Worker Genetic Susceptibility to Mutagenic Risk

Details

• Personal Author:
  Brandt-Rauf PW
• Description:
  Gene-environment interactions between workers' genotypes and hazardous exposures in the workplace are hypothesized to be important for identifying those workers at the highest risk for developing occupational diseases and for targeting potential interventions to reduce that risk and prevent disease. A possible model system for studying this paradigm in occupational carcinogenesis is provided by workers exposed to the carcinogen vinyl chloride (VC) and at risk for the development of angiosarcomas of the liver (ASLs). VC is metabolized (by CYP2E1) to reactive intermediates that generate pro-mutagenic etheno-DNA adducts that can be removed by base excision repair (via XRCC1) or nucleotide excision repair (via XPD), or, if not repaired, result in specific mutations in cancer-related genes (the ras oncogene and the TP53 tumor suppressor gene) that are detectable as circulating mutant protein biomarkers in exposed workers (mutant ras-p21 protein and mutant p53 protein or autoantibodies to mutant p53 protein, respectively). Our epidemiologic studies to date of VC workers demonstrate a statistically significant association between inherited polymorphisms in several genes (CYP2E1, XRCC1 and XPD) and the occurrence of these biomarkers of acquired genetic damage independent of cumulative VC exposure. Experimental studies to date have provided the biological plausibility for this effect of polymorphisms in CYP2E1 and XRCC1, but the largest genetic attributable risk appears to be due to XPD polymorphisms. Thus, the aim of this competing continuation proposal is to demonstrate similar biological plausibility for polymorphisms in XPD on susceptibility to VC-induced genetic damage using an array of experimental in silico, in vitro and in vivo approaches. Once workers are identified as high-risk due to their inherited or acquired genetic defects, interventions targeted at these specific defects can be developed to treat or prevent the resultant cancers in future studies. Since VC is one of the highest production volume chemicals in the world with large numbers of workers exposed, study of the health effects of workers in this major manufacturing sector of the economy are an important target for study under the NIOSH National Occupational Research Agenda. Furthermore, since these same pathways are involved in the genetic damage due to many other workplace chemicals, this study could have wider significance for gene-environment interactions/interventions in the workplace generally. The results confirm most of the aims of the study. In particular, structural studies of the wild-type and polymorphic forms of XPD demonstrated that there is a local conformational alteration at the site of the polymorphism which propagates throughout the whole molecule to produce significant overall differences between the two forms, without any effect on the level of expression of the proteins themselves. These changes in structure help to explain differences in functional ability between the wild-type and polymorphic forms because we found that they result in a disruption of the interactions of the polymorphic form with the other proteins in the nucleotide excision repair apparatus, in particular cdk7 and cyclin H. Finally, this disruption results in a significant impairment in DNA repair capacity such that, compared to wild-type cells, polymorphic cells have a 5-fold decrease in efficiency of repair of etheno-DNA adducts (of the type produced by VC exposure) resulting in a 4.8-fold increase in mutation frequency. These results are thus consistent with the results of the prior epidemiologic studies and provide a biologically plausible explanation for those findings. [Description provided by NIOSH]
• Subjects:
  Epidemiology Hazardous Substances Mutagens Neoplasms Occupational Exposure Occupational Health Risk Assessment Risk Factors Safety
• Keywords:
  Cancer DNA Damage Genetic Factors Genotype Hazardous Materials Liver Cancer Mutagenesis Occupational Exposure Oncogenesis Risk Factors Vinyl Chloride

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• Series:
  Grant Final Reports
• Publisher:
  National Institute for Occupational Safety and Health
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Final Grant Report
• Place as Subject:
  Illinois ; OSHA Region 5
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  OEP - Office of Extramural Programs
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  1-10
• NIOSHTIC Number:
  nn:20054167
• NTIS Accession Number:
  PB2019-100551
• Citation:
  Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, R01-OH-004192, 2015 Aug; :1-10
• Contact Point Address:
  Paul W. Brandt-Rauf, Dr.P.H., M.D., ScD., Office of the Dean, School of Public Health, University of Illinois at Chicago, 1603 West Taylor Street, Chicago, IL 60612
• Email:
  pwb1@uic.edu
• CAS Registry Number:
  Vinyl chloride (CAS RN 75-01-4)
• Federal Fiscal Year:
  2015
• NORA Priority Area:
  Work Environment and Workforce: Special Populations ; Manufacturing
• Performing Organization:
  University of Illinois at Chicago
• Peer Reviewed:
  False
• Start Date:
  20010701
• Source Full Name:
  National Institute for Occupational Safety and Health
• End Date:
  20150831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:76bcb2f9c3bb6e6eab021e9941de86098de61fc57b74e68278ce0def87e09eed0ffee568b3f105ea80a2f1738691c3bf86dc126dee0594c6a46814fdb094f023
• Download URL:
  https://stacks.cdc.gov/view/cdc/218801/cdc_218801_DS1.pdf
• File Type:
  [PDF - 332.35 KB ]