RESUMO
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.
Assuntos
Intoxicação por Chumbo , Exposição Ocupacional , Humanos , Chumbo , Espécies Reativas de Oxigênio , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Reparo do DNA/genética , Intoxicação por Chumbo/genética , DNA , Dano ao DNA , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genéticaRESUMO
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.
Assuntos
Intoxicação por Chumbo , Chumbo , Criança , Pré-Escolar , Estudos Transversais , Metilação de DNA , Genes p16 , Humanos , Chumbo/toxicidade , Intoxicação por Chumbo/epidemiologia , Intoxicação por Chumbo/genética , Sintase do Porfobilinogênio/genética , ZâmbiaRESUMO
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.
Assuntos
Intoxicação por Chumbo/genética , Intoxicação por Chumbo/fisiopatologia , Chumbo/sangue , Exposição Ocupacional , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Adulto , Estudos Transversais , Eletrocardiografia , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Intoxicação por Chumbo/sangue , Modelos Lineares , Modelos Logísticos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Masculino , Análise Multivariada , Protoporfirinas/sangue , Adulto JovemRESUMO
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.
Assuntos
Angiotensinogênio/genética , Intoxicação por Chumbo/genética , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Adulto , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Adulto JovemRESUMO
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.
Assuntos
Ácido Ascórbico/uso terapêutico , Intoxicação por Chumbo/prevenção & controle , Metabolismo dos Lipídeos/efeitos dos fármacos , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Extratos Vegetais/uso terapêutico , Zingiber officinale/química , Animais , Ácido Ascórbico/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Intoxicação por Chumbo/genética , Intoxicação por Chumbo/metabolismo , Intoxicação por Chumbo/patologia , Masculino , Compostos Organometálicos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Ratos WistarRESUMO
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.
Assuntos
Antioxidantes/farmacologia , Curcumina/farmacologia , Dano ao DNA/efeitos dos fármacos , Intoxicação por Chumbo/prevenção & controle , Linfócitos/efeitos dos fármacos , Compostos Organometálicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Catalase/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citoproteção , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Humanos , Intoxicação por Chumbo/sangue , Intoxicação por Chumbo/genética , Intoxicação por Chumbo/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/patologia , Troca de Cromátide Irmã/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Fatores de TempoRESUMO
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.
Assuntos
Povo Asiático/genética , Predisposição Genética para Doença , Intoxicação por Chumbo/genética , Doenças Profissionais/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Adulto , Alelos , Feminino , Testes Genéticos , Humanos , MasculinoRESUMO
Lead toxicity is a major public health issue in developed and developing countries. Both acute and chronic lead exposure has the potential to cause many deleterious systematic effects including hypertension, frank anemia, cognitive deficits, infertility, immune imbalances, delayed skeletal and deciduous dental development, vitamin D deficiency, and gastrointestinal effects. The underlying mechanisms for all these systemic effects have not been elucidated completely. However, the most plausible cause is free radical damage. In addition to this, lead being a divalent cation can surrogate for calcium at multiple levels affecting various cell signaling pathways. The molecular basis of lead exposure resulting in various systemic effects is being extensively explored. The reports include single nucleotide polymorphisms, epigenetic modifications in susceptible individuals, and the most recent reports also feature regulatory RNA molecules - miRNAs. However, many genetic targets are identified, but their possible mechanisms are still an area to be explored. Additional studies are needed in different population groups to validate the existing findings, as well as to find newer targets that may help in better understanding the molecular mechanisms contributing to lead toxicity. Furthermore, newer strategies for lead risk assessment becomes necessary as the previously recognized "safe" level of lead is also being found to be associated with negative health outcomes.
