RESUMEN
OBJECTIVE: Globally millions of people working in various industries and are exposed to different toxins which may affect their genetic stability and DNA integrity. Present study was designed to estimate the expression variation of genes related to DNA repair (XRCC1, PARP1) and lead toxicity (ALAD) in exposed industrial workers. METHODS: About 200 blood samples were collected from workers of brick kiln, welding, furniture and paint industry (50/industry) along with age and gender matched controls. mRNA expression of genes was measured using RT-PCR. Serum levels of total ROS, POD, TBAR activity was calculated. Blood lead levels were estimated by atomic absorption spectrometer. RESULTS: Relative expression of XRCC1 and PARP1 gene was significantly (P < 0.001) upregulated, while ALAD gene expression was downregulated in exposed group compared to control. Expression of XRCC1 and PARP1 was increased (P < 0.001) in exposed workers with > 30 year age compared to control with > 30 year age. Same was observed when < 30 year age group of control and exposed was compared. Likewise, XRCC1 and PARP1 expression was increased (P < 0.001) in exposed workers with > 30 year age compared to workers with < 30 year age. Whereas, ALAD gene showed significant (P < 0.01) decrease in > 30 year age workers compared to control of same age and exposed with < 30 year of age. Relative expression of XRCC1 and PARP1 was increased (P < 0.001) in exposed smokers compared to exposed non-smokers and control smokers. Whereas, ALAD gene expression reduced (P < 0.001) significantly in both groups. Blood lead content was higher (P < 0.001) in exposed group compared to control. Strong correlation was observed between XRCC1, PARP1 and ALAD gene versus age, total exposure duration, exposure per day and lead deposition. ROS, TBARS and POD activity was higher (P < 0.01) in exposed group compared to control group. CONCLUSION: Present study suggested deregulation of genes related to DNA repair and lead intoxication in exposed group compared to controls. Strong correlation was observed between selected genes and demographic parameters. Present results revealed altered activity of oxidative stress markers which would induce oxidative damage to DNA integrity and limit the function of repair enzymes.
Asunto(s)
Intoxicación por Plomo , Exposición Profesional , Humanos , Plomo , Especies Reactivas de Oxígeno , Exposición Profesional/efectos adversos , Exposición Profesional/análisis , Reparación del ADN/genética , Intoxicación por Plomo/genética , ADN , Daño del ADN , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genéticaRESUMEN
Lead (Pb) exposure has adverse health effects and altered DNA methylation may contribute to Pb toxicity. LINE-1 is an interspersed repeated DNA that is used as a surrogate marker for estimating genomic DNA methylation levels, and GSTP1 is an isozyme that detoxifies xenobiotics like Pb, and its expression is inhibited by methylation. Thus, to assess the effects of Pb exposure on global hypomethylation and gene-specific promoter hypermethylation, we examined DNA methylation at LINE-1 repetitive elements and the GSTP1 promoter region. Blood samples were obtained from children (N = 123) living in Pb-polluted areas (as exposed children) and children (N = 63) living in Pb-unpolluted areas (as control children) in Kabwe, Zambia. ICP-MS was used to determine blood lead levels (BLLs), and pyrosequencing and a fluorescence-based polymerase chain reaction assay were used to determine levels of LINE-1 methylation and GSTP1 promoter methylation, respectively. Inverse association was found between BLLs and LINE-1 methylation (ß = - 0.046, p = 0.006). The highest quartile of BLL had significant hypomethylation of LINE-1 (p for trend = 0.03), suggesting the higher the BLL, the lower LINE-1 methylation. GSTP1 methylation levels did not differ significantly between the two areas (p = 0.504), nor was it associated with Pb poisoning risk (OR = 1.03, p = 0.476), indicating GSTP1 methylation may not be a reliable biomarker of Pb exposure in healthy people. Therefore, Pb-related health problems could result from global DNA methylation changes due to high BLLs.
