RESUMEN
The University of Illinois at Chicago, School of Public Health, Doctor of Public Health degree is designed to build leadership skills and an ability to contribute to the evidence base of practice. The competency-based, distance-format, doctoral-level program for midcareer professionals features an action learning approach in which students apply leadership principles from the virtual classroom to real-world problems at their work sites. Students demonstrate mastery of the competencies and readiness to advance to the dissertation stage through completing a portfolio by using a process of systematic reflection. The practice-oriented dissertation demonstrates the ability to contribute to the evidence base of public health practice in an area of emphasis. Preliminary evaluation data indicate that the program is meeting its intended purposes.
Asunto(s)
Educación Basada en Competencias/organización & administración , Educación a Distancia/organización & administración , Educación de Postgrado/organización & administración , Liderazgo , Escuelas de Salud Pública/organización & administración , Chicago , Humanos , Desarrollo de Programa , Evaluación de Programas y Proyectos de SaludRESUMEN
BACKGROUND: Epidemiologic studies suggest that variability in DNA damage from vinyl chloride monomer (VCM) may be partially mediated by genetic polymorphisms in DNA repair. This study aimed to corroborate these observations with controlled experiments in vitro using cell lines from individuals with differing DNA repair genotypes to determine damage following VCM metabolite exposure. METHODS: Matched pairs of lymphoblast cell lines (homozygous wild-type versus homozygous variant for either XRCC1 399 or XPD 751 polymorphism) were exposed to chloroacetaldehyde and analyzed by the cytokinesis-block micronucleus assay. RESULTS: All cell lines demonstrated a dose-response of increasing micronuclei with increasing exposure, but for both XRCC1 and XPD, the polymorphic cells peaked at higher micronucleus frequencies and declined at a slower rate to baseline than the wild-type cells. CONCLUSION: This supports the findings that XRCC1 and XPD polymorphisms may result in deficient DNA repair of VCM-induced genetic damage.
Asunto(s)
Daño del ADN , Reparación del ADN/genética , Linfocitos/efectos de los fármacos , Cloruro de Vinilo/toxicidad , Línea Celular Transformada , Humanos , Técnicas In Vitro , Linfocitos/metabolismo , Pruebas de Micronúcleos , Polimorfismo GenéticoRESUMEN
In this study, a group of 317 workers occupationally exposed to vinyl chloride monomer and 166 normal, unexposed referents in Shandong province (Northern China) were examined for chromosomal damage in peripheral lymphocytes using the cytokinesis-blocked micronucleus (CB-MN) assay. The exposure group (3.47±2.65) showed higher micronucleus frequency than the unexposed workers (2.51±1.96) (P<0.01). We explored the relationship between genetic polymorphisms of XRCC1 (-77C/T, Arg194Trp, Arg280His, Arg399Gln), APE1 Asp148Glu, XPA Ala23Gly, XPC.PAT, XPC Ala499Val, XPC Lys939Gln, XPF 5'-UTR T2063A, XPG Exon15 G-C, ERCC13'-UTR C8092A and susceptibility of chromosomal damage in all the subjects. It was found that XRCC1 -77, XRCC1 280, APE1148, XPC.PAT, XPG Exon15 G-C, and ERCC13'-UTR C8092A polymorphisms showed no significant associations with micronucleus frequency in unexposed workers. However, among the exposed workers individuals with XRCC1 (-77C/T, Arg194Trp, Arg280His, Arg399Gln) polymorphisms had a significantly higher micronucleus frequency as seen in mean frequency ratios (FR) compared with their homozygous wild-type genotypes (FR=1.21, 95% CI: 1.05-1.39; P<0.01); (FR=1.14, 95% CI: 1.00-1.38; P<0.05) and (FR=1.26, 95% CI: 1.11-1.44; P<0.01); (FR=1.23, 95% CI: 1.08-1.46; P<0.01). Four SNP sites in the nucleotide excision repair (NER) pathway were associated with susceptibility for MN frequency in either unexposed or exposed workers. Further, we observed the gene-MN association changed with exposure for XRCC1 (-77C/T, Arg194Trp, Arg280His, Arg399Gln), XPA Ala23Gly, XPC Ala499Val, XPC Lys939Gln, XPF 5'-UTR T2063A. Moreover, Individuals carrying the XPC (PAT)-(499)-(939) diplotype, PAT-CG/PAT-TG, had a higher MN frequency, compared with individuals carrying the wild-type PAT-CA/PAT-CA.
