Implementación del Servicio Bibliotecario en Línea del CI – EPG UPC

Noncases (95% CI) (95% CI) (95% CI) Endometriosis Dioxin-like PCBs4 _{80/1071 1.18 (0.96-1.41) 1.03 (0.84-1.27) 0.97 (0.76-1.23)}+ Dioxin-like PCBs4,7 < 33rd _{29/566 1.00 1.00 1.00} 33rd _{to 66}th _{27/260 1.75 (0.82-3.73) 1.35 (0.62-3.04) 1.48 (0.62-3.51)} ≥ 66th _{24/254 1.89 (0.88-4.07) 1.20 (0.54-2.68) 1.04 (0.46-2.38)} Non- Dioxin-like PCBs5 _{79/1067 1.11 (1.02-1.21)}b _{1.04 (0.93-1.16) 1.04 (0.91-1.18)}* Non-Dioxin-like PCBs4,7 < 33rd _{30/575 1.00 1.00 1.00} 33rd _{to 66}th _{28/317 1.37 (0.77-2.44) 0.92 (0.47-1.77) 1.08 (0.50-2.34)} ≥ 66th _{27/175 2.01 (0.98-4.14) 1.22 (0.53-2.79) 1.23 (0.46-3.30)} Uterine Leiomyomas Dioxin-like PCBs4 _{80/1071 1.47 (1.27-1.71)}a _{1.12 (0.94-1.33) 1.11 (0.94-1.30)}++ Dioxin-like PCBs4,7 < 33rd _{35/550 1.00 1.00 1.00} 33rd _{to 66}th _{71/270 1.99 (1.14-3.49)}b _{1.22 (0.65-2.28) 1.24 (0.65-2.39)} ≥ 66th _{42/126 3.81 (2.22-6.54)}a _{1.59 (0.84-3.02) 1.56 (0.87-2.80)} Non- Dioxin-like PCBs5 _{79/1067 1.23 (1.15-1.31)}a _{1.05 (0.96-1.14) 1.06 (0.97-1.15)}** Non-Dioxin-like PCBs4,7 < 33rd _{36/569 1.00 1.00 1.00} 33rd _{to 66}th _{63/282 2.45 (1.55-3.85)}b _{1.20 (0.70-2.05) 1.39 (0.78-2.45)} ≥ 66th 49/147 3.62 (2.05-6.39)a 1.08 (0.70-2.05) 1.23 (0.63-2.38)

1_{Adjusted for age and race/ethnicity.}

2_{Adjusted for age, race/ethnicity, BMI, parity, age at menarche, oral contraceptive use, smoking, alcohol.} 4_{Dioxin-like PCBs: Sum of lipid adjusted and log transformed PCB Congeners (074 + 118).}

+_{Cases/noncases: 77/962;} ++_{Cases/noncases: 143/896.}

5_{Non-Dioxin-like PCBs: Sum of lipid adjusted and log transformed PCB Congeners (099+138+153+180).}

*_{Cases/noncases: 76/957;} **_{Cases/noncases: 143/890.}

153 DISCUSSION

Evidence supporting the role of PCBs in endometriosis and uterine leiomyoma is conflicting and inconclusive. Experimental animal studies have linked PCB exposure to prolonged estrus and decreased sexual receptivity in rats, decreased sperm fertilizing ability in mice (Fielden et al. 2001), decreased conception in mice, changes in the uterine myometrium and gland formation in mice (Ma and Sassoon 2006), prolonged

menstruation, decreased birth weights, and decreased conception rates in rhesus monkeys (ASTDR 2000), and a significant dose-dependent relationship in the prevalence and severity of endometriosis in rhesus monkeys (Rier et al. 2001). Although these animal studies have shown the have potential endocrine disrupting activities of PCBs, the data on their endocrine disrupting effects in humans is inconsistent (Buck Louis et al. 2005, Porpora et al. 2009, Heiler et al. 2005, Trabert et al. 2010, Pauwels et al. 2001). In this cross-sectional study of U.S. women, we evaluated the concentrations of 6 PCB

congeners, dioxin-like PCBs, and non-dioxin-like PCBs and explored the association between PCB exposure and diagnosis of endometriosis and uterine leiomyomas.

Analysis of dioxin-like PCBs and non-dioxin-like PCBs by endometriosis and uterine leiomyoma status and age and race/ethnicity was done to assess PCB

concentrations in subpopulations. Dioxin-like and non-dioxin-like PCBs showed an increasing trend with age. These results are supported by previously reported associations of PCB body burdens and age in women (Axelrad et al. 2009, Thompson et al. 2013). While this may be a result of lower levels of PCBs in the environment today, it may also be due to the persistent nature of PCBs and increased accumulations in the human body over time. Although not significant, women diagnosed with uterine leiomyomas had the

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highest dioxin-like PCB levels in the 30-39, 40-49 and 50-54 year old age groups. Non- Hispanic black women had significantly higher mean PCB levels compared to non- Hispanic white women and women classified as ‘Other’. This finding is consistent with higher PCB and DDE levels that have been previously reported among African-American women compared with non-Hispanic white women by Millikan et al. (2013) and Zheng et al. (1999), respectively. While these results do not provide any evidence of causal

associations, it is noteworthy that women diagnosed with uterine leiomyomas have higher levels of dioxin-like and non-dioxin-like PCBs and all six PCB congeners compared to women who reported never being diagnosed with uterine leiomyomas.