Asunto(s)
Intoxicación por Plomo , Plomo , Niño , Humanos , Plomo/toxicidad , Intoxicación por Plomo/genética , Metilación de ADN , Gutatión-S-Transferasa pi/genética , Regiones Promotoras Genéticas , ADN , BiomarcadoresRESUMEN
Lead (Pb) poisoning is a major public health concern in environmental justice communities of the USA and in many developing countries. There is no identified safety threshold for lead in blood, as low-level Pb exposures can lead to severe toxicity in highly susceptible individuals and late onset of diseases from early-life exposure. However, identifying "susceptibility genes" or "early exposure biomarkers" remains challenging in human populations. There is a considerable variation in susceptibility to harmful effects from Pb exposure in the general population, likely due to the complex interplay of genetic and/or epigenetic factors. This systematic review summarizes current state of knowledge on the role of genetic and epigenetic factors in determining individual susceptibility in response to environmental Pb exposure in humans and rodents. Although a number of common genetic and epigenetic factors have been identified, the reviewed studies, which link these factors to various adverse health outcomes following Pb exposure, have provided somewhat inconsistent evidence of main health effects. Acknowledging the compelling need for new approaches could guide us to better characterize individual responses, predict potential adverse outcomes, and identify accurate and usable biomarkers for Pb exposure to improve mitigation therapies to reduce future adverse health outcomes of Pb exposure.
Asunto(s)
Intoxicación por Plomo , Plomo , Biomarcadores , Exposición a Riesgos Ambientales , Epigénesis Genética , Humanos , Plomo/toxicidad , Intoxicación por Plomo/genéticaRESUMEN
Delta-aminolevulinic acid dehydratase (δ-ALAD) is involved in the synthesis of haem and exhibits a polymorphic nature. δ-ALAD polymorphism produces two alleles, namely δ-ALAD-1 and δ-ALAD-2, which in turn produce three different phenotypes, namely δ-ALAD1-1, δ-ALAD1-2, and δ-ALAD2-2. δ-ALAD gene is more susceptible to lead (Pb) toxicity than any other genes. Its genotype and phenotype frequencies change with respect to different geographical areas and extent of Pb exposure. The δ-ALAD-2 allele dominancy is linked with high concentration of lead in the body. It has also been thought that the δ-ALAD-2 allele can provoke Pb toxicity by producing a protein that binds more tightly with Pb than δ-ALAD-1 protein. However, few evidences suggest that δ-ALAD-2 may reduce harmful effects by increasing excretion of Pb from the body, thus producing its unavailability towards pathophysiologic alterations. However, the recent evidences have supported that the individuals who are heterozygote for the δ-ALAD-1 allele may be associated with a higher risk of long-term Pb toxicity. In this regard, the individuals who are exposed at occupational levels are among the most frequent study population. The main objective of our study was to explore the gene susceptibility associated with Pb poisoning. Moreover, this study also summarizes various sources of Pb exposure and thereafter outlined multiple strategies to minimize the Pb toxicity in order to save the exposed residential communities.
Asunto(s)
Predisposición Genética a la Enfermedad , Intoxicación por Plomo/genética , Plomo , Exposición Profesional , Porfobilinógeno Sintasa , Humanos , Polimorfismo Genético , Porfobilinógeno Sintasa/genéticaRESUMEN
Lead is a ubiquitous heavy metal toxin of significant public health concern. Every individual varies in their response to lead's toxic effects due to underlying genetic variations in lead metabolizing enzymes or proteins distributed in the population. Earlier studies, including our lab, have attributed the influence of ALAD (δ-Aminolevulinate dehydratase) polymorphism on blood lead retention and ALAD activity. The present study aimed to investigate the influence of VDR (Vitamin D receptor) and HFE (Hemochromatosis) polymorphisms in modulating blood lead levels (BLLs) of occupationally exposed workers. 164 lead-exposed subjects involved in lead alloy manufacturing and battery breaking and recycling processes and 160 unexposed controls with BLLs below 10 µg/dL recruited in the study. Blood lead levels, along with a battery of biochemical assays and genotyping, were performed. Regression analysis revealed a negative influence of BLLs on ALAD activity (p < 0.0001) and a positive influence on smokeless tobacco use (p < 0.001) in lead-exposed subjects. A predicted haplotype of the three VDR polymorphisms computed from genotyping data revealed that T-A-A haplotype increased the BLLs by 0.93 units (p ≤ 0.05) and C-C-A haplotype decreased the BLLs by 7.25 units (p ≤ 0.05). Further analysis revealed that the wild-type CC genotype of HFE H63D presented a higher median BLL, indicating that variant C allele may have a role in increasing the concentration of lead. Hence, the polymorphism of genes associated with lead metabolism might aid in predicting genetic predisposition to lead and its associated effects.
