RESUMEN
BACKGROUND: Particulate matter (PM) air pollution is a human lung carcinogen; however, the components responsible have not been identified. We assessed the associations between PM components and lung cancer incidence. METHODS: We used data from 14 cohort studies in eight European countries. We geocoded baseline addresses and assessed air pollution with land-use regression models for eight elements (Cu, Fe, K, Ni, S, Si, V and Zn) in size fractions of PM2.5 and PM10. We used Cox regression models with adjustment for potential confounders for cohort-specific analyses and random effect models for meta-analysis. RESULTS: The 245,782 cohort members contributed 3,229,220 person-years at risk. During follow-up (mean, 13.1 years), 1878 incident cases of lung cancer were diagnosed. In the meta-analyses, elevated hazard ratios (HRs) for lung cancer were associated with all elements except V; none was statistically significant. In analyses restricted to participants who did not change residence during follow-up, statistically significant associations were found for PM2.5 Cu (HR, 1.25; 95% CI, 1.01-1.53 per 5 ng/m(3)), PM10 Zn (1.28; 1.02-1.59 per 20 ng/m(3)), PM10 S (1.58; 1.03-2.44 per 200 ng/m(3)), PM10 Ni (1.59; 1.12-2.26 per 2 ng/m(3)) and PM10 K (1.17; 1.02-1.33 per 100 ng/m(3)). In two-pollutant models, associations between PM10 and PM2.5 and lung cancer were largely explained by PM2.5 S. CONCLUSIONS: This study indicates that the association between PM in air pollution and lung cancer can be attributed to various PM components and sources. PM containing S and Ni might be particularly important.
Asunto(s)
Contaminantes Atmosféricos/análisis , Exposición a Riesgos Ambientales/análisis , Exposición por Inhalación/análisis , Neoplasias Pulmonares/epidemiología , Material Particulado/análisis , Adulto , Anciano , Estudios de Cohortes , Europa (Continente)/epidemiología , Femenino , Humanos , Incidencia , Neoplasias Pulmonares/etiología , Masculino , Persona de Mediana Edad , Tamaño de la Partícula , Modelos de Riesgos Proporcionales , Estudios Prospectivos , RiesgoRESUMEN
BACKGROUND: Vegetable and/or fruit intakes in association with hepatocellular carcinoma (HCC) risk have been investigated in case-control studies conducted in specific European countries and cohort studies conducted in Asia, with inconclusive results. No multi-centre European cohort has investigated the indicated associations. METHODS: In 486,799 men/women from the European Prospective Investigation into Cancer and nutrition, we identified 201 HCC cases after 11 years median follow-up. We calculated adjusted hazard ratios (HRs) for HCC incidence for sex-specific quintiles and per 100 g d(-1) increments of vegetable/fruit intakes. RESULTS: Higher vegetable intake was associated with a statistically significant, monotonic reduction of HCC risk: HR (100 g d(-1) increment): 0.83; 95% CI: 0.71-0.98. This association was consistent in sensitivity analyses with no apparent heterogeneity across strata of HCC risk factors. Fruit intake was not associated with HCC incidence: HR (100 g d(-1) increment): 1.01; 95% CI: 0.92-1.11. CONCLUSIONS: Vegetable, but not fruit, intake is associated with lower HCC risk with no evidence for heterogeneity of this association in strata of important HCC risk factors. Mechanistic studies should clarify pathways underlying this association. Given that HCC prognosis is poor and that vegetables are practically universally accessible, our results may be important, especially for those at high risk for the disease.