Our results show that women diagnosed with endometriosis have slightly higher body burdens of PCB congeners 138, 153, and 180 compared to women never diagnosed with endometriosis. Our findings of the association between endometriosis and higher body burdens of PCB congeners 138, 153, 180, and the sum of non-dioxin-like PCBs are consistent with a two previously reported case-control studies by Porpora et al. (2006 and 2009). Porpora et al. (2006) reported higher levels of total PCBs in endometriosis cases vs. controls (410 ng/g vs.250 ng/g), as well as an increased risk in involving both dioxin-like (105, 118, 156, 167) and non-dioxin-like (101, 138, 153, 170, 180) congeners, after adjusting for age and smoking. Porpora et al. (2009) found the GM of total PCBs to be significantly higher in cases than controls (301.3 vs. 203.0, p < 0.01). In contrast, Niskar et al. (2009) did not find mean lipid-adjusted PCB concentrations to be

significantly different (179.98 vs. 217.33 vs. 194.76 vs. 193.37) between stage I-II cases, stage III cases, stage IV cases, and controls, respectively. Pauwels et al. (2001) found no association between endometriosis and the median TEQ values (pg TEQ/g lipid) in cases

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and controls (29 vs. 27) and Tsukino et al.(2005) found no difference in median TEQ values for endometriosis cases (stage II-IV) and controls (stage 0-I) (cPCBs: 3.40 vs. 3.59, PCBs: 4.61 vs. 5.14), respectively.

Risk of endometriosis was only present for PCB 74 and non-dioxin-like PCBs in unadjusted logistic regression models and did not remain in any of the adjusted models. These findings are consistent with Trabert et al. (2005), who reported no association between adjusted total and estrogenic PCBs in the highest quartiles and an increased risk of endometriosis (Total PCBs: OR=1.2, 95% CI: 0.6-2.3, Estrogenic PCBs: OR=0.9, 95% CI: 0.5-1.4) after adjusting for age, lipids, income, alcohol consumption, and DDE exposure. Our findings do not agree with Buck Louis et al. (2005) who reported a significant increased risk of endometriosis for the sum of anti-estrogenic PCBs for women in the third tertile (OR=3.77, 95% CI: 1.12-12.68), however, the risk remained elevated but not significant when adjusted for all listed covariates and Porpora et al. (2009) who reported the OR of endometriosis risk in the highest tertile of total PCBs compared with the lowest tertile to be 5.63 (95% CI: 2.25-14.10).

We observed significantly higher body burdens of PCBs in women diagnosed with uterine leiomyomas and an increased risk of uterine leiomyomas in association with PCB 180 after adjusting for age, race/ethnicity, BMI, parity, age at menarche, oral contraceptive use, smoking status, and alcohol consumption. Epidemiological studies demonstrating the association between PCBs and uterine leiomyomas are lacking. Our findings are difficult to compare due to differences in the study population and methods. Findings from Lambertino et al. (2011) reported that uterine leiomyomas were

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breastfed (OR=8.6, 95% CI: 2.0-36.6) but not in women who breastfed (OR=0.80, 95% CI: .023-2.8). Qin et al. (2009) et al. found significantly higher concentrations of PCB 123 (17.8 ng/g vs.11.7 ng/g, p<0.01), 126 (21.0 ng/g vs. 10.4 ng/g, p<0.01), and 180 (13.9 ng/g vs. 6.99 ng/g, p<0.05) in the subcutaneous fat of patients compared to controls. While these results are consistent with our findings for PCB 180, they are difficult to compare because they assessed PCB concentrations in adipose tissue as opposed to serum blood.

There are a number of limitations to our study, the most important of which is its cross-sectional design with self-reported data. Self-reported data increases the risk of misclassification bias of cases and controls. It is possible that false reports or

undiagnosed endometriosis or uterine leiomyoma cases may have occurred. Furthermore, observed associations could be potentially confounded by lack of

information on geographical location of primary residence and family history of some of the variables. Strengths of this cross-sectional study design include the large sample survey size, availability of biological measurements of environmental contaminants, and oversampling of minority populations that make it highly representative and

generalizable to the U.S. population. CONCLUSION

Based on our analysis of serum blood lipid PCB levels in the 1999-2004 NHANES data cycles, biological levels of PCBs may contribute to reproductive

dysfunction among U.S. women. Given the proven contribution of unopposed estrogens to the risk for endometriosis or endometrial neoplasia, it is biologically plausible that an altered endogenous estrogen levels presumably from exposure to estrogen mimicking

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EDCs may contribute to the risk of these diseases. In conclusion, we have identified preliminary evidence suggesting that exposure to PCBs may be associated with uterine leiomyomas. Thus, further research with an epidemiologic approach is warranted to investigate reproductive health outcomes in relation to PCB exposure among women in the general population.

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162 CHAPTER VI MANUSCRIPT 3

ENDOCRINE DISRUPTING COMPOUNDS AND REPRODUCTIVE CANCERS