Asunto(s)
Reparación del ADN/genética , Pruebas de Micronúcleos , Exposición Profesional , Polimorfismo Genético , Cloruro de Vinilo/toxicidad , China , Humanos , Estilo de VidaRESUMEN
The anticancer peptide PNC-27, which contains an HDM-2-binding domain corresponding to residues 12-26 of p53 and a transmembrane-penetrating domain, has been found to kill cancer cells (but not normal cells) by inducing membranolysis. We find that our previously determined 3D structure of the p53 residues of PNC-27 is directly superimposable on the structure for the same residues bound to HDM-2, suggesting that the peptide may target HDM-2 in the membranes of cancer cells. We now find significant levels of HDM-2 in the membranes of a variety of cancer cells but not in the membranes of several untransformed cell lines. In colocalization experiments, we find that PNC-27 binds to cell membrane-bound HDM-2. We further transfected a plasmid expressing full-length HDM-2 with a membrane-localization signal into untransformed MCF-10-2A cells not susceptible to PNC-27 and found that these cells expressing full-length HDM-2 on their cell surface became susceptible to PNC-27. We conclude that PNC-27 targets HDM-2 in the membranes of cancer cells, allowing it to induce membranolysis of these cells selectively.
Asunto(s)
Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/farmacología , Secuencia de Aminoácidos , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Secuencia de Bases , Sitios de Unión , Muerte Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Membrana Celular/metabolismo , Cristalografía por Rayos X , Femenino , Colorantes Fluorescentes , Humanos , Masculino , Microscopía Confocal , Modelos Moleculares , Datos de Secuencia Molecular , Resonancia Magnética Nuclear Biomolecular , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/farmacología , Plásmidos/genética , Conformación Proteica , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Transfección , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Any gene therapy for cancer will be predicated upon its selectivity against cancer cells and non-toxicity to normal cells. Therefore, safeguards are needed to prevent its activation in normal cells. We designed a minimal p14ARF promoter with upstream Ap1 and E2F enhancer elements and a downstream MDR1 inhibitory element, TATA box, and a transcription initiation site (hereafter p14ARFmin). The modified p14ARFmin promoter was linked to bicistronic P14 and truncated BID (tBID) genes, which led to synergistic apoptosis via the intrinsic and extrinsic pathways of apoptosis when expressed. The promoter was designed to be preferentially activated by mutant Ras and completely inhibited by wild-type p53 so that only cells with both mutant Ras and mutant p53 would activate the construct. In comparison to most p53 gene therapies, this construct has selective advantages: (1) p53-based gene therapies with a constitutive CMV promoter cannot differentiate between normal cells and cancer cells, and can be toxic to normal cells; (2) our construct does not induce p21WAF/CIPI in contrast to other p53-based gene therapies, which can induce cell cycle arrest leading to increased chemotherapy resistance; (3) the modified construct (p14ARFmin-p14-tBID) demonstrates bidirectional control of its promoter, which is completely repressed by wild-type p53 and activated only in cells with both RAS and P53 mutations; and (4) a novel combination of genes (p14 and tBID) can synergistically induce potent intrinsic and extrinsic apoptosis in cancer cells.
