This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Since 1987, we have examined over 100 DNA bases and nucleosides that are modified with carcinogenic polycyclic aromatic hydrocarbons (PAH). More recently, we have expanded the research to include potentially carcinogenic steroid hormones (e.g., estrogens). These materials share a chemical property with that of PAH;that is both materials cause modification and depurination of DNA. One aspect of the method development work is a means of highly specific biomarker detection. The hypothesis is that estrogen oxidation affords quinones that undergo Michael addion to DNA bases, causing damage and leading to mutations. We are looking at potential biomarkers that would be released by depurination. If the hypothesis is correct, the identification and quantification of estrogen metabolites, conjugates, and depurinating DNA adducts in human specimens could provide early diagnostic tools for detg. the risk of developing breast, prostate, and other human cancers. These possible biomarkers could include the estrogens E1 and E2 themselves, the catechol estrogens, methoxy catechol estrogens, catechol estrogens-GSH conjugates and/or their derivs., catechol estrogen-cysteine and catechol estrogen-N-acetylcysteine conjugates, as well as the depurinating DNA adducts 4-OHE1(E2)-1-N3-adenine (Ade), 4-OHE(E2)-1-N7-guanine, and 2-OHE1(E2)-6-N3-Ade. The anal. of estrogens and their metabolites, conjugates and depurinating DNA adducts is an area of interest for the Gross lab.
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