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Proteína de la Hemocromatosis/efectos de los fármacos , Intoxicación por Plomo/sangre , Intoxicación por Plomo/genética , Plomo/sangre , Exposición Profesional/efectos adversos , Polimorfismo Genético , Receptores de Calcitriol/efectos de los fármacos , Adulto , Femenino , Predisposición Genética a la Enfermedad , Proteína de la Hemocromatosis/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Receptores de Calcitriol/metabolismoRESUMEN
Metallothionein (MT) is a protein with function of heavy metal detoxification. However, studies about how single nucleotide polymorphisms (SNPs) of MT genes influence lead nephropathy are relatively scarce. Therefore, our aim is to investigate the association between blood lead levels and renal biomarkers and to study whether this association is influenced by the combination of MT1A and MT2A SNPs. Blood lead, urinary uric acid (UA), and urinary N-acetyl-beta-d-glucosaminidase (NAG) levels were analyzed from 485 participants. Genotyping were performed on MT1A SNPs (rs11640851 and rs8052394) and MT2A SNPs (rs10636 and rs28366003). The combined MT1A 2A SNPs were divided into 16 groups. Among renal biomarkers, urinary UA was negatively significant associated with the time-weighted index of cumulative blood lead (TWICL), while urinary NAG was positively significant with TWICL. Furthermore, the association between urinary UA and TWICL was significantly modified by group 6 of combined SNPs (MT1A 2 A SNPs combination were AAAGGGAA, ACAGGGAA, and ACGGGGAA). In conclusion, the negative association of urinary UA and TWICL is modified by group 6, which means participants of group 6 are more susceptible to lead nephrotoxicity.
Asunto(s)
Riñón/efectos de los fármacos , Intoxicación por Plomo/genética , Plomo/sangre , Metalotioneína/genética , Polimorfismo de Nucleótido Simple/genética , Acetilglucosaminidasa/orina , Adulto , Biomarcadores/orina , Femenino , Humanos , Masculino , Metalotioneína/metabolismo , Persona de Mediana Edad , Ácido Úrico/orinaRESUMEN
BACKGROUND: Lead (Pb) is a well-known toxic heavy metal which can have serious public health hazards. As of today, there is no safe threshold for Pb exposure, especially for children. Lead exposure has been associated with adverse health outcomes involving epigenetic mechanisms, such as aberrant DNA methylation. The objective of the present study was to elucidate the associations between blood lead levels (BLLs) and gene-specific promoter DNA methylation status in environmental Pb-exposed children from Kabwe, Zambia. METHODS: A cross-sectional study was conducted using 2 to 10-year-old children from high Pb exposed area (N = 102) and low Pb exposed area (N = 38). We measured BLLs using a LeadCare II analyzer and investigated the methylation status of the ALAD and p16 gene promoters by methylation-specific PCR. RESULTS: The mean BLLs were 23.7 µg/dL and 7.9 µg/dL in high Pb exposed and low Pb exposed children, respectively. Pb exposure was correlated with increased methylation of the ALAD and p16 genes. The promoter methylation rates of ALAD and p16 in high Pb exposed children were 84.3% and 67.7%, and 42.1% and 44.7% in low Pb exposed children, respectively. Significantly increased methylation was found in both genes in high Pb exposed children compared with low Pb exposed children (p < 0.05). Children with methylated ALAD and p16 genes showed an increased risk of Pb poisoning (odd ratio >1) compared to the unmethylated status. CONCLUSIONS: This study for the first time tries to correlate promoter methylation status of the ALAD and p16 genes in environmental Pb-exposed children from Kabwe, Zambia as a representative. The result suggests that Pb exposure increases aberrations in ALAD and p16 gene methylation, which may be involved in the mechanism of Pb toxicity.