RESUMEN
We previously demonstrated that a synthetic monomer peptide derived from the C-terminus of p53 (aa 361−382) induced preferential apoptosis in mutant p53 malignant cells, but not normal cells. The major problem with the peptide was its short half-life (half-life < 10 min.) due to a random coil topology found in 3D proton NMR spectroscopy studies. To induce secondary/tertiary structures to produce more stability, we developed a peptide modelled after the tetrameric structure of p53 essential for activation of target genes. Starting with the above monomer peptide (aa 361−382), we added the nuclear localization sequence of p53 (aa 353−360) and the end of the C-terminal sequence (aa 383−393), resulting in a monomer spanning aa 353−393. Four monomers were linked by glycine to maximize flexibility and in a palindromic order that mimics p53 tetramer formation with four orthogonal alpha helices, which is required for p53 transactivation of target genes. This is now known as the 4 repeat-palindromic-p53 peptide or (4R-Pal-p53p). We explored two methods for testing the activity of the palindromic tetrapeptide: (1) exogenous peptide with a truncated antennapedia carrier (Ant) and (2) a doxycycline (Dox) inducer for endogenous expression. The exogenous peptide, 4R-Pal-p53p-Ant, contained a His tag at the N-terminal and a truncated 17aa Ant at the C-terminal. Exposure of human breast cancer MB-468 cells and human skin squamous cell cancer cells (both with mutant p53, 273 Arg->His) with purified peptide at 7 µM and 15 µM produced 52% and 75%, cell death, respectively. Comparatively, the monomeric p53 C-terminal peptide-Ant (aa 361−382, termed p53p-Ant), at 15 µM and 30 µM induced 15% and 24% cell death, respectively. Compared to the p53p-Ant, the exogenous 4R-pal-p53p-Ant was over five-fold more potent for inducing apoptosis at an equimolar concentration (15 µM). Endogenous 4R-Pal-p53p expression (without Ant), induced by Dox, resulted in 43% cell death in an engineered MB468 breast cancer stable cell line, while endogenous p53 C-terminal monomeric peptide expression produced no cell death due to rapid peptide degradation. The mechanism of apoptosis from 4R-Pal-p53p involved the extrinsic and intrinsic pathways (FAS, caspase-8, Bax, PUMA) for apoptosis, as well as increasing reactive oxygen species (ROS). All three death pathways were induced from transcriptional/translational activation of pro-apoptotic genes. Additionally, mRNA of p53 target genes (Bax and Fas) increased 14-fold and 18-fold, respectively, implying that the 4R-Pal-p53p restored full apoptotic potential to mutant p53. Monomeric p53p only increased Fas expression without a transcriptional or translational increase in Fas, and other genes and human marrow stem cell studies revealed no toxicity to normal stem cells for granulocytes, erythrocytes, monocytes, and macrophages (CFU-GEMM). Additionally, the peptide specifically targeted pre-malignant and malignant cells with mutant p53 and was not toxic to normal cells with basal levels of WT p53.
RESUMEN
The manufacture, use and disposal of various plastics can pose numerous health risks, including the risk of cancer. A model example of carcinogenic risk from plastics is provided by polyvinyl chloride, since it is composed of the known human carcinogen vinyl chloride (VC). In recent years, much has been learned about the molecular biological pathways of VC carcinogenesis. This has led to molecular epidemiologic studies of VC carcinogenesis in exposed human populations which have identified useful biomarkers of exposure, effect and susceptibility for VC. These studies have in turn provided the basis for new molecular approaches for the prevention and treatment of VC cancers. This model could have much wider applicability for many other carcinogenic exposures and many other human cancers.
RESUMEN
OBJECTIVES: To identify biomarkers for cancer in asbestosis patients. METHODS: SELDI-TOF and CART were used to identify serum biomarker profiles in 35 asbestosis patients who subsequently developed cancer and 35 did not develop cancer. RESULTS: Three polypeptide peaks (5707.01, 6598.10, and 20,780.70 Da) could predict the development of cancer with 87% sensitivity and 70% specificity. The first two peaks were identified as KIF18A and KIF5A, respectively, and are part of the Kinesin Superfamily of proteins. CONCLUSIONS: We identified two Kinesin proteins that can be potentially used as blood biomarkers to identify asbestosis patients at risk of developing lung cancer.
