Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


ucin1076103320.pdf (745.09 KB)

ETD Abstract Container

Abstract Header

IRON AS A CO-FACTOR IN CHROMIUM MUTAGENESIS AND CARCINOGENESIS

SONNTAG, DAVID M
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1076103320

Abstract Details

2004, PhD, University of Cincinnati, Medicine : Environmental Health Sciences.
Iron is the most abundant transition metal in the body and on earth. Its ability to cause or promote DNA damage is therefore important for environmental mutagenesis and carcinogenesis. Iron's complex biology makes this a challenging task, requiring a multidisciplinary approach that considers both internal targets and external sources. Since in vitro evidence suggests iron potentiates oxidative DNA damage by chromate, this study examined internal mechanisms by which iron could promote chromium DNA damage, and identified external sources of co-exposure to the two metals. Mice exposed by intratracheal instillation showed greater chromium deposition and lacI transgene mutations in lung, liver and kidney. The mutational spectrum resembled that of hydrogen peroxide, suggesting Fenton-related chemistry. Similarity of human tumor p53 mutational spectra to lacI chromate spectra for large cell lung tumors, renal cell carcinoma, and cholangiocarcinoma could not be ruled out. An in silico model using lacI and p53 mutation databases was developed and validated to determine whether mutations cluster potential iron binding (PIB) DNA motifs. There was a significant association between PIB motifs and mutational odds, not only for chromate, but also for other compounds, some not thought to directly cause oxidative DNA damage. Randomly simulated mutations had no association with PIB motifs. Chromate induces oxidative damage at motifs susceptible to chromosomal instability, which is the predominant type of damage observed in chromate-linked cancers. The known ability of iron-binding to alter DNA strand conformation, viscosity and electrostatic charge may explain how iron promotes carcinogenicity of so many agents, many of which do not cause direct oxidative DNA damage. Iron’s ability to promote chromate damage raises concerns about workplace co-exposures to the two metals. Department of Labor data from 40,000 individuals revealed patterns of co-exposure to iron and chromium from 1990-2000. Steel and cement industries—both noted for increased lung cancer risk, showed the highest co-exposures. Job tasks with the highest co-exposures were painting and welding, also noted for increased cancer risk. Since the Department of Labor agrees that the current chromate exposure limit is too high, these findings can be used in future cancer biomarker studies and exposure interventions.
Dr. Glenn Talaska (Advisor)
133 p.
Health Sciences, General
Iron; chromium; mutagenesis; carcinogenesis

Recommended Citations

Citations

  • SONNTAG, D. M. (2004). IRON AS A CO-FACTOR IN CHROMIUM MUTAGENESIS AND CARCINOGENESIS [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1076103320

    APA Style (7th edition)

  • SONNTAG, DAVID. IRON AS A CO-FACTOR IN CHROMIUM MUTAGENESIS AND CARCINOGENESIS. 2004. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1076103320.

    MLA Style (8th edition)

  • SONNTAG, DAVID. "IRON AS A CO-FACTOR IN CHROMIUM MUTAGENESIS AND CARCINOGENESIS." Doctoral dissertation, University of Cincinnati, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1076103320

    Chicago Manual of Style (17th edition)

ucin1076103320
953
© 2004, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.