Asunto(s)
Intoxicación por Plomo , Plomo , Niño , Preescolar , Estudios Transversales , Metilación de ADN , Genes p16 , Humanos , Plomo/toxicidad , Intoxicación por Plomo/epidemiología , Intoxicación por Plomo/genética , Porfobilinógeno Sintasa/genética , ZambiaRESUMEN
BACKGROUND: The present investigation of genotoxicity of lead (Pb) among workers exposed to inorganic Pb environment, which appears to be first of its kind in South India, was undertaken to assess the seriousness, the ill effects of health contributed by this serious environmental pollutant. METHODS: A total of 144 samples comprising of exposed (n=72), and control (n=72) subjects were screened. Demographic data and their associated health levels were undertaken by means of a questionnaire. The blood samples collected were subjected to chromosomal analysis, micronuclei assessment and comet assay. RESULTS: A higher level of Pb was quantified in the blood samples of all exposed subjects. An overview of the genotoxic assessment helped us understand parameters such as age do not affect or bring about any difference in the genotoxic potential of the exposed and control subjects. The only signification feature that resulted in an enhanced genotoxic potential was the years of exposure to the Pb environment that accumulated the dosage of Pb over the years. CONCLUSION: The high positivity of genotoxic potential of Pb in a country like India highlights the need for labelling hazardous metals in paint containers as a means to assure strict regulations.
Asunto(s)
Aberraciones Cromosómicas/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Intoxicación por Plomo/genética , Exposición Profesional/efectos adversos , Adulto , Estudios de Casos y Controles , Ensayo Cometa , Humanos , India , Plomo/sangre , Intoxicación por Plomo/sangre , Intoxicación por Plomo/epidemiología , Intoxicación por Plomo/etiología , Masculino , Pruebas de Micronúcleos , Persona de Mediana Edad , Mutágenos/efectos adversos , Exposición Profesional/estadística & datos numéricos , Encuestas y CuestionariosRESUMEN
BACKGROUND: To determine if the rs7079 polymorphism located in the 3' UTR of the angiotensinogen gene (AGT) altered AGT gene expression and the risk of lead poisoning. A case-control study and luciferase reporter gene assay identified a significant association between rs7079 variants and the risk of lead poisoning. RESULTS: Serum AGT levels were significantly higher in individuals carrying the rs7079 CA genotype, as compared to those carrying the rs7079 CC genotype. The binding of the miRNA mimics miR-31-5p and miR-584-5p to the 3' UTR of AGT differed based on which rs7079 variant was present, implying that AGT gene expression depends on the rs7079 variant carried. CONCLUSIONS: The rs7079 C to A substitution reduced the binding of miR-31-5p/miR-584-5p to the 3' UTR of AGT, possibly altering the risk of lead poisoning.
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Angiotensinógeno/genética , Intoxicación por Plomo/genética , MicroARNs/metabolismo , Regiones no Traducidas 3' , Adulto , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Adulto JovenRESUMEN
Chronic lead (Pb) exposure has been shown to reduce the expression of some synaptic proteins which are involved in vesicular trafficking and affect presynaptic neurotransmitter release. However, the precise mechanisms by Pb impairs neurotransmitter release are still not well defined. In the current study, we aimed to elucidate the changes of Huntingtin-associated protein 1 (HAP1) in Pb exposed rats and PC12 cells models and its molecular mechanism. Repressor element-1 silencing transcription (REST) modulates the expression of genes containing the repressor element 1 (RE-1) cis-regulatory DNA sequence. HAP1 promoter region contains a RE-1 binding motif. We also observed whether Pb exposure regulated the HAP1 transcription level through influencing the expression of REST. Mother rats were exposed to 0.5 and 2 g/L Pb acetate (PbAc) in drinking water from the first day of gestation until postnatal 21 days, then the offspring rats were continued to drink PbAc for 1 year, while the control groups received drinking water. PC12 cells were divided into 3 groups: 0 µM, 1 µM and 100 µM PbAc. The results revealed that Pb levels in blood and brain of Pb exposed groups were significantly higher than that of the control group. The ability of learning and memory in Pb exposed rats was decreased. Pb exposure reduced the expression of HAP1 and increased the REST expression. Silencing REST could reverse the decreasing of HAP1 in Pb exposed PC12 cells. Our findings raise a possibility that the decreasing of HAP1 expression by Pb exposure may affect neurotransmitter release and results in impairments in spatial learning and memory ability.