Asunto(s)
Asbestosis/sangre , Biomarcadores de Tumor/sangre , Proteínas Sanguíneas/análisis , Cinesinas/sangre , Neoplasias Pulmonares/sangre , Adenocarcinoma/sangre , Adenocarcinoma/etiología , Adenocarcinoma/fisiopatología , Adenocarcinoma del Pulmón , Asbestosis/complicaciones , Asbestosis/fisiopatología , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Finlandia , Humanos , Estudios Longitudinales , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/fisiopatología , Masculino , Persona de Mediana Edad , Proteómica , Factores de Riesgo , Sensibilidad y Especificidad , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
In this study, a group of 313 workers occupationally exposed to vinyl chloride monomer (VCM) and 141 normal unexposed referents were examined for chromosomal damage using the cytokinesis-blocked micronucleus (CBMN) assay in peripheral lymphocytes. We explored the relationship between genetic polymorphisms of XRCC1 (Arg194Trp, Arg280His and Arg399Gln), MGMT(Leu84Phe) and hOGG1 (Ser326Cys) and susceptibility of chromosomal damage induced by VCM. Polymerase chain reaction-restriction fragment length polymorphism techniques were used to detect polymorphisms in XRCC1, hOGG1 and MGMT. It was found that the micronuclei (MN) frequency of exposed workers (4.86 +/- 2.80) per thousand was higher than that of the control group (1.22 +/- 1.24) per thousand (P < 0.01). Increased susceptibility to chromosomal damage as evidenced by higher MN frequency was found in workers with hOGG1 326 Ser/Cys genotype [frequency ratio (FR) = 1.21, 95% confidence interval (CI): 1.02-1.46; P < 0.05], XRCC1 194 Arg/Trp (FR = 1.12, 95% CI: 1.00-1.25; P < 0.05) and XRCC1 280 Arg/His and His/His genotypes (FR = 1.12, 95% CI 1.00-1.26, P < 0.05). Moreover, among susceptibility diplotypes, CGA/CAG carriers had more risk of MN frequency compared with individuals with wild-type CGG/CGG (FR = 1.67, 95% CI: 1.19-2.23; P < 0.05). MN frequency also increased significantly with age in the exposed group (FR = 1.13, 95% CI: 1.00-1.28; P < 0.05). Thus, CB-MN was a sensitive index of early damage among VCM-exposed workers. Genotype XRCC1 Arg194Trp, Arg280His, hOGG1 Ser326Cys, diplotype CGA/CAG and higher age may have an impact on the chromosome damage induced by VCM.
Asunto(s)
ADN Glicosilasas/genética , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Pruebas de Micronúcleos , Exposición Profesional , Polimorfismo Genético , Proteínas Supresoras de Tumor/genética , Cloruro de Vinilo/toxicidad , Adulto , Secuencia de Bases , China , Cartilla de ADN , Femenino , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Distribución de Poisson , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos XRESUMEN
BACKGROUND AND AIMS: A prospective cohort study was conducted to evaluate the effect of arsenic (As) exposure from drinking water on respiratory symptoms using data from the Health Effects of Arsenic Exposure Longitudinal Study (HEALS), a large prospective cohort study established in Ariahazar, Bangladesh in 2000-2002. A total of 7.31, 9.95 and 2.03% of the 11 746 participants completing 4 years of active follow-up reported having a chronic cough, breathing problem or blood in their sputum, respectively, as assessed by trained physicians. METHODS: Cox regression models were used to estimate HRs for respiratory symptoms during the follow-up period in relation to levels of chronic As exposure assessed at baseline, adjusting for age, gender, smoking, body mass index, education and arsenic-related skin lesion status. RESULTS: Significant positive associations were found between As exposure and respiratory symptoms. As compared with those with the lowest quintile of water As level (
Asunto(s)
Arsénico/toxicidad , Trastornos Respiratorios/inducido químicamente , Abastecimiento de Agua , Adulto , Arsénico/análisis , Arsénico/orina , Bangladesh/epidemiología , Relación Dosis-Respuesta a Droga , Monitoreo del Ambiente/métodos , Métodos Epidemiológicos , Monitoreo Epidemiológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Respiratorios/epidemiología , Fumar/efectos adversos , Fumar/epidemiología , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/toxicidad , Abastecimiento de Agua/análisisRESUMEN
BACKGROUND: XRCC1 is a scaffold protein involved in the early and late stages of Base Excision Repair (BER). Three DNA polymorphisms occur in XRCC1, resulting in non-synonymous amino acid changes, which could alter the binding or regulatory activities of XRCC1. MATERIALS AND METHODS: We used a family-based case-control study design to evaluate the association between XRCC1 polymorphisms and breast cancer risk. Participants were breast cancer cases and their unaffected sisters enrolled in the New York Site of the Breast Cancer Family Registry. Conditional logistic regression was used to assess associations between genotype and breast cancer. XRCC1 mRNA levels and DNA nicking activity were measured in lymphoblastoid cell lines from unaffected sisters to determine whether the XRCC1 R399Q polymorphism has a functional effect on expression or protein activity. RESULTS: XRCC1 194W was associated with a non-significant increase in breast cancer, while XRCC1 280H and XRCC1 399Q were associated with a non-significant decrease in breast cancer. We found a significant increase in XRCC1 expression in 399Q/Q lymphoblastoid cell lines from unaffected sisters (n=28, P=0.03). An increase in median nicking activity was not statistically significant. CONCLUSIONS: Our results suggest that XRCC1 399Q may alter mRNA expression and DNA repair phenotype, although the main effects of the genotype were not significantly associated with familial cancer risk. Additional research on the regulation of XRCC1 expression will contribute to an understanding of how this polymorphism may impact disease risk.