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Carcinoma Hepatocelular/epidemiología , Dieta/estadística & datos numéricos , Neoplasias Hepáticas/epidemiología , Anciano , Carcinoma Hepatocelular/etiología , Estudios de Casos y Controles , Estudios de Cohortes , Europa (Continente)/epidemiología , Femenino , Frutas , Humanos , Neoplasias Hepáticas/etiología , Masculino , Persona de Mediana Edad , Factores de Riesgo , VerdurasRESUMEN
Several modifiable lifestyle factors, including smoking, alcohol, certain dietary factors and weight are independently associated with gastric cancer (GC); however, their combined impact on GC risk is unknown. We constructed a healthy lifestyle index to investigate the joint influence of these behaviors on GC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The analysis included 461,550 participants (662 first incident GC cases) with a mean follow-up of 11.4 years. A healthy lifestyle index was constructed, assigning 1 point for each healthy behavior related to smoking status, alcohol consumption and diet quality (represented by the Mediterranean diet) for assessing overall GC and also body mass index for cardia GC and 0 points otherwise. Risk of GC was calculated using Cox proportional hazards regression models while adjusting for relevant confounders. The highest versus lowest score in the healthy lifestyle index was associated with a significant lower risk of GC, by 51% overall (HR 0.49 95% CI 0.35, 0.70), by 77% for cardia GC (HR 0.23 95% CI 0.08, 0.68) and by 47% for noncardia GC (HR 0.53 (95% CI 0.32, 0.87), p-trends<0.001. Population attributable risk calculations showed that 18.8% of all GC and 62.4% of cardia GC cases could have been prevented if participants in this population had followed the healthy lifestyle behaviors of this index. Adopting several healthy lifestyle behaviors including not smoking, limiting alcohol consumption, eating a healthy diet and maintaining a normal weight is associated with a large decreased risk of GC.
Asunto(s)
Adenocarcinoma/epidemiología , Adenocarcinoma/etiología , Estilo de Vida , Riesgo , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/etiología , Adulto , Europa (Continente)/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vigilancia de la Población , Estudios ProspectivosRESUMEN
A functionally normal TP53 is essential to protect organisms from developing cancer. Somatic mutations in the gene represent one of the highest recurring perturbations in human tumours, including colorectal cancer (CRC). However, the variegated phenotype of wide spectrum of somatic mutations in TP53 and the complexity of the disease prevent a straight interpretation of the mutational analysis in tumours. In addition to the presence of somatic mutations, polymorphic features of the gene may also contribute to alteration of the normal TP53 functioning and variants, mainly in the form of single nucleotide polymorphisms, can be expected to impact susceptibility to sporadic CRC. In the present study, we reviewed the potential role of alterations in the TP53 gene, both somatic mutations and inherited sequence variations, in predisposition to CRC and in the prognosis and response to therapy. The available data from association studies have mostly shown contradictory outcomes. The majority of the studies were based on limited sample sizes and focussed on a limited number of polymorphisms, with main being the rs1042522 (Arg72Pro). Thus far, there is no possible generalisation of the role of TP53 as also a predictor of therapeutic response and prognosis. The effects of TP53, and its abnormalities, on the response of tumours to cytotoxic drugs, radiation and chemoradiation are complex. However, from studies it is emerging that the inherited genetics of TP53 pathway components could be utilised to further define patient populations in their abilities to induce p53 activity in response to either DNA damaging or p53-targeted therapies.
Asunto(s)
Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Mutación/genética , Polimorfismo Genético/genética , Proteína p53 Supresora de Tumor/genética , Humanos , PronósticoRESUMEN
AIM: Ornithine decarboxylase (ODC) is a modifier of adenomatous polyposis coli-dependent tumourigenesis. The G316 > A polymorphism in intron 1 of the ODC gene lies between two myc-binding domains and alters the expression of the gene to affect polyamine metabolism. This variant may be associated with recurrence of colorectal adenoma. We examined whether this variant also modified the susceptibility to sporadic colorectal cancer (CRC). METHOD: The G316 > A variant was analysed in a large (n = 754) CRC case-controlled series of hospital patient volunteers (n = 627) in the Czech Republic, and the relationship with cancer risk was estimated by conditional logistic regression. RESULTS: After adjusting for age and sex, G316 > A was associated with no decrease in CRC risk for either heterozygotes [odds ratio 0.98, 95% confidence interval (CI) 0.77-1.23] or rare allele homozygotes (odds ratio 0.92, 95% CI 0.61-1.37). CONCLUSION: The G316 > A functional variant in the ODC gene is unlikely to make much impact on reducing CRC risk regardless of the reduction in risk found for the recurrence of colorectal adenoma.
