Estrogen-DNA Adducts and Breast Cancer Risk in Premenopausal Asian Women.

The incidence of breast cancer among premenopausal women has been increasing rapidly in recent decades in East Asia. This case-control study investigated whether estrogen-DNA adducts were associated with breast cancer risk in Taiwan. The control group (n = 146) comprised healthy female volunteers and women with non-proliferative breast disease. The case group (n = 221) comprised women either with proliferative benign breast disease or breast cancer. The ratios of estrogen-DNA adducts to their respective metabolites and conjugates in plasma were analyzed using ultraperformance LC/MS-MS. The SNPs of CYP1A1, CYP1B1, and COMT were genotyped. Logistic regression model was used to compare the estrogen-DNA adduct ratios between the two groups. The estrogen-DNA adduct ratio in the case group was significantly higher than that in the control group (median ratio: 58.52 vs. 29.36, P = 0.004). A multiple logistic regression model demonstrated that a unit increase in the natural log of the estrogen-DNA adduct ratio in premenopausal women was a significant predictor of breast cancer risk, with an estimated hazard ratio of 1.718 (1.444-2.046, P < 0.001). However, the CYP1A1, CYP1B1, and COMT SNPs were not associated with the estrogen-DNA adduct ratios. In conclusion, plasma estrogen-DNA adduct ratio was associated with the presence of breast cancer or proliferating benign breast disease in premenopausal women in Taiwan. PREVENTION RELEVANCE: This study provides evidence that endogenous estrogen-induced genotoxicity may contribute to the carcinogenesis of breast cancer in premenopausal Asian women. This work could have important preventive implication for the emerging disease in East Asia.

Breast health and reducing breast cancer risk: a functional medicine approach.

BACKGROUND/OBJECTIVE: A functional medicine approach to reduce breast cancer risk is preferable to early detection and treatment in maintaining breast health. Estrogens are implicated in breast cancer initiation through conversion to metabolites that react with DNA to form specific adducts associated with the development of breast cancer. The purpose of this study was to determine the ability of a defined clinical intervention, the AVERTi-Healthy Breast Program (AHBP), to reduce breast cancer risk conditions likely to develop into breast disease. METHODS: To obtain evidence that risk conditions in breast tissue can be reduced with a defined, multifaceted approach, this small clinical trial of 21 women measured indicators of breast health. A detailed clinical evaluation was conducted with all participants, including identification of physical symptoms, such as areas of tenderness upon palpation. Two laboratory assessments were conducted to determine the efficacy of the AHBP. First, 31 estrogen metabolites, estrogen conjugates, and depurinating estrogen-DNA adducts in urine samples taken before intervention were analyzed. The ratio of DNA adducts to metabolites and conjugates was calculated for each sample. Second, oxidative stress was analyzed by measuring the redox potential of glutathione and cysteine in blood plasma. All assessments were conducted before and after participation. RESULTS: The estrogen adduct ratio and redox potential were improved after 90 days on the AHBP. A significant mean reduction of 3.31 (p=0.03) was observed in the adduct ratio, along with a significant improvement in the redox potential of 3.80 (p=0.05). The significant change in the adduct ratio occurred in women whose oxidative stress profile also improved. CONCLUSION: These significant within-individual decreases suggest that the AHBP can reduce the risk for breast cancer in a relatively short time.

Unbalanced estrogen metabolism in ovarian cancer.

Greater exposure to estrogens is a risk factor for ovarian cancer. To investigate the role of estrogens in ovarian cancer, a spot urine sample and a saliva sample were obtained from 33 women with ovarian cancer and 34 age-matched controls. Thirty-eight estrogen metabolites, conjugates and DNA adducts were analyzed in the urine samples using ultraperformance liquid chromatography/tandem mass spectrometry, and the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen-DNA adducts to estrogen metabolites and conjugates was significantly higher in cases compared to controls (p < 0.0001), demonstrating high specificity and sensitivity. DNA was purified from the saliva samples and analyzed for genetic polymorphisms in the genes for two estrogen-metabolizing enzymes. Women with two low-activity alleles of catechol-O-methyltransferase plus one or two high-activity alleles of cytochrome P450 1B1 had higher levels of estrogen-DNA adducts and were more likely to have ovarian cancer. These findings indicate that estrogen metabolism is unbalanced in ovarian cancer and suggest that formation of estrogen-DNA adducts plays a critical role in the initiation of ovarian cancer.

Unbalanced estrogen metabolism in thyroid cancer.

Well-differentiated thyroid cancer most frequently occurs in premenopausal women. Greater exposure to estrogens may be a risk factor for thyroid cancer. To investigate the role of estrogens in thyroid cancer, a spot urine sample was obtained from 40 women with thyroid cancer and 40 age-matched controls. Thirty-eight estrogen metabolites, conjugates and DNA adducts were analyzed by using ultraperformance liquid chromatography/tandem mass spectrometry and the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen-DNA adducts to estrogen metabolites and conjugates significantly differed between cases and controls (p < 0.0001), demonstrating high specificity and sensitivity. These findings indicate that estrogen metabolism is unbalanced in thyroid cancer and suggest that formation of estrogen-DNA adducts might play a role in the initiation of thyroid cancer.