Assuntos
Intoxicação por Chumbo , Chumbo , Doenças Cardiovasculares , Disruptores Endócrinos , Exposição Ambiental , Epigenômica , Técnicas Genéticas , Humanos , Chumbo/sangue , Chumbo/toxicidade , Intoxicação por Chumbo/sangue , Intoxicação por Chumbo/genética , Estresse OxidativoRESUMO
Although attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental condition, there is also considerable scientific and public interest in environmental modulators of its etiology. Exposure to neurotoxins is one potential source of perturbation of neural, and hence psychological, development. Exposure to lead in particular has been widely investigated and is correlated with neurodevelopmental outcomes, including ADHD. To investigate whether this effect is likely to be causal, we used a Mendelian randomization design with a functional gene variant. In a case-control study, we examined the association between ADHD symptoms in children and blood lead level as moderated by variants in the hemochromatosis (HFE) gene. The HFE gene regulates iron uptake and secondarily modulates lead metabolism. Statistical moderation was observed: The magnitude of the association of blood lead with symptoms of ADHD was altered by functional HFE genotype, which is consistent with a causal hypothesis.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/sangue , Transtorno do Deficit de Atenção com Hiperatividade/genética , Proteína da Hemocromatose/genética , Ferro/metabolismo , Chumbo/sangue , Adolescente , Estudos de Casos e Controles , Criança , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Intoxicação por Chumbo/sangue , Intoxicação por Chumbo/genética , Masculino , Polimorfismo de Nucleotídeo Único , Estudos de Validação como AssuntoRESUMO
Many existing cohort studies designed to investigate health effects of environmental exposures also collect data on genetic markers. The Early Life Exposures in Mexico to Environmental Toxicants project, for instance, has been genotyping single nucleotide polymorphisms on candidate genes involved in mental and nutrient metabolism and also in potentially shared metabolic pathways with the environmental exposures. Given the longitudinal nature of these cohort studies, rich exposure and outcome data are available to address novel questions regarding gene-environment interaction (G × E). Latent variable (LV) models have been effectively used for dimension reduction, helping with multiple testing and multicollinearity issues in the presence of correlated multivariate exposures and outcomes. In this paper, we first propose a modeling strategy, based on LV models, to examine the association between repeated outcome measures (e.g., child weight) and a set of correlated exposure biomarkers (e.g., prenatal lead exposure). We then construct novel tests for G × E effects within the LV framework to examine effect modification of outcome-exposure association by genetic factors (e.g., the hemochromatosis gene). We consider two scenarios: one allowing dependence of the LV models on genes and the other assuming independence between the LV models and genes. We combine the two sets of estimates by shrinkage estimation to trade off bias and efficiency in a data-adaptive way. Using simulations, we evaluate the properties of the shrinkage estimates, and in particular, we demonstrate the need for this data-adaptive shrinkage given repeated outcome measures, exposure measures possibly repeated and time-varying gene-environment association.
Assuntos
Exposição Ambiental/estatística & dados numéricos , Interação Gene-Ambiente , Modelos Estatísticos , Bioestatística/métodos , Pré-Escolar , Simulação por Computador , Feminino , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Lactente , Recém-Nascido , Intoxicação por Chumbo/etiologia , Intoxicação por Chumbo/genética , Estudos Longitudinais , Proteínas de Membrana/genética , México , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/genéticaRESUMO
Lead (Pb) poisoning has always been a serious health concern, as it permanently damages the central nervous system. Chronic Pb accumulation in the human body disturbs oligodendrocytes (OLs) differentiation, resulting in dysmyelination, but the molecular mechanism remains unknown. In this study, Pb at 1 µM inhibits OLs precursor cells (OPCs) differentiation via decreasing the expression of Olig 2, CNPase proteins in vitro. Moreover, Pb treatment inhibits the sodium/calcium exchanger 3 (NCX3) mRNA expression, one of the major means of calcium (Ca(2+)) extrusion at the plasma membrane during OPCs differentiation. Also addition of KB-R7943, NCX3 inhibitor, to simulate Pb toxicity, resulted in decreased myelin basic protein (MBP) expression and cell branching. Ca(2+) response trace with Pb and KB-R7943 treatment did not drop down in the same recovery time as the control, which elevated intracellular Ca(2+) concentration reducing MBP expression. In contrast, over-expression of NCX3 in Pb exposed OPCs displayed significant increase MBP fluorescence signal in positive regions and CNPase expression, which recovered OPCs differentiation to counterbalance Pb toxicity. In conclusion, Pb exposure disturbs OLs differentiation via affecting the function of NCX3 by inducing intracellular calcium overload.