Asunto(s)
Carcinoma/genética , Neoplasias del Colon/genética , Ornitina Descarboxilasa/genética , Polimorfismo de Nucleótido Simple , Neoplasias del Recto/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , República Checa , Femenino , Genotipo , Humanos , Intrones , Modelos Logísticos , Masculino , Persona de Mediana EdadRESUMEN
Pancreatic carcinoma is the fourth leading cause of cancer-related deaths in the Czech Republic, with only a minimum of patients surviving 5 years. The aetiology and molecular pathogenesis are still weakly understood. TP53 has a fundamental role in cell cycle and apoptosis and is frequently mutated in solid tumours, including pancreatic cancer. Based on the assumption that genetic variation may affect susceptibility to cancer development, the role of TP53 polymorphisms in modulating the risk of pancreatic cancer may be of major importance. We investigated four selected polymorphisms in TP53 (rs17878362:A(1)>A(2), rs1042522:G>C, rs12947788:C>T and rs17884306:G>A) in association with pancreatic cancer risk in a case-control study, including 240 cases and controls (for a total of 1827 individuals) from the Czech Republic. Carriers of the variant C allele of rs1042522 polymorphism were at an increased risk of pancreatic cancer [odds ratio (OR) 1.73; 95% confidence interval (CI) 1.26-2.39; P = 0.001]. Haplotype analysis showed that in comparison with the most common haplotype (A(1)GCG), the A(2)CCG haplotype was associated with an increased risk (OR 1.39; 95% CI 1.02-1.88; P = 0.034) and the A(1)CCG with a reduced risk (OR 0.30; 95% CI 0.12-0.76; P = 0.011) for this cancer. These results reflect previous findings of a recent association study, where haplotypes constructed on the same TP53 variants were associated with colorectal cancer risk [Polakova et al. (2009) Genotype and haplotype analysis of cell cycle genes in sporadic colorectal cancer in the Czech Republic. Hum. Mutat., 30, 661-668.]. Genetic variation in TP53 may contribute, alone or in concert with other risk factors, to modify the inherited susceptibility to pancreatic cancer, as well as to other gastrointestinal cancers.
Asunto(s)
Genes p53 , Haplotipos , Neoplasias Pancreáticas/genética , Adulto , Anciano , Anciano de 80 o más Años , República Checa , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , RiesgoRESUMEN
The Czech Republic has one of the highest incidences of colorectal cancer (CRC) in the world. To assess the role of genetic variants on the disease, we genotyped polymorphisms in the TP53 (rs17878362:A(1)>A(2), rs1042522:G>C, rs12947788:C>T, and rs17884306:G>A), CDKN1A (rs1801270:C>A and rs1059234:C>T), and CDKN2A (rs3731249:G>A, rs11515:C>G, and rs3088440:C>T) genes in 614 hospital-based CRC cases and 614 matched controls from the country. Despite the tendency toward differential distribution of variant allele frequencies for some polymorphisms, none was significantly associated with CRC risk. We observed differential distribution of major haplotypes arising from four polymorphisms in the TP53 gene between cases and controls (global P<0.0001). The two most common haplotypes, A(1)GCG and A(2)CCG, were present in 81% of the cases compared to 71% of the controls. In comparison to the most common haplotype (A(1)GCG), the haplotype A(2)CCG was associated with an increased risk (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.07-1.82), while the four other haplotypes A(1)CCG (OR, 0.60; 95% CI, 0.45-0.79), A(2)GCG (OR, 0.53; 95% CI, 0.35-0.81), A(1)GTG (OR, 0.31; 95% CI, 0.15-0.64), and A(1)GCA (OR, 0.19; 95% CI, 0.07-0.51) were associated with a decreased risk. The effect of haplotypes in the TP53 gene was similar in colon (global P<0.0001) and rectal cancers (P=0.006). No association with the disease was observed with haplotypes of the CDKN1A and CDKN2A polymorphisms. The results from this study suggest that prevalent haplotypes within the TP53 gene may modulate CRC risks in the population.
