was significantly higher than that (61.73+ 9.77) of male teachers (P<0.05). The mental workload (65.66+10.42) of "-35" years old group was the highest. When age of teachers was younger than 35 years old, there was a positive correlation between the mental workload and age (r=0.146, P<0.05). When age of teachers was older than 35 years old, there was a negative correlation between the mental workload and age (r=-0.190, P<0.05). The teachers with higher education level felt higher mental workload (unstandardized coefficients B=1.524, standardized coefficients /=0.111, P<0.05). There was a positive correlation between the mental workload and working hours per day (unstandardized coefficients B =4.659, standardized coefficients/3 =0.223, P<0.001). CONCLUSION: Mental workload of the teachers in primary schools is closely related to age, educational level and work hours per day. Work hours per day is an important risk factor for mental workload. Reducing work hours per day (8 hours) is an effective measure of alleviating the mental workload of teachers in primary schools.
Asunto(s)
Estrés Psicológico/epidemiología , Encuestas y Cuestionarios , Carga de Trabajo/psicología , Adolescente , Adulto , Anciano , Docentes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Instituciones Académicas , Adulto JovenRESUMEN
OBJECTIVE: To study the effects of occupational stressors on coping resources of nurses. METHODS: Coping resources (recreation, self-care, social support, rational coping) and occupational stressors (role overload, role insufficiency, role ambiguity, role boundary, responsibility, physical environment) were measured on 387 nurses by personal resources questionnaire (PRQ) and Occupational Role Questionnaire (ORQ) respectively. RESULTS: The higher the level of occupational stressors was, the lower the coping resources of nurses were (P < 0.01). The level of occupational stressors was in a negative correlation with the coping resources of nurses, and the correlation with social support was the closest (P < 0.01). Except responsibility, all items in occupational stressors were correlated negatively with coping resources. The role insufficiency and role ambiguity in occupational stressors were in a closer correlation with coping resources (P < 0.01). CONCLUSION: Decresing the levels of occupational stressors for nurses in Nanchang, especially decreasing the levels of role insufficiency and role ambiguity, would enhance the coping resources of nurses, so as to enhance their capability to relieve strain.