RESUMEN
A prior study in New York City observed that airborne concentrations of three metals found in steel - iron, manganese, and chromium - are more than 100 times higher in the subway system than in aboveground air. To investigate the potential for health effects of exposure at these levels, we conducted a pilot study of subway workers comparing personal exposures to steel dust with biomarkers of metal exposure, oxidative stress, and DNA damage in blood and urine samples. Workers wore a personal air sampler operating at 4L/m for one to three work shifts with blood and urine samples collected at the end of the final shift. We found that PM(2.5) exposures varied among subway workers on the basis of job title and job activity. The subway workers' mean time-weighted PM(2.5) exposure was 52 microg/m3, with a median of 27 microg/m3, and a range of 6-469 microg/m3. The observed concentrations of PM(2.5), iron, manganese, and chromium fell well below occupational standards. Biomarker concentrations among the 39 subway workers were compared with a group of 11 bus drivers, and a group of 25 suburban office workers. Concentrations of DNA-protein crosslinks and chromium in plasma were significantly higher in subway workers than in bus drivers, but no significant difference was observed for these biomarkers between subway workers and office workers. Urinary isoprostane concentrations were significantly correlated with the number of years working in the subway system, and were detected at higher, though not significantly higher, concentrations in subway workers than in bus drivers or office workers. At the group level, there was no consistent pattern of biomarker concentrations among subway workers significantly exceeding those of the bus drivers and office workers. At the individual level, steel dust exposure was not correlated with any of the biomarkers measured.
Asunto(s)
Contaminantes Ocupacionales del Aire/análisis , Monitoreo del Ambiente , Exposición por Inhalación/análisis , Metales Pesados/análisis , Material Particulado/análisis , Vías Férreas , Adulto , Contaminantes Ocupacionales del Aire/sangre , Contaminantes Ocupacionales del Aire/toxicidad , Contaminantes Ocupacionales del Aire/orina , Daño del ADN , Polvo , Humanos , Metales Pesados/sangre , Metales Pesados/toxicidad , Metales Pesados/orina , Microscopía Electrónica de Rastreo , Persona de Mediana Edad , Ciudad de Nueva York , Estrés Oxidativo/efectos de los fármacos , Tamaño de la Partícula , Material Particulado/sangre , Material Particulado/toxicidad , Material Particulado/orina , Proyectos Piloto , Vías Férreas/normas , Acero , Propiedades de Superficie , Lugar de Trabajo/normasRESUMEN
BACKGROUND: Few studies have described protein and amino acid intakes in rural Bangladesh, a country with considerable undernutrition. OBJECTIVE: The purpose of this population-based study was to assess and describe protein and amino acid intakes in Araihazar, Bangladesh. METHODS: The study participants were 11,170 adult men and women who participated in the Health Effects of Arsenic Longitudinal Study (HEALS), which had a 98% participation rate. Dietary exposures were assessed by a food-frequency questionnaire that had been designed and validated for the HEALS study population. RESULTS: The mean body mass index (BMI) was 19.7 among all participants, and 34.9% of women and 44.4% of men had a BMI below 18.5. The average caloric intake was 2142 and 2394 kcal/day among women and men, respectively, and the mean protein intake was 67.5 and 78.2 g/day. The largest sources of protein were from rice and fish. Greater protein intake was related to younger age and several socioeconomic measures, including more years of education, land and television ownership, and employment in business, farming, or as a laborer (for men) or as a homemaker (for women). CONCLUSIONS: This study found a high prevalence of underweight among study participants. Nonetheless, most participants had adequate protein intake according to Food and Agriculture Organization standards for body weight.
