The objective of this proposal is to develop new biomonitoring methodologies designed to measure DNA adducts in tissues of humans exposed to chemical carcinogens. Our chemical model for this project is structurally related nitro-phenanthrene carboxylic acids, a class of human carcinogens and nephrotoxicants that include aristolochic acids (AA). These compounds are universally present in herbs of the genus Aristolochia, used for medicinal purposes throughout the world for 2000 years. The nephrotoxicity and carcinogenicity of herbs containing AA are very well documented. Epidemiologic studies reveal AA to be the causal agent for the clinical syndromes known as Chinese herb and Balkan endemic nephropathies. In the latter, exposure to AA involves ingestion of bread prepared from flour contaminated with seeds of Aristolochia clematitis. Due to their toxicities, importation of traditional Chinese herbs containing AA are banned in some, but not all countries. Despite the Food and Drug Administration's warnings concerning the safety of botanical remedies containing AA, these herbs are still widely distributed in the United States via the Internet, and the incidence of chronic renal failure and urothelial cancer worldwide attributed to exposure to AA remains very high. Recently, we provided unequivocal evidence for the presence of AA-DNA adducts in the renal cortex of patients affected by BEN, using a novel, multi-stage ion trap mass spectrometry (MSn) method. Quantitative MS methods are essential for measuring DNA adduct biomarkers of this devastating and uniformally fatal disease. The biomonitoring methods will be used in translational research studies conducted in Balkan countries where the residents have dietary exposure to AA. A critical technological advance in DNA adduct screening methodologies will be achieved by extending the analysis of AA-DNA adducts from freshly frozen tissue samples to archived, formalin-fixed renal tissues, an untapped but rich source of material for toxico- logical research. Finally, a novel screening method will be established, employing an automated chip-based infusion nano-electrospray tandem MS method. This technique will provide a rapid throughput and cost- effective method to screen for DNA adducts in population-based studies. Traditional herbal remedies containing carcinogenic AA are used worldwide and are a global health problem. Recent epidemiological studies have linked herbs containing AA with renal failure and cancer. Rapid and quantitative analytical MS data to screen for AA-DNA adducts are needed to assess the exposure and the causal role of AA in nephropathy and upper urothelial cancer risk. The AA-DNA adducts also serve as critical biomarkers in studies of genetic susceptibility to Balkan endemic nephropathy and its associated upper urothelial cancer. The novel biomonitoring techniques established in this application can be appllied to examine the role of other chemical carcinogens in the etiology of human cancer.

Public Health Relevance

Novel mass spectrometry biomonitoring methods will be established to measure DNA adducts of aristolochic acids (AA), potent nephrotoxicants and carcinogens found in herbs of the genus Aristolochia, which have been used for medicinal purposes world-wide. These novel screening techniques will be employed to measure AA-DNA adducts in human populations exposed to AA and diagnosed with upper urothelial cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
7R01ES019564-04
Application #
8738198
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Balshaw, David M
Project Start
2011-02-01
Project End
2015-01-31
Budget Start
2013-09-19
Budget End
2015-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$339,680
Indirect Cost
$104,882
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Balbo, Silvia; Turesky, Robert J; Villalta, Peter W (2014) DNA adductomics. Chem Res Toxicol 27:356-66
Yun, Byeong Hwa; Yao, Lihua; Jelakovi?, Bojan et al. (2014) Formalin-fixed paraffin-embedded tissue as a source for quantitation of carcinogen DNA adducts: aristolochic acid as a prototype carcinogen. Carcinogenesis 35:2055-61
Yun, Byeong Hwa; Rosenquist, Thomas A; Nikolic, Jovan et al. (2013) Human formalin-fixed paraffin-embedded tissues: an untapped specimen for biomonitoring of carcinogen DNA adducts by mass spectrometry. Anal Chem 85:4251-8
Hoang, Margaret L; Chen, Chung-Hsin; Sidorenko, Viktoriya S et al. (2013) Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing. Sci Transl Med 5:197ra102
Jelakovic, Bojan; Karanovic, Sandra; Vukovic-Lela, Ivana et al. (2012) Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid. Kidney Int 81:559-67
Chen, Chung-Hsin; Dickman, Kathleen G; Moriya, Masaaki et al. (2012) Aristolochic acid-associated urothelial cancer in Taiwan. Proc Natl Acad Sci U S A 109:8241-6
Yun, Byeong Hwa; Rosenquist, Thomas A; Sidorenko, Viktoriya et al. (2012) Biomonitoring of aristolactam-DNA adducts in human tissues using ultra-performance liquid chromatography/ion-trap mass spectrometry. Chem Res Toxicol 25:1119-31