Asunto(s)
Proteínas de Ciclo Celular/genética , Neoplasias Colorrectales/genética , Haplotipos , Adulto , Alelos , Estudios de Casos y Controles , Neoplasias Colorrectales/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , República Checa , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Modelos Logísticos , Masculino , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The Czech Republic presents one of the highest incidences of colorectal cancer in the world. We genotyped 10 single nucleotide polymorphisms in five DNA mismatch repair genes in 614 colorectal cancer cases and 614 matched controls from this country. The carriers of T-allele of the hMSH6-556G>T polymorphism were at increased risk of colorectal cancer (OR 1.29; 95% CI 1.02-1.62). The stratification of data showed that risk associated with the polymorphism was confined to rectal cancer (OR 1.42; 95% CI 1.03-1.95). The A-allele of the Ex1-145G>A polymorphism in the hMSH6 gene was associated with a decreased risk of colorectal cancer (OR 0.76; 95% CI 0.60-0.98). The C-allele of the IVS4-101G>C polymorphism in hMSH6 was associated with an increased risk of colon cancer (OR 1.34; 95% CI 1.03-1.74). The carriers of the variant allele for the polymorphism IVS9-1406C>T in hMLH1 exhibited a decreased risk of rectal cancer (OR 0.71; 95% CI 0.51-0.98). We observed a differential distribution of haplotypes based on three hMSH6 polymorphisms (-556G>T-Ex1-145G>A-IVS4-101G>C) in the cases and controls (global P=0.02). The TAG haplotype was associated with a decreased risk of colorectal cancer (OR 0.74; 95% CI 0.59-0.92), whereas the most frequent haplotype GGG was associated with increased risk of rectal cancer (OR 1.32; 95% CI 1.05-1.65). However, multiple hypotheses testing diminishes a statistical significance of above associations. Our data suggest a limited role for the investigated individual variants in mismatch repair genes for the susceptibility to the disease. The haplotypes covering hMSH6 gene may, however, be involved in risk modulation in this population.
Asunto(s)
Carcinoma/genética , Neoplasias Colorrectales/genética , Reparación de la Incompatibilidad de ADN/genética , Haplotipos/fisiología , Polimorfismo de Nucleótido Simple/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Colorectal cancer represents a complex disease where susceptibility may be influenced by genetic polymorphisms in the DNA repair system. In the present study we investigated the role of nine single nucleotide polymorphisms in eight DNA repair genes on the risk of colorectal cancer in a hospital-based case-control population (532 cases and 532 sex- and age-matched controls). Data analysis showed that the variant allele homozygotes for the Asn148Glu polymorphism in the APE1 gene were at a statistically non-significant increased risk of colorectal cancer. The risk was more pronounced for colon cancer (odds ratio, OR: 1.50; 95% confidence interval, CI: 1.01-2.22; p=0.05). The data stratification showed increased risk of colorectal cancer in the age group 64-86 years in both individuals heterozygous (OR: 1.79; 95% CI: 1.04-3.07; p=0.04) and homozygous (OR: 2.57; 95% CI: 1.30-5.06; p=0.007) for the variant allele of the APE1 Asn148Glu polymorphism. Smokers homozygous for the variant allele of the hOGG1 Ser326Cys polymorphism showed increased risk of colorectal cancer (OR: 4.17; 95% CI: 1.17-15.54; p=0.03). The analysis of binary genotype combinations showed increased colorectal cancer risk in individuals simultaneously homozygous for the variant alleles of APE1 Asn148Glu and hOGG1 Ser326Cys (OR: 6.37; 95% CI: 1.40-29.02; p=0.02). Considering the subtle effect of the DNA repair polymorphisms on the risk of colorectal cancer, exploration of gene-gene and gene-environmental interactions with a large sample size with sufficient statistical power are recommended.
Asunto(s)
Neoplasias Colorrectales/genética , Reparación del ADN , Polimorfismo de Nucleótido Simple , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , República Checa , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Riesgo , Factores de Riesgo , FumarRESUMEN
Genotoxic effects related to exposure to styrene have been a matter of investigation for many years by employing markers of exposure, effect and susceptibility. The role of individual DNA-repair capacity in response to exposure to styrene may explain the controversial results so far obtained, but it is still scarcely explored. In the present study, we measured capacity to repair oxidative DNA damage in cell extracts obtained from 24 lamination workers occupationally exposed to styrene and 15 unexposed controls. The capacity to repair oxidative DNA damage was determined by use of a modified comet assay, as follows: HeLa cells, pre-treated with photosensitizer and irradiated with a halogen lamp in order to induce 7,8-dihydroxy-8-oxoguanine, were incubated with cell extracts from mononuclear leukocytes of each subject. The level of strand breaks reflects the removal of 7,8-dihydroxy-8-oxoguanine from substrate DNA by the enzymatic extract. In styrene-exposed subjects a moderate, non-significant increase in oxidative DNA repair was observed. Stratification for sex and smoking habit showed that unexposed males (P=0.010) and unexposed smokers (P=0.037) exhibited higher DNA-repair rates. The repair capacity did not correlate with parameters of styrene exposure and biomarkers of genotoxic effects (DNA strand breaks, N1-styrene-adenine DNA adducts, chromosomal aberrations and mutant frequencies at the HPRT locus). Significantly higher levels of DNA-repair capacity were observed in carriers of GSTM1-plus, compared to those with a deletion in GSTM1. The DNA-repair capacity was significantly lower in individuals with variant Gln/Gln genotype in XRCC1 Arg399Gln than in those with heterozygous Arg/Gln and wild-type Arg/Arg genotypes. Significantly lower repair capacity was also found in individuals with the wild-type Lys/Lys genotype in XPC Lys939Gln as compared with those homozygous for the Gln/Gln variant genotype.