Atrazine and nitrate in public drinking water supplies and non-hodgkin lymphoma in nebraska, USA.

A secondary analysis of 1999-2002 Nebraska case-control data was conducted to assess the risk of non-Hodgkin lymphoma (NHL) associated with exposure to nitrate- and atrazine-contaminated drinking water. Water chemistry data were collected and weighted by well contribution and proximity of residence to water supply, followed by logistic regression to determine odds ratios (OR) and 95% confidence intervals (CI). We found no association between NHL risk and exposure to drinking water containing atrazine or nitrate alone. Risk associated with the interaction of nitrate and atrazine in drinking water was elevated (OR, 2.5; CI, 1.0-6.2). Risk of indolent B-cell lymphoma was higher than risk of aggressive B-cell lymphoma (indolent: OR, 3.5; CI, 1.0-11.6 vs. aggressive: OR, 1.9; CI, 0.6-5.58). This increased risk may be due to in vivo formation and subsequent metabolism of N-nitrosoatrazine. A larger study is warranted to confirm our findings.

Evaluation of serum estrogen-DNA adducts as potential biomarkers for breast cancer risk.

This study was conducted to determine whether the ratio of estrogen-DNA adducts to their respective metabolites and conjugates in serum differed between women with early-onset breast cancer and those with average or high risk of developing breast cancer. Serum samples from women at average risk (n=63) or high risk (n=80) for breast cancer (using Gail model) and women newly diagnosed with early breast cancer (n=79) were analyzed using UPLC-MS/MS. Adduct ratios were statistically compared among the three groups, and the Area Under the Receiver Operating Characteristic Curve (AUC) was used to identify a diagnostic cut-off point. The median adduct ratio in the average-risk group was significantly lower than that of both the high-risk group and the breast cancer group (p values<0.0001), and provided good discrimination between those at average versus high risk of breast cancer (AUC=0.84, 95% CI 0.77-0.90). Sensitivity and specificity were maximized at an adduct ratio of 77. For women in the same age and BMI group, the odds of being at high risk for breast cancer was 8.03 (95% CI 3.46-18.7) times higher for those with a ratio of at least 77 compared to those with a ratio less than 77. The likelihood of being at high risk for breast cancer was significantly increased for those with a high adduct ratio relative to those with a low adduct ratio. These findings suggest that estrogen-DNA adducts deserve further study as potential biomarkers for risk of developing breast cancer.

Imbalanced estrogen metabolism in the brain: possible relevance to the etiology of Parkinson's disease.

Damage to DNA by dopamine quinone and/or catechol estrogen quinones may play a significant role in the initiation of Parkinson's disease (PD). Depurinating estrogen-DNA adducts are shed from cells and excreted in urine. The aim of this study was to discover whether higher levels of estrogen-DNA adducts are associated with PD. Forty estrogen metabolites, conjugates, and DNA adducts were analyzed in urine samples from 20 PD cases and 40 matched controls by using ultra performance liquid chromatography/tandem mass spectrometry. The levels of adducts in cases versus controls (P < 0.005) suggest that unbalanced estrogen metabolism could play a causal role in the initiation of PD.

Depression and pesticide exposures among private pesticide applicators enrolled in the Agricultural Health Study.

BACKGROUND: We evaluated the relationship between diagnosed depression and pesticide exposure using information from private pesticide applicators enrolled in the Agricultural Health Study between 1993 and 1997 in Iowa and North Carolina. METHODS: There were 534 cases who self-reported a physician-diagnosed depression and 17,051 controls who reported never having been diagnosed with depression and did not feel depressed more than once a week in the past year. Lifetime pesticide exposure was categorized in three mutually exclusive groups: low (< 226 days, the reference group), intermediate (226-752 days), and high (> 752 days). Two additional measures represented acute high-intensity pesticide exposures: an unusually high pesticide exposure event (HPEE) and physician-diagnosed pesticide poisoning. Logistic regression analyses were performed relating pesticide exposure to depression. RESULTS: After adjusting for state, age, education, marital status, doctor visits, alcohol use, smoking, solvent exposure, not currently having crops or animals, and ever working a job off the farm, pesticide poisoning was more strongly associated with depression [odds ratio (OR) = 2.57; 95% confidence interval (CI), 1.74-3.79] than intermediate (OR = 1.07; 95% CI, 0.87-1.31) or high (OR = 1.11; 95% CI, 0.87-1.42) cumulative exposure or an HPEE (OR = 1.65; 95% CI, 1.33-2.05). In analysis of a subgroup without a history of acute poisoning, high cumulative exposure was significantly associated with depression (OR = 1.54; 95% CI, 1.16-2.04). CONCLUSION: These findings suggest that both acute high-intensity and cumulative pesticide exposure may contribute to depression in pesticide applicators. Our study is unique in reporting that depression is also associated with chronic pesticide exposure in the absence of a physician-diagnosed poisoning.