Asunto(s)
Intoxicación por Plomo/metabolismo , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/efectos de los fármacos , Co-Represor 1 de Receptor Nuclear/efectos de los fármacos , Proteínas Represoras/biosíntesis , Proteínas Represoras/efectos de los fármacos , Animales , Encéfalo/metabolismo , Femenino , Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Plomo/sangre , Plomo/metabolismo , Intoxicación por Plomo/genética , Intoxicación por Plomo/psicología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Células PC12 , Embarazo , ARN Interferente Pequeño/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas Represoras/genéticaRESUMEN
BACKGROUND: Lead (Pb) is broadly used in various industries and causes irreversible damage to human tissues, organs, and systems. Studies have revealed that lead exerts toxic effects via interfering with calcium channel. METHODS: In the present study, we investigated whether single nucleotide polymorphisms (SNPs) in TRPV5, a calcium channel-related gene, were associated with lead exposure susceptibility. By using TaqMan SNP genotyping, we performed genotyping of eight TRPV5 tag-SNPs in 1,130 lead-exposed Chinese workers with similar lead exposure level. RESULTS: Single nucleotide polymorphism rs4252424 was significantly associated with lead susceptibility, measured by blood lead level (BLL) (ß = -0.069, plinear = 0.029). However, there was no significant association between any other seven SNPs and BLL. The further expression Quantitative Trait Loci displayed that CC genotype of rs4252424 is significant associated with higher BLL than CT (p < 0.0001). CONCLUSION: We conclude that SNP rs4252424 has the potential to evaluate lead susceptibility in the Chinese occupational population, and further enhance lead exposure prevention and intervention.
Asunto(s)
Intoxicación por Plomo/genética , Enfermedades Profesionales/genética , Polimorfismo de Nucleótido Simple , Canales Catiónicos TRPV/genética , Adulto , Anciano , China , Femenino , Humanos , Plomo/sangre , Intoxicación por Plomo/sangre , Masculino , Persona de Mediana Edad , Enfermedades Profesionales/sangreRESUMEN
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.
Asunto(s)
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
Exposure to toxic elements is greatly unavoidable in our daily activities due to several routes of coming in contact with these elements. Thus lead (Pb), is one of the major causes of health hazard in human. In this study, evaluation of Zingiber officinale as mitigating measure against Pb induced biochemical and cytogenic toxicity in albino rats was investigated. Experimental rats were grouped into five with five animals per group, group I serves as control and groups 2-5 were induced intraperitoneal with lead acetate dissolved in distilled water at 3 mg/kg body weight whereas group 3-5 were orally administered with 200 mg/kg vitamin C, 200 mg/kg, and 100 mg/kg of Z. officinale, respectively for 7 d. The obtained results show that aspartate aminotransferase (AST), alkaline phosphatase (ALP), lipid peroxidation, urea, creatinine, bilirubin, and gamma-glutamyl transferase (GGT) were significantly increased (p < 0.05) and catalase (CAT) were reduced progressively in Pb alone induced rats. Hematological parameters showed a progressive reduction (p < 0.05) in lead acetate alone rats. There were significant changes in micronuclei (MN), chromosomal aberrations (CA) frequency, and oxidative damages in the bone marrow cells from lead acetate alone induced rats, although, mitotic index scores in these cells were reduced gradually (p < 0.05). The altered parameters were significantly reversed toward the levels observed in normal control rats administered with vitamin C and aqueous extract of Z. officinale. Hence, these results suggest that Z. officinale roots might contain therapeutic potential that can ameliorate the hazard effect of lead acetate poison.