Asunto(s)
Aminoácidos/administración & dosificación , Proteínas en la Dieta/administración & dosificación , Desnutrición/epidemiología , Población Rural/estadística & datos numéricos , Adulto , Envejecimiento , Animales , Bangladesh/epidemiología , Índice de Masa Corporal , Estudios Transversales , Ingestión de Energía , Femenino , Peces , Humanos , Masculino , Persona de Mediana Edad , Oryza , Prevalencia , Alimentos Marinos , Semillas , Caracteres Sexuales , Factores Socioeconómicos , Encuestas y CuestionariosRESUMEN
BACKGROUND: In Bangladesh, millions of people are exposed to arsenic in drinking water; arsenic is associated with increased risk of cancer. Once ingested, arsenic is metabolized via methylation and excreted in urine. Knowledge about nutritional factors affecting individual variation in methylation is limited. OBJECTIVES: The purpose of this study was to examine associations between intakes of protein, methionine, and cysteine total urinary arsenic in a large population-based sample. METHODS: The study subjects were 10,402 disease-free residents of Araihazar, Bangladesh, who participated in the Health Effects of Arsenic Longitudinal Study (HEALS). Food intakes were assessed using a validated food frequency questionnaire developed for the study population. Nutrient composition was determined by using the U.S. Department of Agriculture National Nutrient Database for Standard Reference. Generalized estimating equations were used to examine association between total urinary arsenic across quintiles of nutrient intakes while controlling for arsenic exposure from drinking water and other predictors of urinary arsenic. RESULTS: Greater intakes of protein, methionine, and cysteine were associated with 10-15% greater total urinary arsenic excretion, after controlling for total energy intake, body weight, sex, age, tobacco use, and intake of some other nutrients. CONCLUSIONS: Given previously reported risks between lower rates of arsenic excretion and increased rates of cancer, these findings support the role of nutrition in preventing arsenic-related disease.
Asunto(s)
Arsénico/orina , Cisteína/farmacología , Dieta , Metionina/farmacología , Proteinuria/fisiopatología , Bangladesh , Estudios de Cohortes , Cisteína/administración & dosificación , Femenino , Humanos , Masculino , Metionina/administración & dosificaciónRESUMEN
AIM: The xeroderma pigmentosum D (XPD) protein is a DNA helicase involved in the repair of DNA damage, including nucleotide excision repair (NER) and transcription-coupled repair (TCR). The C-terminal domain of XPD has been implicated in interactions with other components of the TFIIH complex, and it is also the site of a common genetic polymorphism in XPD at amino acid residue 751 (Lys->Gln). Some evidence suggests that this polymorphism may alter DNA repair capacity and increase cancer risk. The aim of this study was to investigate whether these effects could be attributable to conformational changes in XPD induced by the polymorphism. MATERIALS AND METHODS: Molecular dynamics techniques were used to predict the structure of the wild-type and polymorphic forms of the C-terminal domain of XPD and differences in structure produced by the polymorphic substitution were determined. RESULTS: The results indicate that, although the general configuration of both proteins is similar, the substitution produces a significant conformational change immediately N-terminal to the site of the polymorphism. CONCLUSION: These results provide support for the hypothesis that this polymorphism in XPD could affect DNA repair capability, and hence cancer risk, by altering the structure of the C-terminal domain.
