Estrogens can become endogenous carcinogens via formation of catechol estrogen quinones, which react with DNA to form specific depurinating estrogen-DNA adducts. The mutations resulting from these adducts can lead to cell transformation and the initiation of breast cancer. Estrogen metabolites, conjugates and depurinating DNA adducts in urine samples from 46 healthy control women, 12 high-risk women and 17 women with breast cancer were analyzed. The estrogen metabolites, conjugates and depurinating DNA adducts were identified and quantified by using ultraperformance liquid chromatography/tandem mass spectrometry. The levels of the ratios of depurinating DNA adducts to their respective estrogen metabolites and conjugates were significantly higher in high-risk women (p < 0.001) and women with breast cancer (p < 0.001) than in control subjects. The high-risk and breast cancer groups were not significantly different (p 5 0.62). After adjusting for patient characteristics, these ratios were still significantly associated with health status. Thus, the depurinating estrogen-DNA adducts are possible biomarkers for early detection of breast cancer risk and response to preventive treatment. ' 2007 Wiley-Liss, Inc.Key words: breast cancer risk; depurinating estrogen-DNA adducts; estrogen biomarkers; balance in estrogen metabolism Development of noninvasive tests of breast cancer risk has been a major goal for more than 30 years. In this article we present biomarkers of risk that are related to the hypothesized first critical step in the initiation of breast cancer, namely, the reaction of catechol estrogen quinone metabolites with DNA.1 Prevention of cancer can be achieved by blocking this DNA damage, which generates the mutations leading to the initiation, promotion and progression of cancer. 2Exposure to estrogens is a known risk factor for breast cancer.3,4 The discovery that specific oxidative metabolites of estrogens, namely, catechol estrogen quinones, can react with DNA [5][6][7][8][9] led to and supports the hypothesis that these metabolites can become endogenous chemical carcinogens. Some of the mutations generated by this specific DNA damage can result in the initiation of cancer. 1,5 This paradigm suggests that specific, critical mutations generate abnormal cell proliferation leading to cancer. 1,[10][11][12][13] As illustrated in Figure 1, in the metabolism of catechol estrogens there are activating pathways 14 that lead to the formation of the estrogen quinones, estrone (estradiol) quinones [E 1 (E 2 )-Q], which can react with DNA. There are also deactivating pathways that limit formation of the quinones and/or prevent their reaction with DNA. These are methylation of catechol estrogens, 15 conjugation of the E 1 (E 2 )-Q with glutathione (GSH) 16 and reduction of the quinones to catechols 17 (Fig. 1). When E 1 (E 2 )-3,4-Q react with DNA, they form predominantly the depurinating adducts 4-hydroxyestrone(estradiol)-1-N3Ade-nine [4-OHE 1 (E 2 )-1-N3Ade] and 4-hydroxyestrone(estradiol)-1-N7Guanine [4-OHE 1 (E 2...

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Endogenous estrogens can be bio-activated to endogenous carcinogens via formation of estrogen quinones. Estrogen-3,4-quinones react with DNA to form mutagenic depurinating estrogen-DNA adducts. The carcinogenicity of endogenous estrogens is related to unbalanced estrogen metabolism leading to excess estrogen quinones and formation of depurinating DNA adducts. The present studies were initiated to confirm that relatively high levels of depurinating estrogen-DNA adducts are present in women at high risk for breast cancer or diagnosed with the disease. These adducts may be biomarkers for early detection of breast cancer risk. The estrogen metabolites, conjugates and depurinating DNA adducts were identified and quantified by using ultraperformance liquid chromatography/tandem mass spectrometry to analyze urine samples from 40 healthy control women, 40 high-risk women and 40 women with newly diagnosed breast cancer. Estrogen metabolism was shifted from protective methoxylation and conjugation pathways in healthy control women towards activating pathways leading to formation of depurinating DNA adducts in women at high risk or with breast cancer. These results support the hypothesis that breast cancer is initiated by mutations derived from depurination of estrogen-DNA adducts. Therefore, relative levels of depurinating estrogen-DNA adducts could become biomarkers for early detection of breast cancer risk and aid in determining preventive strategies.

Effective treatment and reuse of the massive quantities of agricultural and food wastes generated daily has the potential to improve the sustainability of food production systems. Anaerobic digestion (AD) is used throughout the world as a waste treatment process to convert organic waste into two main products: biogas and nutrient-rich digestate, called AD effluent. Biogas can be used as a source of renewable energy or transportation fuels, while AD effluent is traditionally applied to land as a soil amendment. However, there are economic and environmental concerns that limit widespread land application, which may lead to underutilization of AD for the treatment of agricultural and food wastes. To combat these constraints, existing and novel methods have emerged to treat or reuse AD effluent. The objective of this review is to analyze several emerging methods used for efficient treatment and reuse of AD effluent. Overall, the application of emerging technologies is limited by AD effluent composition, especially the total solid content. Some technologies, such as composting, use the solid fraction of AD effluent, while most other technologies, such as algae culture and struvite crystallization, use the liquid fraction. Therefore, dewatering of AD effluent, reuse of the liquid and solid fractions, and land application could all be combined to sustainably manage the large quantities of AD effluent produced. Issues such as pathogen regrowth and prevalence of emerging organic micro-pollutants are also discussed.

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With the properties of efficacy, safety, tolerability, practicability and low cost, foods containing bioactive phytochemicals are gaining significant attention as elements of chemoprevention strategies against cancer. Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane], a naturally occurring isothiocyanate produced by cruciferous vegetables such as broccoli, is found to be a highly promising chemoprevention agent against not only variety of cancers such as breast, prostate, colon, skin, lung, stomach or bladder carcinogenesis, but also cardiovascular disease, neurodegenerative diseases, and diabetes. For reasons of experimental exigency, pre-clinical studies have focused principally on sulforaphane itself, while clinical studies have relied on broccoli sprout preparations rich in either sulforaphane or its biogenic precursor, glucoraphanin. Substantive subsequent evaluation of sulforaphane pharmacokinetics and pharmacodynamics has been undertaken using either pure compound or food matrices. Sulforaphane affects multiple targets in cells. One key molecular mechanism of action for sulforaphane entails activation of the Nrf2-Keap1 signaling pathway although other actions contribute to the broad spectrum of efficacy in different animal models. This review summarizes the current status of pre-clinical chemoprevention studies with sulforaphane and highlights the progress and challenges for the application of foods rich in sulforaphane and/or glucoraphanin in the arena of clinical chemoprevention.