Paul W. Brandt-Rauf

University of Illinois at Chicago, Chicago, Illinois, United States

Are you Paul W. Brandt-Rauf?

Claim your profile

Publications (187)543.47 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract 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.
    Biomarkers 04/2014; 19(4). DOI:10.3109/1354750X.2014.907345 · 2.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the association between polymorphisms in the p53 pathway genes and chromosomal damage in vinyl chloride (VC)-exposed workers. Cytokinesis block micronucleus test was performed in 310 VC-exposed workers and 149 non-exposed workers to determine chromosomal damage. The polymerase chain reaction and restriction fragment length polymorphism technique were used to detect six SNPs in the p53 pathway genes involved in the cell cycle. There was a highly significant dose-response relationship between VC exposure and chromosomal damage. Individuals carrying the variant genotypes were at higher risk for chromosomal damage compared with their wild type genotype: p53rs1042522, MDM2 Del1518rs3730485, MDM2rs2279744 and GADD45Ars532446. On the other hand, individuals possessing the variant genotype of CDKN2A rs3088440 had significantly decreased risk compared with the corresponding wild-type. Genetic polymorphisms in P53 pathway genes may have an impact on VC-induced chromosomal damage.
    International Journal of Occupational Medicine and Environmental Health 12/2013; 26(6):825-36. DOI:10.2478/s13382-013-0155-6 · 1.09 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer cell lines with mutated ras underwent an alternative form of cell death (aponecrosis) when treated concomitantly with clinically achievable concentrations of arsenic trioxide, ascorbic acid and disulfiram (Antabuse) (AAA). AAA's major effects are mediated through generation of intracellular reactive oxygen species (ROS) and over 50% decline in intracellular ATP. N-acetyl cysteine and a superoxide dismutase mimetic, prevented aponecrosis and restored intracellular ATP levels. DIDS, the pan- Voltage-Dependent Anion Channel (VDAC), -1, 2, 3 inhibitor and shRNA to VDAC-1 blocked cell death and ROS accumulation. In vivo exposure of AAA led to a 61% reduction in mean tumor size and eliminated tumors in 30% of nude mice with PANC-1 xenografts. We concluded that early caspase-independent apoptosis was shifted to VDAC-mediated "targeted" aponecrosis by the addition of disulfiram to arsenic trioxide and ascorbic acid. Conceptually, this work represents a paradigm shift where switching from apoptosis to aponecrosis death pathways, a.k.a. targeted aponecrosis, could be utilized to selectively kill pancreatic cancer cells resistant to apoptosis.
    Molecular Cancer Therapeutics 10/2013; 12(12). DOI:10.1158/1535-7163.MCT-13-0234 · 6.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Mutation Research/Genetic Toxicology and Environmental Mutagenesis 06/2013; 754(s 1–2):7–14. DOI:10.1016/j.mrgentox.2013.03.007 · 2.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: To explore the association of the methylation status of MGMT and hMLH1 with chromosome damage induced by vinyl chloride monomer (VCM). Materials and Methods: Methylation of MGMT and hMLH1 was measured in 101 VCM-exposed workers by methylation-specific PCR. Chromosome damage in peripheral blood lymphocytes was measured by the cytokinesis-block micronucleus assay. The subjects were divided into chromosome damaged and non-damaged groups based on the normal reference value of micronuclei frequencies determined for two control groups. Results: MGMT promoter methylation was detectable in 5 out of 49 chromosome damaged subjects, but not in the chromosome non-damaged subjects; there was a significant difference in MGMT methylation between the two groups (p < 0.05). Conclusions: We detected aberrant promoter methylation of MGMT in a small number of chromosome damaged VCM-exposed workers, but not in the chromosome non-damaged subjects. This preliminary observation warrants further investigation in a larger study.
    International Journal of Occupational Medicine and Environmental Health 02/2013; DOI:10.2478/S13382-013-0079-1 · 1.09 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: The aim of this study was to estimate a benchmark dose (BMD) for chromosome damage induced by vinyl chloride monomer (VCM) in VCM-exposed workers in central China and validate the published results in Shanghai. Methods: VCM-exposed workers who had been exposed to VCM for at least one year (n=463) and matched subjects not exposed to VCM or other toxins (n=273) were asked to participate in this study. Micronucleus (MN) frequency based on the cytokinesis-block micronucleus assay (CBMN) was used as a biomarker for chromosome damage induced by VCM exposure. Results: The MN frequency in the VCM-exposed workers was significantly higher than that in the control group, and