Assuntos
Cálcio/metabolismo , Regulação para Baixo/efeitos dos fármacos , Intoxicação por Chumbo/metabolismo , Intoxicação por Chumbo/patologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Trocador de Sódio e Cálcio/genética , Diferenciação Celular/efeitos dos fármacos , Humanos , Intoxicação por Chumbo/genética , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Oligodendroglia/metabolismo , RNA Mensageiro/genética , Trocador de Sódio e Cálcio/antagonistas & inibidores , Trocador de Sódio e Cálcio/metabolismo , Tioureia/análogos & derivados , Tioureia/farmacologiaRESUMO
CONTEXT: GSTP1 is induced by lead, and thus serves as a biomarker of lead exposure. Lead exposure changes DNA methylation status. OBJECTIVE: We attempted to prove that the methylation of the GSTP1 promoter plays an important role in lead toxicity. MATERIALS AND METHODS: We conducted a case-control study of 53 workers from a battery plant and 53 age and sex matched healthy volunteers to determine whether the methylation level of the GSTP1 promoter is associated with the risk of lead poisoning. We employed methylation-specific PCR (MSP) in cell models to determine the relationship between the GSTP1 methylation level and lead exposure. RESULTS: We found no association between GSTP1 methylation and lead exposure. The difference in methylation frequencies between the exposure group and the controls was not statistically significant (p = 0.401), and individuals with the methylated GSTP1 gene was not associated with the risk of lead poisoning (adjusted OR = 1.36, 95% CI, 0.22-8.24). CONCLUSION: This study suggests that GSTP1 methylation is not involved in the early phase of lead toxicity. Further studies should be performed to detect the association between GSTP1 methylation and the risk of lead poisoning in later phases.
Assuntos
Ilhas de CpG , Metilação de DNA , Glutationa S-Transferase pi/genética , Intoxicação por Chumbo/genética , Exposição Ocupacional , Adulto , Sequência de Bases , Estudos de Casos e Controles , Primers do DNA , Feminino , Células HEK293 , Humanos , Masculino , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas , Transcrição GênicaRESUMO
Lead (Pb) body burden and toxicity may be influenced by genetic polymorphisms. The aim of this study was to investigate the influence of G177C delta-aminolevulinic acid dehydratase (ALAD) polymorphism (rs1800435) on selected Pb exposure biomarkers in a population of workers highly exposed to this metal in the past. A cross-sectional survey was conducted between 2007 and 2009 within the cohort of ex-employees of a smelter in the north of France that closed down in 2003. A questionnaire was completed by each participant and blood samples enabled determination of Pb levels and ALAD polymorphism. Five parameters estimating the Pb body burden and its variations were studied: last blood lead level (BLL) during activity, cumulative blood Pb index, BLL at the time of the study, and absolute and percent changes in BLL after cessation of metal exposure. Multiple regression models were used to evaluate links between ALAD polymorphism and the selected Pb exposure biomarkers. Two hundred and four men were included. At the time of inclusion, the median age was 53.5 yr. The median duration of Pb exposure was 25 yr and the median latency since end of exposure was 5.6 yr. The frequency of ALAD-2 allele was 9.3%, with 34 subjects being heterozygous (ALAD1-2) and 2 homozygous (ALAD2-2). According to genotype, there was no significant difference for any of the five selected Pb exposure biomarkers. These results lend support to the notion that ALAD polymorphism exerts no marked impact on Pb body burden.