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Biomarcadores/análisis , Reparación del ADN , Guanina/análogos & derivados , Exposición Profesional , Estireno/toxicidad , Adulto , Ensayo Cometa , Daño del ADN , Susceptibilidad a Enfermedades , Femenino , Genotipo , Guanina/metabolismo , Células HeLa , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Mutagenicidad , Polimorfismo GenéticoRESUMEN
A biomonitoring study to evaluate chromosome and DNA damage respectively in somatic and germ cells of a group of male workers exposed to styrene by using biomarkers of genotoxicity was carried out. Styrene-exposed workers from three different areas of Tuscany and healthy subjects, of comparable mean age, sex and lifestyle characteristics, as a control group not exposed to chemicals, have been enrolled. In addition to previous reports [L. Migliore, A. Naccarati, A. Zanello, R. Scarpato, L. Bramanti and M. Mariani (2002) Hum. Reprod., 17, 2912-2918; L. Migliore, A. Naccarati, F. Coppedè et al. (2006) Pharmacogenet. Genomics, 16, 87-99] we present now data on a cross-sectional investigation involving a homogeneous group of subjects for which data on both somatic and germ cells have been obtained from individuals (42 exposed and 25 controls). Somatic cell genotoxicity was assessed by analysing the frequency of micronucleated binucleated cells (MNBN) in blood lymphocytes. The micronucleus assay was coupled with centromeric fluorescence in situ hybridization (FISH) analysis. Primary DNA damage in germ cells was evaluated by alkaline single-cell gel electrophoresis (Comet assay) and the percentage of the tail DNA (%TD) was used as parameter of Comet evaluation. Moreover, to investigate the frequencies of aneuploidy and diploidy in sperm, we performed multicolour FISH, using DNA probes specific for the centromeric regions of sex chromosomes and chromosome 2, in decondensed sperm nuclei of samples with normal semen parameters in a subgroup of individuals. Mandelic and phenylglyoxylic acids (MAPGA) in end of shift samples were determined as biomarkers of internal dose. MAPGA excretion was consistent with an exposure to styrene above the threshold limit value-time weighted average concentration of 20 p.p.m. Styrene workers showed significantly higher frequency of MNBN as compared to controls (13.8 +/- 5.2 versus 6.2 +/- 5.1; P < 0.001), due to higher proportions of both micronuclei (MN) arising from chromosomal breakage (C-MN) and harbouring whole chromosomes (C+MN). DNA damage in sperm cells was also higher among styrene-exposed, the %TD being 11.02 +/- 2.99 versus 7.42 +/- 2.30 in controls (P < 0.001). The incidence of aneuploidy and diploidy for the tested chromosomes in sperm did not show a statistically significant difference between workers and controls. However, a positive correlation was found between genotoxic damage detected in somatic and in germ cells, even after removing the effect of age (r = 0.475; P < 0.001). Although cytogenetic biomarkers detected both in somatic and germ cells were interrelated, no relationships were apparent with exposure parameters. Styrene exposure may increase the likelihood of both chromosome and DNA damage in somatic and germ cells, thus supporting the hypothesis of an interference on reproductive capacity among exposed workers. This is the first time that a field study shows a correlation between two biomarkers of genotoxicity evaluated at the same time in somatic and germ cells.