multivariate Poisson regression suggested that gender, smoking status and VCM exposure were the significant factors influencing the risk of increased MN frequency. When subjects were further stratified according to gender and smoking status, the results showed that female VCM-exposed workers were more susceptible than the males to the risk of increased MN frequency. The MN frequency of smokers was significantly higher than that of nonsmokers in the control group. Our study also suggested that there was a strong dose-response relationship between VCM CED and the increased risk of MN frequency in the total group, males and females. The BMDL10 was found to be 630.6, 670.2 and 273.7 mg-year for all VCM-exposed workers, males and females, respectively. Conclusions: These results invite further scrutiny of the current VCM occupational exposure limits and warrant further study of the risk of VCM genotoxicity and carcinogenicity.
    Journal of Occupational Health 05/2012; · 1.10 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In this study, we estimated the possibility of using benchmark dose (BMD) to assess the dose-response relationship between vinyl chloride monomer (VCM) exposure and chromosome damage. A group of 317 workers occupationally exposed to vinyl chloride monomer and 166 normal, unexposed control in Shandong Province northern China were examined for chromosomal damage in peripheral blood lymphocytes (PBL) using the cytokinesis-blocked micronucleus (CB-MN) assay of DNA damage. The exposed group (3.47±2.65)‰ showed higher micronucleus frequency than the control (1.60±1.30)‰ (P<0.01). Occupational exposure level based on micronucleus occurrence in all individuals was analyzed with benchmark dose (BMD) methods. The benchmark dose lower limit of a one-sided 95% confidence interval (BMDL) for 10% excess risk was also determined. Results showed a dose-response relationship between cumulative exposure and MN frequency, and a BMDL of 0.54mg/m(3) and 0.23mg/m(3) for males and females, respectively. Female workers were more susceptible to MN damage than male workers.
    International journal of hygiene and environmental health 03/2012; 216(1). DOI:10.1016/j.ijheh.2012.02.008 · 3.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Journal of Carcinogenesis 03/2012; 11:5. DOI:10.4103/1477-3163.93700
  • [Show abstract] [Hide abstract]
    ABSTRACT: To identify biomarkers for cancer in asbestosis patients. 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. 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. We identified two Kinesin proteins that can be potentially used as blood biomarkers to identify asbestosis patients at risk of developing lung cancer.
    Biomarkers 03/2011; 16(2):181-91. DOI:10.3109/1354750X.2010.543289 · 2.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Genetic testing in the workplace holds the promise of improving worker health but also raises ethical, legal, and social issues. In considering such testing, it is critical to understand the perspectives of workers, who are most directly affected by it, and occupational health professionals, who are often directly involved in its implementation. Therefore, a series of focus groups of unionized workers (n=25) and occupational medicine physicians (n=23) was conducted. The results demonstrated strikingly different perspectives of workers and physicians in several key areas, including the goals and appropriateness of genetic testing, and methods to minimize its risks. In general, workers were guided by a profound mistrust of the employer, physician, and government, while physicians were guided primarily by scientific and medical concerns, and, in many cases, by the business concerns distrusted by the workers.
    NEW SOLUTIONS A Journal of Environmental and Occupational Health Policy 01/2011; 21(1):89-102. DOI:10.2190/NS.21.1.j
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Few studies have described protein and amino acid intakes in rural Bangladesh, a country with considerable undernutrition. The purpose of this population-based study was to assess and describe protein and amino acid intakes in Araihazar, Bangladesh. 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. 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). 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.