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Ácido Ascórbico/uso terapéutico , Intoxicación por Plomo/prevención & control , Metabolismo de los Lípidos/efectos de los fármacos , Micronúcleos con Defecto Cromosómico/inducido químicamente , Extractos Vegetales/uso terapéutico , Zingiber officinale/química , Animales , Ácido Ascórbico/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Intoxicación por Plomo/genética , Intoxicación por Plomo/metabolismo , Intoxicación por Plomo/patología , Masculino , Compuestos Organometálicos , Extractos Vegetales/administración & dosificación , Extractos Vegetales/aislamiento & purificación , Ratas WistarRESUMEN
Oxidative stress and DNA damage are considered as possible mechanisms involved in lead toxicity. To test this hypothesis, DNA damage and expression variations of aminolevulinic acid dehydratase (ALAD), superoxide dismutase 2 (SOD2), and 8-oxoguanine DNA glycosylase 2a (OGG1-2a) genes was studied in a cohort of 100 exposed workers and 100 controls with comet assay and real-time polymerse chain reaction (PCR). Results indicated that increased number of comets was observed in exposed workers versus controls (p < 0.001). After qPCR analysis, significant down-regulation in ALAD (p < 0.0001), SOD2 (p < 0.0001), and OGG1-2a (p < 0.0001) level was observed in exposed workers versus controls. Additionally, a positive spearmen correlation was observed between ALAD versus SOD2 (r = 0.402**, p < 0.001), ALAD versus OGG1-2a (r = 0.235*, p < 0.05), and SOD2 versus OGG1-2a (r = 0.292*, p < 0.05). This study showed that lead exposure induces DNA damage, which is accompanied by an elevated intensity of oxidative stress and expression variation of lead-related gene.
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Industria de la Construcción , Daño del ADN , Intoxicación por Plomo/genética , Exposición Profesional/análisis , Porfobilinógeno Sintasa/genética , Adulto , Ensayo Cometa , Humanos , Masculino , Pakistán , Reacción en Cadena de la Polimerasa , Polimorfismo Genético/efectos de los fármacos , ARN Mensajero , Adulto JovenRESUMEN
Use of lead-adulterated opium has become one of the major sources of lead poisoning in Iran. This study was designed to assess clinical effects and oxidative stress and its association with GSTM1, GSTT1, NQO1, and ALAD genes polymorphisms and blood lead level (BLL) in lead-adulterated opium users. The oxidative stress status in 192 opium users with lead poisoning symptoms measured and compared with 102 healthy individuals. Gluthatione S-transferase (GST)-M1 and -T1 genes deletion, NQO1 rs1800566, and δ-aminolevulinic acid dehydratase (ALAD) rs1800435 polymorphisms were determined using PCR and PCR-RFLP. The relation between the polymorphisms, BLL, and oxidative stress parameters were analysed using multivariate linear regressions. The common symptoms of lead toxicity were gastrointestinal and neurologic complications. Oxidative stress was significantly higher in opium addicts and lipid peroxidation significantly correlated with BLL. There was significant association between ALAD rs1800435 and BLL, and the BLL was significantly lower in the patients with ALAD 1-2 genotype. Use of lead-adulterated opium causes high frequency of lead toxicity symptoms, hematological and biochemical abnormalities, and oxidative stress which are associated with BLL. Route of opioid use and the polymorphism of rs1800435 in ALAD gene are the major determinants of BLL in lead-adulterated opium users.