Asunto(s)
Biomarcadores , Daño del ADN , Pruebas de Micronúcleos/métodos , Cromosomas/ultraestructura , Ensayo Cometa , Citogenética , Humanos , Hibridación Fluorescente in Situ , Linfocitos/metabolismo , Masculino , Exposición Profesional , Espermatozoides/metabolismo , Estirenos/químicaRESUMEN
1-SO-adenine DNA adducts, DNA single-strand breaks (SBs), chromosomal aberrations (CAs), mutant frequency (MF) at the HPRT gene, and immune parameters (hematological and of humoral immunity) were studied in styrene-exposed human subjects and controls. Results were correlated with genetic polymorphisms in DNA repair genes (XPD, exon 23, XPG, exon 15, XPC, exon 15, XRCC1, exon 10, XRCC3, exon 7) and cell cycle gene cyclin D1. Results for biomarkers of genotoxicity after stratification for the different DNA repair genetic polymorphisms showed that the polymorphism in exon 23 of the XPD gene modulates levels of chromosomal and DNA damage, HPRT MF, and moderately affects DNA adduct levels. The highest levels of biomarkers were associated with the wild-type homozygous AA genotype. The exposed individuals with the wild-type GG genotype for XRCC1 gene exhibited the lowest CA frequencies, compared to those with an A allele (P < 0.05). Cyclin D1 polymorphism seems to modulate the number of leukocytes and lymphocytes in the analyzed subjects. The number of eosinophiles was positively associated with XPD variant C allele and negatively with XRCC1 variant A allele (P < 0.05) and XPC variant C allele (P < 0.05). Immunoglobulin IgA was positively associated with an XRCC3 variant T allele (P < 0.01) and negatively with XPC variant C allele (P < 0.05). Both C3- and C4-complement components were lower in individuals with XRCC3 CT (P < 0.05) and TT genotypes (P < 0.01). Adhesion molecules sL-selectin and sICAM-1 were associated with XPC genotype (P < 0.05). Individual susceptibility may be reflected in genotoxic and immunotoxic responses to environmental and occupational exposures to xenobiotics.
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Ciclina D1/genética , Reparación del ADN , Sistema Inmunológico/efectos de los fármacos , Mutágenos/toxicidad , Polimorfismo Genético , Estireno/toxicidad , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Exposición ProfesionalRESUMEN
Endogenous oxidative stress is believed to play a key role in the pathogenesis of mitochondrial diseases (MD). In this group of heterogeneous disorders the increased production of radical species caused by compromised mitochondrial respiratory function could affect both mitochondrial and nuclear DNA integrity. The aim of the present study was to assess the basal level of nuclear DNA (nDNA) damage in terms of chromosome and DNA alterations in leukocytes of 13 patients (age range 29-74 years) presenting several forms of MD. A further objective of this work was the evaluation of possible changes in nDNA in a subgroup of patients (10 individuals) before and after a 2 week therapy with ubidecarenone, a coenzyme Q10 analogue. The extent of cytogenetic damage, expressed as chromosome breakage and chromosome loss, was assessed employing the cytokinesis block micronucleus method in cultured peripheral blood lymphocytes, coupled with fluorescence in situ hybridization analysis using a digoxigenin-labelled pancentromeric DNA probe. A modified version of the single cell gel electrophoresis assay was used to quantify primary and oxidative DNA damage in leukocytes. In MD patients an increased level of chromosome damage, expressed as frequency of micronucleated lymphocytes, was detected in comparison with healthy individuals of corresponding sex, age and lifestyle. The FISH analysis revealed a preferential occurrence of micronuclei arising from loss of whole chromosomes in patients, with no substantial difference in frequencies observed in matched controls. The Comet assay indicated a slightly higher level of primary DNA damage in patients compared with controls and also a difference in oxidative DNA damage, however, this was not statistically significant. Patients receiving ubidecarenone showed a statistically significant reduction in the frequency of micronucleated cells after therapy, while only a slight decrease was observed in the levels of both primary DNA damage and oxidized bases.
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Análisis Citogenético/métodos , Daño del ADN/genética , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Mitocondriales/genética , Ubiquinona/análogos & derivados , Ubiquinona/uso terapéutico , Adulto , Anciano , Células Cultivadas , Coenzimas , Ensayo Cometa , Femenino , Humanos , Hibridación Fluorescente in Situ , Leucocitos/efectos de los fármacos , Linfocitos/efectos de los fármacos , Linfocitos/fisiología , Masculino , Pruebas de Micronúcleos , Persona de Mediana Edad , Ubiquinona/efectos adversosRESUMEN
A cross-sectional study was carried out on laminators producing glass-fibre reinforced plastics, to evaluate the role of genetic polymorphism of xenobiotic metabolising enzymes on the genotoxicity of styrene. Clastogenic effects, evaluated by the micronucleus test, are related with end-of-shift urinary concentration of 4-vinylphenol and seem to be modulated by NQO1 polymorphism; aneuploidogenic effects, evaluated by the identification of centromers in micronuclei using the fluorescence in situ hybridisation technique with a pancentromeric probe, are related with before-shift urinary levels of mandelic and phenylglyoxylic acids and seem to be modulated by the GSTM1 polymorphism.