RESUMEN
BACKGROUND: Recent epidemiologic evidence suggests that the common polymorphism at amino acid residue 399 of the x-ray cross complementing-1 (XRCC1) protein, a key component of the base excision repair (BER) pathway for DNA damage, plays a significant role in the genetic variability of individuals in terms of the mutagenic damage they experience following exposure to the carcinogen vinyl chloride (VC). The aim of this study was to provide support for the biological plausibility of these epidemiologic observations with experimental data derived from cell lines in culture from individuals who were either homozygous wild-type or homozygous variant for this XRCC1 polymorphism following exposure to chloroethylene oxide (CEO), the active metabolite of VC, with measurement of the induced etheno-DNA adducts before and after repair. MATERIALS AND METHODS: Immortalized lymphoblast cell lines from seven VC workers (four homozygous wild-type and three homozygous variant for the 399 XRCC1 polymorphism) were exposed to CEO, and etheno-adenosine (epsilonA) adduct levels were determined by enzyme-linked immunosorbent assay (ELISA) pre-exposure and at 0, 4, 8 and 24 h following exposure. RESULTS: The average epsilonA adduct levels were statistically significantly higher in the variant cells compared to the wild-type cells at 8 and 24 h following exposure (P Conclusion: These results are consistent with the epidemiologic findings of the types of VC-induced biomarkers observed in exposed individuals and the mutational spectra found in the resultant tumors as well as the key role that BER, especially XRCC1, plays in this carcinogenic pathway.
RESUMEN
We have recently suggested that polymorphisms in metabolism and repair pathways may play a role in modulating the effects of exposure to the carcinogen vinyl chloride in the production of biomarkers of its mutagenic damage. The aim of the present study was to extend these observations by examining gene-environment interactions between several common polymorphisms in the DNA repair genes XRCC1 and ERCC2/XPD and vinyl chloride exposure on the production of vinyl chloride-induced biomarkers of mutation. A cohort of 546 French vinyl chloride workers were genotyped for the XRCC1 codon 194 (Arg>Trp; rs1799782), 280 (Arg>His; rs25489) and 399 (Arg>Gln; rs25487) polymorphisms and the ERCC2/XPD codon 312 (Asp>Asn; rs1799793) and 751 (Lys>Gln; rs13181) polymorphisms. The results demonstrated a statistically significant allele dosage effect of the XRCC1 399 variant on the production of the vinyl chloride-induced mutant p53 biomarker, even after controlling for confounders including cumulative vinyl chloride exposure (p = 0.03), with a potentially supramultiplicative gene-environment interaction. In addition, the results demonstrate statistically significant allele dosage effects of the ERCC2/XPD 312 and 751 variants on the production of the vinyl chloride-induced mutant ras-p21 biomarker, even after controlling for confounders including cumulative vinyl chloride exposure (p < 0.0001 and p = 0.0006, respectively), with a potentially supramultiplicative gene-environment interaction for the codon 751 allele. Finally, the results suggest potential supramultiplicative gene-gene interactions between CYP2E1 (c2 allele; rs3813867) and ERCC2/XPD polymorphisms that are consistent with the proposed carcinogenic pathway for vinyl chloride, which requires metabolic activation by CYP2E1 to reactive intermediates that form DNA adducts that, if not removed by DNA repair mechanisms, result in oncogenic mutations.
Asunto(s)
Carcinógenos/toxicidad , Reparación del ADN/genética , Genes , Exposición Profesional , Polimorfismo Genético , Cloruro de Vinilo/toxicidad , Secuencia de Bases , Estudios de Casos y Controles , Cartilla de ADN , HumanosRESUMEN
Various growth factors, including platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-beta, have been implicated in the pathogenesis of asbestos-induced disease. PDGF and TGF-beta levels were determined by enzyme-linked immunosorbent assays in the banked serum samples of a cohort of workers with asbestosis, and the relationships of the growth factor levels to the subsequent development of cancer and to the radiographic severity and progression of asbestosis in the cohort were examined. Serum levels of PDGF and TGF-beta were found to be unrelated to the development of cancer, and serum levels of PDGF were found to be unrelated to the severity and progression of asbestosis. However, serum levels of TGF-beta were found to be statistically significantly related to disease severity (p = 0.01), increasing approximately 2.4-fold from ILO radiographic category 0 to category 3, and they were marginally related to disease progression (p = 0.07), in multivariate analysis controlling for other contributory factors including cumulative asbestos exposure. This suggests that serum TGF-beta may be a useful biomarker for asbestos-induced fibrotic disease.