Prostate cancer is the most frequently diagnosed malignancy and second leading cause of cancer-related death among men in the United States. Identifying risk factors of this disease and developing strategies for prevention are critical. A number of epidemiologic studies have reported an association between frequent consumption of well-done cooked meats, containing the heterocyclic aromatic amine (HAA) 2-amino-1-methyl- 6-phenylimidazo[4,5-b]pyridine (PhIP) and prostate cancer risk. PhIP is a potent rodent prostate carcinogen, and it induces oxidative stress, atrophy of the acini, and inflammation of the prostate. These are critical features that occur in human prostate carcinogenesis. A paradigm has been put forth for a causal role of consumption of well-done cooked meats containing PhIP (and other HAAs) in the etiology of prostate cancer;however, biomarkers of exposure and DNA damage are lacking to validate this model. Our long-term goal is to assess the cancer risk posed by HAAs, by employing chemical markers that may distinguish individuals at different levels of risk. In this grant renewal, our objective is to assess dietary exposure to PhIP and its potential to induce damage to DNA in the prostate in relation to other HAAs, meat genotoxicants, and endogenous electrophiles produced in the cell, by employing mass spectrometric (MS)- based methods to measure genotoxicants and identify their biomarkers of DNA damage in the prostate. We will implement our recently established biomarkers of HAAs and other cooked meat genotoxicants and their DNA adduction products in cohorts of African American and Caucasian men with benign prostate hyper- plasia or prostate cancer who frequently eat well-done cooked meat.
In Aim 1) HAA exposure will be assessed by measurement of HAAs accrued in hair;DNA adducts of HAAs, other meat genotoxicants, and endogenous electrophiles, will be determined by different MS scanning methods, in prostate.
In Aim 2) Formalin-fixed paraffin embedded prostate tissue, an underutilized biospecimen in biomonitoring DNA damage, will be employed to screen for HAA-DNA adducts in subjects undergoing prostatectomy. Adduct levels will be compared to those values obtained by current but non-specific immunohistochemical techniques. MS methods will also be implemented to measure PhIP-serum albumin adducts as long-lived biomarkers of the biologically effective dose.
In Aim 3) we will conduct high density genotyping of genes encoding enzymes involved carcinogen metabolism that may impact DNA damage in the prostate. Prostate HAA-DNA adduct levels will be correlated to HAA levels in hair;the levels of HAA and other DNA adducts in prostate will be correlated to genotypes of phase I and II xenobiotic metabolism enzymes, which impact biological activity. Our findings will provide direct measurement of DNA damage and assess the relative contribution of HAAs, other cooked meat genotoxicants and endogenous electrophiles to the genetic damage of DNA in the prostate.
The cooking of meat well-done produces heterocyclic aromatic amines (HAAs), which are prostate carcinogens in experimental animals and potential human carcinogens. The quantitative measurement of HAA exposure and identification of mutation-prone DNA adducts of HAAs in the human prostate would strengthen the biological plausibility for a role of HAAs in the etiology of prostate cancer. With these data in hand, educational and primary cancer prevention efforts may be devised because there are methods of cooking meats that do not lead to substantial formation of hazardous HAAs.
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