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Intoxicación por Plomo/genética , Plomo/análisis , Opio/química , Estrés Oxidativo/genética , Polimorfismo Genético , Adulto , Anciano , Biomarcadores/metabolismo , Femenino , Glutatión Transferasa/genética , Humanos , Irán , Plomo/sangre , Plomo/toxicidad , Intoxicación por Plomo/sangre , Intoxicación por Plomo/fisiopatología , Masculino , Persona de Mediana Edad , NAD(P)H Deshidrogenasa (Quinona)/genética , Opio/administración & dosificación , Adicción al Opio/sangre , Adicción al Opio/genética , Adicción al Opio/fisiopatología , Porfobilinógeno Sintasa/genéticaRESUMEN
This study explored the association between the lncRNA HOTAIR polymorphism and susceptibility to lead poisoning in a Chinese population. We speculated that lead poisoning caused elevated levels of oxidative stress, which, in turn, activate the HOTAIR gene to cause apoptosis. Three lncRNA HOTAIR tagSNPs (rs7958904, rs4759314, and rs874945) were genotyped by TaqMan genotyping technology in 113 lead-sensitive and 113 lead-resistant Chinese workers exposed to lead. Rs7958904 was significantly associated with susceptibility to lead poisoning (P = 0.047). The rs7958904 G allele had a protective effect compared with the C allele and reduced the risk of lead poisoning (P = 0.016). Rs7958904 may act as a potential biomarker for predicting the risk of lead poisoning and distinguishing lead-sensitive individuals from lead-resistant individuals.
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Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad , Intoxicación por Plomo/genética , Enfermedades Profesionales/genética , Polimorfismo de Nucleótido Simple , ARN Largo no Codificante/genética , Adulto , Alelos , Femenino , Pruebas Genéticas , Humanos , MasculinoRESUMEN
Lead is an environmental hazard with great public health concern and has been known to inhibit delta-aminolevulinate dehydratase (ALAD) activity involved in the heme biosynthetic pathway. The study aimed to investigate the influence of ALAD polymorphism (G177C) on retention of Pb-B levels and ALAD activity on occupationally exposed lead workers. In the present study, we enrolled 561 lead exposed and 317 non-occupationally exposed subjects and performed a comprehensive analysis of Pb-B levels along with ALAD activity and genotyping. The frequency of ALAD variants observed in the total subjects (nâ¯=â¯878) was 70.04% for ALAD 1-1, 27.44% for heterozygous ALAD 1-2 and 2.5% for homozygous mutant ALAD 2-2. Our study revealed that ALAD 1-2 carriers presented higher Pb-B levels compared to wild type ALAD 1-1 carriers. Further, a significant difference was observed in the activity of ALAD between ALAD 1-2/ 2-2 and ALAD 1-1 carriers of non-occupationally exposed group indicating that the polymorphic nature of the enzyme may contribute to altered activity of ALAD irrespective of lead exposure. Hence, ALAD 2 allele might contribute to increased susceptibility to high Pb-B retention, and genotyping of ALAD in lead exposed subjects might be used as a prediction marker to impede tissue/organ damage due to lead toxicity.
Asunto(s)
Contaminantes Ocupacionales del Aire/sangre , Intoxicación por Plomo/genética , Plomo/sangre , Polimorfismo Genético , Porfobilinógeno Sintasa/genética , Adolescente , Adulto , Contaminantes Ocupacionales del Aire/efectos adversos , Estudios de Casos y Controles , Estudios Transversales , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Heterocigoto , Homocigoto , Humanos , India , Plomo/efectos adversos , Intoxicación por Plomo/sangre , Intoxicación por Plomo/enzimología , Masculino , Persona de Mediana Edad , Exposición Profesional/efectos adversos , Fenotipo , Porfobilinógeno Sintasa/metabolismo , Medición de Riesgo , Factores de Riesgo , Adulto JovenRESUMEN
