Bladder cancer (BC) is the fourth most common cancer in men with more than 70,000 new cases and 14,680 deaths in 2010. Major risk factors of BC include tobacco smoking and occupational exposure to aromatic amines in the dye and rubber industries. These exposures are thought to account for about 50% of bladder cases. Several epidemiological studies have linked the consumption of well-done cooked meat containing structurally related heterocyclic aromatic amines (HAAs) with BC risk. Endogenous lipid peroxidation products also may contribute to bladder mutagenesis. However, the specific chemicals that contribute to BC are largely unknown. Urine is a promising biospecimen for the analysis of cancer biomarkers. For example, vesicles (exosomes) excreted in urine serve as carriers of genetic information and a novel source of cancer biomarkers. We propose that exfoliated urinary cells also may serve as a non-invasive biospecimen to assess DNA damage of the upper and lower urinary tract. The goal of this grant renewal, New biomonitoring methodologies to measure DNA adducts in human tissues is to validate exfoliated urinary cells as a source of specimen to assess exposures to chemicals, some of which may contribute to upper urothelial cancer (UUC) and BC. We will examine DNA adducts formed in exfoliated urinary cells and in urothelial tissues from exposure to environmental, dietary, medicinal, and endogenous genotoxicants. Our preliminary data demonstrate that DNA adducts of aristolochic acid (AA), a urothelial carcinogen found in traditional Chinese medicine (TCM) or as a contaminant of flour, can be quantified in exfoliated urinary cells, by ultraperformance liquid chromatography/multistage scan mass spectrometry (UPLC/MSn), a method with superior sensitivity to that of the commonly used but non-specific 32P-postlabeling assay. We propose to use exfoliated urinary cells as a noninvasive source of biospecimen to assess DNA damage, using UPLC/MSn, in the upper urothelium and/or bladder of subjects at risk of developing UUC and BC.
In Aim 1, we examine DNA adducts of AA in urothelial tissues and exfoliated urothelial cells of subjects exposed to AA via TCM or contaminated bread.
In Aim 2, we establish techniques to measure DNA adducts of other genotoxicants, that can damage bladder, including aromatic amines, HAAs, and lipid peroxides in the urothelium and urinary cells of mice exposed to these chemicals or to tobacco smoke, using targeted and adductomics scanning approaches.
In Aim 3, MS methods are applied to measure DNA adducts formed in urothelium and exfoliated urinary cells of patients who have undergone cystectomy for BC, and urinary cells of non-smokers and smokers. Our proposed research is highly relevant to the NIEHS mission, which is to understand how environmental exposures contribute to health outcomes. Exfoliated urinary cells are an untapped biospecimen that can be used to screen for damage to DNA induced by chemicals that contribute to the etiology of BC.

Public Health Relevance

Exfoliated urinary cells are a largely untapped, noninvasive source of biospecimens for assessment of DNA damage of the urothelium caused by hazardous chemicals in the environment, tobacco smoke, diet, medicines, or by endogenously produced electrophiles. We will establish robust mass spectrometry-based assays employing exfoliated urinary cells to screen for DNA adducts of these chemicals. This novel biomonitoring approach can help to identify the major chemicals that damage DNA and contribute to the etiology of bladder and upper urinary tract cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES019564-05A1
Application #
9106110
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Balshaw, David M
Project Start
2011-02-01
Project End
2021-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Guo, Jingshu; Villalta, Peter W; Weight, Christopher J et al. (2018) Targeted and Untargeted Detection of DNA Adducts of Aromatic Amine Carcinogens in Human Bladder by Ultra-Performance Liquid Chromatography-High-Resolution Mass Spectrometry. Chem Res Toxicol :
Yun, Byeong Hwa; Bellamri, Medjda; Rosenquist, Thomas A et al. (2018) Method for Biomonitoring DNA Adducts in Exfoliated Urinary Cells by Mass Spectrometry. Anal Chem 90:9943-9950
Yun, Byeong Hwa; Guo, Jingshu; Turesky, Robert J (2018) Formalin-Fixed Paraffin-Embedded Tissues-An Untapped Biospecimen for Biomonitoring DNA Adducts by Mass Spectrometry. Toxics 6:
Hwa Yun, Byeong; Guo, Jingshu; Bellamri, Medjda et al. (2018) DNA adducts: Formation, biological effects, and new biospecimens for mass spectrometric measurements in humans. Mass Spectrom Rev :
Springer, Simeon U; Chen, Chung-Hsin; Rodriguez Pena, Maria Del Carmen et al. (2018) Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy. Elife 7:
Guo, Jingshu; Villalta, Peter W; Turesky, Robert J (2017) Data-Independent Mass Spectrometry Approach for Screening and Identification of DNA Adducts. Anal Chem 89:11728-11736
Yun, Byeong Hwa; Xiao, Shun; Yao, Lihua et al. (2017) A Rapid Throughput Method To Extract DNA from Formalin-Fixed Paraffin-Embedded Tissues for Biomonitoring Carcinogenic DNA Adducts. Chem Res Toxicol 30:2130-2139
Hoang, Margaret L; Chen, Chung-Hsin; Chen, Pau-Chung et al. (2016) Aristolochic Acid in the Etiology of Renal Cell Carcinoma. Cancer Epidemiol Biomarkers Prev 25:1600-1608
Guo, Jingshu; Turesky, Robert J (2016) Human Biomonitoring of DNA Adducts by Ion Trap Multistage Mass Spectrometry. Curr Protoc Nucleic Acid Chem 66:7.24.1-7.24.25
Turesky, Robert J; Yun, Byeong Hwa; Brennan, Paul et al. (2016) Aristolochic acid exposure in Romania and implications for renal cell carcinoma. Br J Cancer 114:76-80

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