Assuntos
Predisposição Genética para Doença , Intoxicação por Chumbo/genética , Metalurgia , Doenças Profissionais/genética , Exposição Ocupacional/efeitos adversos , Polimorfismo Genético , Sintase do Porfobilinogênio/genética , Biomarcadores/sangue , Carga Corporal (Radioterapia) , Estudos de Coortes , Estudos Transversais , Humanos , Intoxicação por Chumbo/sangue , Intoxicação por Chumbo/enzimologia , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/sangue , Doenças Profissionais/enzimologia , Sintase do Porfobilinogênio/metabolismo , Inquéritos e Questionários , Fatores de TempoRESUMO
OBJECTIVE: To investigate the relationship between genetic polymorphism of X-ray repair cross-complementing gene 3 (XRCC3) and susceptibility to lead poisoning in male lead-exposed workers. METHODS: Peripheral venous blood and morning urine samples were collected from 326 male lead-exposed workers in a storage battery factory in Fuzhou. Blood lead, urine lead, blood zinc protoporphyrin (ZPP), blood calcium, and blood iron were measured. The genotype of XRCC3 was determined by polymerase chain reaction-restriction fragment length polymorphism method. The relationship between XRCC3 gene polymorphism and susceptibility to lead poisoning in male lead-exposed workers was analyzed. RESULTS: Genetic polymorphism of XRCC3 was seen in the 326 subjects. The frequency distribution of XRCC3 genotypes, XRCC3-241CC (wild type), XRCC3-241CT (heterozygous mutation), and XRCC3-241TT (homozygous mutation), was in accordance with the Hardy-Weinberg equilibrium (P > 0.05). There were no significant differences in urine lead, blood ZPP, blood calcium, and blood iron between the lead-exposed workers with different XRCC3 genotypes (P > 0.05). The workers with XRCC3-241CT/TT had a significantly higher mean blood lead level than those with XRCC3-241CC (P < 0.05). With a blood lead level of 1.90 µmol/L as the cutoff value, the chi-square test and logistic regression analysis showed that the proportion of workers with XRCC3-241CT/TT was significantly higher than that of workers with XRCC3-241CC in the subjects with high blood leads (P < 0.05) and that the risk of high blood lead was significantly higher in the workers with XRCC3-241CT/TT than in those with XRCC3-241CC (OR = 2.34, 95%CI = 1.61 â¼ 5.13); the multivariate linear regression analysis showed that the workers with XRCC3-241CT/TT had high blood lead levels (ß = 0.116, P < 0.05), the workers with smoking habit demonstrated marked lead absorption (ß = 0.188, P < 0.05), good individual protection could reduce lead absorption (ß = -0.247, P < 0.05), and the individuals with low serum Ca²âº levels had high blood lead levels (ß = -0.145, P < 0.05). CONCLUSION: When exposed to the same level of lead at workplace, the workers with XRCC3-241CT/TT have a significantly higher blood lead level than those with XRCC3-241CC, so the genotype of XRCC3-241CT/TT accounts for higher susceptibility to lead poisoning.
Assuntos
Proteínas de Ligação a DNA/genética , Intoxicação por Chumbo/genética , Doenças Profissionais/genética , Polimorfismo Genético , Adulto , Predisposição Genética para Doença , Genótipo , Humanos , Chumbo/sangue , Masculino , Adulto JovemRESUMO
Many existing cohort studies initially designed to investigate disease risk as a function of environmental exposures have collected genomic data in recent years with the objective of testing for gene-environment interaction (G × E) effects. In environmental epidemiology, interest in G × E arises primarily after a significant effect of the environmental exposure has been documented. Cohort studies often collect rich exposure data; as a result, assessing G × E effects in the presence of multiple exposure markers further increases the burden of multiple testing, an issue already present in both genetic and environment health studies. Latent variable (LV) models have been used in environmental epidemiology to reduce dimensionality of the exposure data, gain power by reducing multiplicity issues via condensing exposure data, and avoid collinearity problems due to presence of multiple correlated exposures. We extend the LV framework to characterize gene-environment interaction in presence of multiple correlated exposures and genotype categories. Further, similar to what has been done in case-control G × E studies, we use the assumption of gene-environment (G-E) independence to boost the power of tests for interaction. The consequences of making this assumption, or the issue of how to explicitly model G-E association has not been previously investigated in LV models. We postulate a hierarchy of assumptions about the LV model regarding the different forms of G-E dependence and show that making such assumptions may influence inferential results on the G, E, and G × E parameters. We implement a class of shrinkage estimators to data adaptively trade-off between the most restrictive to most flexible form of G-E dependence assumption and note that such class of compromise estimators can serve as a benchmark of model adequacy in LV models. We demonstrate the methods with an example from the Early Life Exposures in Mexico City to Neuro-Toxicants Study of lead exposure, iron metabolism genes, and birth weight.
