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We present a combined environmental epidemiologic, genomic, and bioinformatics approach to identify: exposure of environmental chemicals with estrogenic activity; epidemiologic association between endocrine disrupting chemical (EDC) and health effects, such as, breast cancer or endometriosis; and gene-EDC interactions and disease associations. Human exposure measurement and modeling confirmed estrogenic activity of three selected class of environmental chemicals, polychlorinated biphenyls (PCBs), bisphenols (BPs), and phthalates. Meta-analysis showed that PCBs exposure, not Bisphenol A (BPA) and phthalates, increased the summary odds ratio for breast cancer and endometriosis. Bioinformatics analysis of gene-EDC interactions and disease associations identified several hundred genes that were altered by exposure to PCBs, phthalate or BPA. EDCs-modified genes in breast neoplasms and endometriosis are part of steroid hormone signaling and inflammation pathways. All three EDCs–PCB 153, phthalates, and BPA influenced five common genes—CYP19A1, EGFR, ESR2, FOS, and IGF1—in breast cancer as well as in endometriosis. These genes are environmentally and estrogen responsive, altered in human breast and uterine tumors and endometriosis lesions, and part of Mitogen Activated Protein Kinase (MAPK) signaling pathways in cancer. Our findings suggest that breast cancer and endometriosis share some common environmental and molecular risk factors.

Introduction: Estrogen is a driver in the growth and progression of gynecologic cancers (cervical, ovarian, and uterine). A number of estrogenically active chemicals are suspected to contribute in the development of gynecologic lesions, including an increased risk of estrogen-dependent cancer in women. Humans are exposed to estrogenic endocrine disruptors (EEDs), such as-polychlorinated biphenyls (PCBs), phthalates and bisphenol A (BPA). Therefore, we examined the cross-sectional relationship between exposure to PCBs, phthalates, and BPA and gynecologic cancers (cervical, ovarian, and uterine). Methods: We analyzed data from female participants (20 years of age and older) who provided blood and urine samples for the Centers for Disease Control and Prevention's National Health and Nutrition Examination Survey (NHANES) between 1999 and 2010. Exposure was examined based on lipid adjusted serum levels of 6 individual PCB congeners (74, 99, 118, 138, 153, and 180), the sum of dioxin-like PCBs (074 and 118), the sum of non-dioxinlike PCBs (099+138+153+187), 8 urinary phthalate metabolites (MNP, MEP, MEHP, MBzP, MCPP, MEHHP, MEOHP, and MIB), the sum of DEHP metabolites (MHP+MHH+MOH), the sum of total phthalates, and urinary BPA in conjunction with data obtained from the medical and reproductive health questionnaires. We calculated geometric means to compare EEDs concentrations in women who self-reported a cervical, ovarian, or uterine cancer diagnosis vs. women who self-reported never being diagnosed with cancer. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between exposure to EEDs and r gynecologic cancers. We also evaluated age, race/ethnicity, body mass index (BMI; kg/m 2), and age at menarche as potential confounding variables in our final models. Results: Separate analyses showed weighted geometric mean (GM) levels of individual PCB congeners to be significantly higher among women with ovarian cancer, and uterine cancer when compared to the rest of the study population. Mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) was found to be significantly higher and BPA was higher among women with ovarian cancer compared to women never diagnosed with any gynecologic cancer. After adjusting for age, race, BMI, and age at menarche, we found that PCB 138 was significantly associated with cervical cancer, and uterine cancer [odds ratios of 3.05, 95% CI: 1.21-7.69; and 5.83, 95% CI: 1.63-20.9], respectively. PCB 74 and 118 however, were significantly associated with ovarian cancer with an odds ratios of 6.47, 95% CI: 1.23-3.41 (for PCB 74) and 6.68, 95% CI: 1.39-32.3 (for PCB 118). We also found the sum of non-dioxin-like PCBs to be significantly associated with uterine cancer (OR of 1.12, 95% CI: 1.03-1.23) and the sum of dioxin-like PCBs to be significantly associated with ovarian cancer (OR of 2.02, 95% CI: 1.06-3.85). We did not find significant associations between urinary phthalates and BPA and gynecologic cancers. Conclusions: Our findings point to...

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The main objective of this study was to examine the cross-sectional relationship between exposure to PCBs or their congeners and breast cancer among US women. There is limited information on the association of specific PCB congener or their combination levels in blood serum with increased breast cancer risk. PCBs are weak estrogens which has been shown to act as endocrine disrupters by increasing or blocking estrogen like activities in animals and humans. We analyzed National Health and Nutrition Examination Survey (NHANES) data from 1999-2004 in the lipid adjusted blood samples of female participants (>20 years of age). Exposure assessment was based on lipid adjusted serum levels of 6 individual PCB congeners (PCB 074, 099, 118, 138, 153, and 180), the sum of dioxin-like PCBs (074 and 118), and the sum of non-dioxin-like PCBs (099 + 138 + 153+187) in conjunction with data obtained from the medical and reproductive health questionnaires. We calculated geometric means to compare PCB concentrations in women's blood samples who also self-reported a breast cancer diagnosis and women who were never diagnosed with cancer. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the association between PCB, their congener or their combinations and breast cancer. We evaluated age, race/ethnicity, age at menarche, body mass index (BMI; kg/m2), and lactation as potential confounders. Our results show a weighted geometric mean levels of 6 PCB congeners to be significantly higher in blood serum among women with breast cancer when compared to the rest of the study population. After adjusting for age, race, BMI, lactation, and age at menarche we found significant association of PCB 138 with breast cancer [odds ratios of 2.88; 95% confidence interval (CI): 1.14-7.30; 2.93, 95% CI: 1.04-8.26; and 3.43, 95% CI: 1.12-10.4] in women with higher body burdens of individual PCB congeners (> 50th percentile, 50th-75th percentile, and ≥75th percentile), respectively. After adjusting for age and race, it was also found that the sum of non-dioxin-like PCBs (074 and 118) in blood serum is significantly associated with breast cancer [OR of 1.14; 95% CI: 1.00-1.29]. In summary, our results suggest a possible link between environmental exposures to PCBs and increased risk of breast cancer among U.S. women. Citation Format: Marisa Morgan, Alok Deoraj, Deodutta Roy. Association between serum concentrations of polychlorinated biphenyls (PCBs) and increased risk of breast cancer among US women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3433.