Lead (Pb), a widely distributed environmental pollutant, is known to induce mitochondrial damage as well as autophagy in vitro and in vivo. In this study, we found that Pb could trigger mitophagy in both HEK293 cells and the kidney cortex of male Kunming mice. However, whether ataxia telangiectasis mutated (ATM) which is reported to be linked with PTEN-induced putative kinase 1 (PINK1)/Parkin pathway (a well-characterized mitophagic pathway) participates in the regulation of Pb-induced mitophagy and its exact role remains enigmatic. Our results indicated that Pb activated ATM in vitro and in vivo, and further in vitro studies showed that ATM could co-localize with PINK1 and Parkin in cytosol and interact with PINK1. Knockdown of ATM by siRNA blocked Pb-induced mitophagy even under the circumstance of enhanced accumulation of PINK1 and mitochondrial Parkin. Intriguingly, elevation instead of reduction in phosphorylation level of PINK1 and Parkin was observed in response to ATM knockdown and Pb did not contribute to the further increase of their phosphorylation level, implying that ATM indirectly regulated PINK1/Parkin pathway. These findings reveal a novel mechanism for Pb toxicity and suggest the regulatory importance of ATM in PINK1/Parkin-mediated mitophagy.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Intoxicación por Plomo/genética , Intoxicación por Plomo/patología , Mitofagia/efectos de los fármacos , Proteínas Quinasas/genética , Ubiquitina-Proteína Ligasas/genética , Animales , Citosol/metabolismo , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Corteza Renal/efectos de los fármacos , Corteza Renal/metabolismo , Masculino , Potencial de la Membrana Mitocondrial , Ratones , Fosforilación/efectos de los fármacos , Proteínas Quinasas/efectos de los fármacos , ARN Interferente Pequeño/farmacología , Transducción de Señal/efectos de los fármacos , Ubiquitina-Proteína Ligasas/efectos de los fármacosRESUMEN
Lead (Pb) is an environmental neurotoxic metal. Chronic exposure to Pb causes deficits of learning and memory in children and spatial learning deficits in developing rats. In this study we investigated the effects of Pb exposure on the expression of HMGB1 and HO-1 in rats and PC12 cells. The animals were randomly divided to three groups: control group; low lead exposure group; high lead exposure group; PC12 cells were divided into 3 groups: 0⯵M (control group), 1⯵M and 100⯵M Pb acetate. The results showed that Pb levels in blood and brain of Pb exposed groups were significantly higher than that of the control group (pâ¯<â¯0.05). The expression of HMGB1 and HO-1 were increased in Pb exposed groups than that of the control group (pâ¯<â¯0.05). Moreover, we found that the up-regulation of HO-1 in Pb exposure environment inhibited the expression of HMGB1.
Asunto(s)
Proteína HMGB1/biosíntesis , Hemo Oxigenasa (Desciclizante)/biosíntesis , Intoxicación por Plomo/genética , Plomo/toxicidad , Animales , Encéfalo/metabolismo , Femenino , Proteína HMGB1/genética , Hemo Oxigenasa (Desciclizante)/genética , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Plomo/farmacocinética , Intoxicación por Plomo/psicología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Células PC12 , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Lead, a heavy metal and multifaceted toxicant, is well studied for its distribution and toxicity in ecosystem, yet there is no consensus on its amelioration by any synthetic or phytochemical compounds. Curcumin, a known antioxidant and dietary element, is a well-known herb, for its therapeutic uses and having a wide spectrum of its beneficial properties against several adverse effects. Hence, the current study was taken into consideration to evaluate the ameliorative effects of curcumin (3.87 µM, i.e. 1.43 µg/ml) against lead acetate (doses: 10-6 M, i.e. 0.379 µg/ml and 10-4 M, i.e. 37.9 µg/ml, durations: 24 h and 69 h) induced genotoxicity and oxidative stress in human peripheral blood lymphocyte cultures (PBLC). On one hand, antigenotoxic and antioxidative potentials of curcumin against lead were simultaneously evaluated by the array of genotoxicity and oxidative stress indices. The result postulated that lead acetate showed dose- and duration-dependent increase in both genotoxicity and oxidative stress whereas curcumin, when added along with lead acetate, showed the significant amelioration in all genotoxic and oxidative stress-related indices. The study indicated that, due to alteration in antioxidant defense system, there is an adverse genotoxic effect of lead. On the other hand, curcumin, a potent antidote, can protect chromatin material against lead -mediated genotoxicity by balancing the activity of antioxidant defense system.