Assuntos
Biometria/métodos , Exposição Ambiental , Interação Gene-Ambiente , Modelos Estatísticos , Análise de Variância , Viés , Peso ao Nascer/efeitos dos fármacos , Estudos de Casos e Controles , Simulação por Computador , Fatores Epidemiológicos , Feminino , Humanos , Recém-Nascido , Ferro/metabolismo , Intoxicação por Chumbo/genética , Intoxicação por Chumbo/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Análise de Componente PrincipalRESUMO
OBJECTIVES: Critically shortening of telomere length caused by various factors including environmental pollutants results in genome instability and age-associated diseases. Lead is one of the ubiquitous environmental and occupational pollutants, potentially affecting public health even at a low level. However, it is still unclear whether lead exposure affects telomere length. This study aims to investigate the association between lead exposure and peripheral white blood cell telomere length (PWBTL) in Chinese battery manufacturing plant workers. METHODS: Lead levels in blood (BLL) and urine (ULL) were evaluated using flame atomic absorption spectrometry and lead mobilisation test for body lead burden (BLB) assessment, respectively. Quantitative PCR was employed to determine relative PWBTL. Univariate and multivariate analyses were performed to examine the associations of telomere length and other variables. RESULTS: PWBTL averaged 1.76 (telomere/single-copy gene of albumin, T/S) in 144 battery plant workers. Significantly shorter PWBTL was observed in the workers with abnormal BLL and/or ULL than those with normal ones (1.66±0.63 vs 1.91±0.46, p=0.010). In all workers, PWBTL was in negative correlations with BLL, ULL, time working at the plant (working length) and body mass index. A strong inverse correlation was observed between PWBTL and BLB (r=-0.70, p<0.0001) in those with abnormal BLL and ULL. GLMSELECT model showed in the subgroup of inpatient workers, working length and BLB were significantly in inverse associations with PWBTL, while BLL was in weak positive association with PWBTL. CONCLUSIONS: These findings suggest that PWBTL shortening is associated with long-term lead exposure and that PWBTL may be one of the targets damaged by lead toxicity.
Assuntos
Substâncias Perigosas/efeitos adversos , Intoxicação por Chumbo/genética , Chumbo/efeitos adversos , Doenças Profissionais/genética , Exposição Ocupacional/efeitos adversos , Encurtamento do Telômero , Telômero , Carga Corporal (Radioterapia) , China , Substâncias Perigosas/sangue , Substâncias Perigosas/urina , Humanos , Indústrias , Chumbo/sangue , Chumbo/urina , Intoxicação por Chumbo/sangue , Intoxicação por Chumbo/urina , Leucócitos/ultraestrutura , Modelos Biológicos , Análise Multivariada , Doenças Profissionais/sangue , Doenças Profissionais/urina , Exposição Ocupacional/análise , Ocupações , Fatores de TempoRESUMO
Although adverse health effects produced by lead (Pb) have long been recognized, studies regarding the immunotoxic effects of occupational exposure report conflicting results. In a previous study, alterations in some immunological parameters were noted in 70 Pb-exposed workers. In view of these results, it was of interest to extend this study comprising a larger population and increasing the number of immunological endpoints assessed. Accordingly, in this study the immunotoxic effects of occupational exposure to Pb were assessed by analyzing (1) percentages of lymphocyte subsets (CD3âº, CD4âº, CD8âº, CD19âº, and CD56âº/16âº); (2) concentration of plasma cytokines, namely, interleukin (IL) 2, IL4, IL6, IL10, tumor necrosis factor (TNF) α, and interferon (IFN) γ; and (3) plasma concentrations of neopterin, tryptophan (Trp), and kynurenine (Kyn). In addition, the possible influence of genetic polymorphisms in the vitamin D receptor (VDR) and δ-aminolevulinic acid dehydratase (ALAD) genes on immunotoxicity parameters was studied. Exposed workers showed significant decreases in %CD3âº, %CD4âº/%CD8⺠ratio, IL4, TNFα, IFNγ, and Kyn to Trp ratio (Kyn/Trp), and significant increases in %CD8âº, IL10, and Trp levels. All these parameters, except Trp, were significantly correlated with exposure biomarkers. No significant influence of genetic polymorphisms was observed. Significant correlation between Kyn/Trp and neopterin concentrations suggests an involvement of indoleamine 2,3-dioxygenase in the Trp metabolic alterations, which may contribute to some of the immune alterations observed. Results obtained suggest that occupational exposure to PB may influence the immune system by impairing several mechanisms, which might ultimately produce deregulation of the immune response and diminish immunosurveillance in exposed individuals.