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Enzimas/genética , Polimorfismo Genético , Estireno/farmacocinética , Adulto , Biotransformación , Estudios Transversales , Femenino , Humanos , Masculino , Estireno/toxicidadRESUMEN
Recent studies indicate an important role of endogenous oxidative stress in the onset and/or in the progression of mitochondrial encephalomyopathies. In particular, the increased production of radical species caused by altered mitochondrial functionality could affect both mitochondrial and nuclear DNA integrity. We performed the micronucleus assay coupled with fluorescence in situ hybridization (FISH) to detect chromosome damage in peripheral blood lymphocytes in a group of patients affected by different forms of mitochondrial encephalomyopathies. Moreover the comet assay has been carried out to detect primary and oxidative damage in the nuclear DNA. Our results show a significant presence of both DNA and chromosome damage in patients compared to a matched group of controls. A reduction in DNA alterations is also observed in patients after treatment with coenzyme-Q10.
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Aberraciones Cromosómicas/sangre , Daño del ADN/fisiología , Linfocitos/patología , Encefalomiopatías Mitocondriales/genética , Estrés Oxidativo/genética , Adulto , Anciano , Aberraciones Cromosómicas/genética , Trastornos de los Cromosomas , Coenzimas , Ensayo Cometa/métodos , ADN/efectos de los fármacos , ADN/metabolismo , Daño del ADN/efectos de los fármacos , Análisis Mutacional de ADN , Femenino , Humanos , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Masculino , Pruebas de Micronúcleos , Persona de Mediana Edad , Encefalomiopatías Mitocondriales/tratamiento farmacológico , Encefalomiopatías Mitocondriales/metabolismo , Estrés Oxidativo/efectos de los fármacos , Resultado del Tratamiento , Ubiquinona/análogos & derivados , Ubiquinona/uso terapéuticoRESUMEN
Aim of the present paper was to assess by using the in vitro micronucleus (MN) test in human lymphocytes the effect of two plant extracts isolated from Blupeurum fruticosum (saponins) on the clastogenicity and cytotoxicity of the anticancer drugs mitomycin C (MMC) and bleomycin (BLM). One saponin showed a dose-dependent MMC-induced mutagenesis inhibition together with co-genotoxic effect on BLM-treated cultures. The remaining saponin did not significantly alter MN induction of both chemotherapeutic agents whereas it enhanced BLM cytotoxicity.
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Antimetabolitos Antineoplásicos/toxicidad , Bleomicina/toxicidad , Mitomicina/toxicidad , Inhibidores de la Síntesis del Ácido Nucleico/toxicidad , Saponinas/farmacología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Linfocitos/química , Linfocitos/efectos de los fármacos , Masculino , Pruebas de Micronúcleos , Mutágenos/farmacología , Plantas/químicaRESUMEN
The frequencies of aneuploidy and diploidy for chromosomes 2, X and Y in sperm nuclei of five nonsmoking normal donors were assessed by three-colour fluorescence in situ hybridization. We detected neither significant interindividual variability nor age effect (age range of the study group: 26-38 yr) on the mean frequencies of aneuploid and diploid sperm. Nullisomic sperm were observed more frequently than disomic sperm. In addition, sex chromosomal meiotic nondisjunction occurred at a higher rate than autosomal nondisjunction, and disomic sperm for the sex chromosomes were formed mainly by errors in the second meiotic division. Our data indicate that diploidy occurs at a very low frequency in comparison with aneuploidy. Furthermore, the overall proportion of X-bearing sperm nuclei aneuploid for chromosome 2 is significantly higher than that of Y-bearing sperm (0.14% vs. 0.05%, respectively; p < 0.001). This finding adds further evidence that autosomal aneuploidy can be preferentially associated with the presence of one of the two gonosomes.