    Food and nutrition bulletin 06/2010; 31(2):206-13. · 1.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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. 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. Significant positive associations were found between As exposure and respiratory symptoms. As compared with those with the lowest quintile of water As level (<or=7 microg/l), the HRs for having respiratory symptoms were 1.27 (95% CI 1.09 to 1.48), 1.39 (95% CI 1.19 to 1.63), 1.43 (95% CI 1.23 to 1.68) and 1.43 (95% CI 1.22 to 1.68) for the second to fifth quintiles of baseline water As concentrations (7-40, 40-90, 90-178 and >178 microg/l), respectively. Similarly, the corresponding HRs in relation to the second to fifth quintiles of urinary arsenic were 1.10 (95% CI 0.94 to 1.27), 1.11 (95% CI 0.95 to 1.29), 1.29 (95% CI 1.11 to 1.49) and 1.35 (95% CI 1.16 to 1.56), respectively. These associations did not differ appreciably by cigarette smoking status. This prospective cohort study found a dose-response relationship between As exposure and clinical symptoms of respiratory diseases in Bangladesh. In particular, these adverse respiratory effects of As were clearly evident in the low to moderate dose range, suggesting that a large proportion of the country's population may be at risk of developing serious lung diseases in the future.
    Thorax 06/2010; 65(6):528-33. DOI:10.1136/thx.2009.119347 · 8.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Carcinogenesis 04/2010; 31(6):1068-73. DOI:10.1093/carcin/bgq075 · 5.27 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Proceedings of the National Academy of Sciences 02/2010; 107(5):1918-23. DOI:10.1073/pnas.0909364107 · 9.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate whether polymorphisms in metabolizing enzymes contributed to susceptibility of chromosomal damage induced by vinyl chloride monomer (VCM). Cytokinesis block micronucleus test was performed on 185 VCM-exposed workers and 41 control subjects to detect chromosomal damage in peripheral lymphocytes. The polymerase chain reaction and restriction fragment length polymorphism technique was applied to detect polymorphisms of GSTT1, GSTM1, GSTP1G/A, CYP2E1G/C, and CYP2D6G/C. Poisson regression analysis was performed. Sex, age, VCM exposure, GSTP1, and CYP2E1 genotype can influence chromosomal damage. There was a 1.51-fold increased micronucleus frequency for GSTP1GG genotypes individuals compared with those GSTP1AA/GA genotype individuals (P < 0.05), the effect of polymorphism in CYP2E1 gene was more pronounced for allele C compared with allele G (P < 0.05). Polymorphisms of GSTP1G/A and CYP2E1G/C, which are potential susceptibility biomarkers of chromosomal damage in VCM-exposed worker.
    Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine 02/2010; 52(2):163-8. DOI:10.1097/JOM.0b013e3181cac00b · 1.80 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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. 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. 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. 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.
    Journal of Carcinogenesis 01/2010; 9(1):4. DOI:10.4103/1477-3163.62535
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Environmental Research 11/2009; 110(1):1-11. DOI:10.1016/j.envres.2009.10.006 · 3.95 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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 (εA) 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 εA adduct levels were statistically significantly higher in the variant cells compared to the wild-type cells at 8 and 24 h following exposure (P< 0.05) with an overall average repair efficiency of 32% in the variant cells compared to 82% in the wild-type cells. 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.
    Journal of Carcinogenesis 10/2009; 8:14. DOI:10.4103/1477-3163.56290
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Journal of Carcinogenesis 08/2009; 8(1):12. DOI:10.4103/1477-3163.54918
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Biomarkers 03/2009; 14(3):148-55. DOI:10.1080/13547500902811266 · 2.52 Impact Factor

Publication Stats

3k Citations
543.47 Total Impact Points


  • 2010–2014
    • University of Illinois at Chicago
      • • Division of Environmental and Occupational Health Sciences
      • • School of Public Health
      Chicago, Illinois, United States
  • 2008–2012
    • Fudan University
      • School of Public Health
      Shanghai, Shanghai Shi, China
  • 2011
    • University of Colorado
      • Division of Allergy and Clinical Immunology
      Denver, CO, United States
  • 1990–2009
    • Columbia University
      • • Department of Environmental Health Sciences
      • • Mailman School of Public Health
      • • Department of Medicine
      New York, New York, United States
    • Devry College of New York, USA
      New York, New York, United States
    • New York Medical College
      New York City, New York, United States
  • 1995–2001
    • State University of New York College of Environmental Science and Forestry
      Syracuse, New York, United States
    • Karolinska Institutet
      Solna, Stockholm, Sweden
  • 1996
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 1987–1991
    • New York Presbyterian Hospital
      • Department of Pain Medicine
      New York, New York, United States
  • 1989
    • CUNY Graduate Center
      New York City, New York, United States