Assuntos
Imunossupressores/toxicidade , Intoxicação por Chumbo/imunologia , Chumbo/toxicidade , Exposição Ocupacional , Adulto , Biomarcadores/sangue , Citocinas/sangue , Estudos de Associação Genética , Humanos , Imunossupressores/sangue , Indústrias , Cinurenina/sangue , Chumbo/sangue , Intoxicação por Chumbo/sangue , Intoxicação por Chumbo/enzimologia , Intoxicação por Chumbo/genética , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Neopterina/sangue , Polimorfismo Genético , Sintase do Porfobilinogênio/sangue , Sintase do Porfobilinogênio/genética , Portugal , Receptores de Calcitriol/sangue , Receptores de Calcitriol/genética , Fumar/sangue , Espanha , Triptofano/sangueRESUMO
PURPOSE: We investigated genotoxic effects of occupational exposure to lead acetate in pottery-glaze ceramic workers. METHODS: The study was carried out in 30 exposed workers and 30 matched controls, to whom several biochemical parameters-the blood lead (B-Pb; range: exposed, 41.68-404.77; controls, 12-52) and cadmium (B-Cd) level, the activity of delta-aminolevulinic acid dehydratase (ALAD), erythrocyte protoporphyrin (EP), the level of vitamin B(12) and folate in serum-were measured. The genotoxic effects were evaluated by the alkaline comet assay, the DNA diffusion assay and micronucleus test in peripheral blood lymphocytes. RESULTS: Subjects exposed to lead had significantly higher B-Pb level and, consequently, increased values of tail intensity (TI), frequency of apoptotic and necrotic cells, and frequency of micronuclei (MN). In contrast, their activity of ALAD, the level of vitamin B(12) and folate in serum were significantly lower compared to controls. Poisson regression analysis showed a significant correlation of profession, duration of exposure, smoking, level of cadmium in blood, ALAD and EP with primary DNA damage. A majority of primary damage repairs in a short period after exposure to a genotoxic agent. In addition, the influence of gender and level of vitamin B(12) and folate in serum MN frequency in exposed group was observed. CONCLUSIONS: In this study, DNA diffusion and micronucleus test showed higher influence of tested parameters to DNA damage. The results indicate a need for concomitant use of at least two different biomarkers of exposure when estimating a genetic risk of lead exposure.
Assuntos
Cerâmica , Intoxicação por Chumbo/genética , Chumbo/toxicidade , Mutagênicos/toxicidade , Exposição Ocupacional/efeitos adversos , Adolescente , Adulto , Cádmio/sangue , Ciclo Celular/efeitos dos fármacos , Ensaio Cometa , Citocalasina B/farmacologia , DNA/química , DNA/efeitos dos fármacos , Fragmentação do DNA , Feminino , Humanos , Intoxicação por Chumbo/sangue , Linfócitos/efeitos dos fármacos , Masculino , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Testes para Micronúcleos , Pessoa de Meia-Idade , Doenças Profissionais , Adulto JovemRESUMO
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.
Assuntos
Intoxicação por Chumbo , Chumbo , Biomarcadores , Exposição Ambiental , Epigênese Genética , Humanos , Chumbo/toxicidade , Intoxicação por Chumbo/genéticaRESUMO
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.