Endometriosis and Organochlorinated Environmental Pollutants: A Case–Control Study on Italian Women of Reproductive Age

The possible role of the exposure to environmental chemicals as a co-causal factor in the etiology of endometriosis has been the object of scientific debate in the last 20 years. Endometriosis is a common gynecologic disease characterized by the ectopic growth of endometrial tissue and is often associated with pelvic pain and/or infertility. It affects approximately 10% of women of reproductive age in Italy as well as in other industrialized countries (Eskenazi and Warner 1997; Gruppo Italiano per lo Studio dell’Endometriosi 1994), and its prevalence and severity are reported to be increasing in developing countries (Donnez et al. 2002). Its etiology is unclear, although a multifactorial origin, resulting from the contribution of immunologic, genetic, and environmental factors, is considered to be most plausible. The hypothesis that exposure to immunotoxic endocrine-disrupting environmental pollutants could play a role in the disease etiology first arose from the study of Rier and coworkers (Rier et al. 1993). These authors observed a dose-dependent increase of incidence and severity of spontaneous endometriosis in a colony of monkeys chronically exposed to dioxin [2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD)], the most toxic member of the family of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), 210 different molecules or congeners generally referred to as dioxins. Although criticized by some scientists (Guo 2004; Hitchin 1994), this study opened the way to a number of studies on the relationship between the disease and environmental pollutants. Major criticism involved the incidental nature of the observation—endometriosis was not a prospectively defined end point of the experiment, and its presence in monkeys was observed many years after the end of the treatment—and appropriateness of statistical analysis of the results. The small sample size (24 animals assigned to three groups of 8 animals each), the limited values of dioxin exposure levels (a low-dose and a high-dose group), and the use of linear regression and t-test based on normality assumption were the study elements deemed to be more critical in interpreting study results. Together with dioxins, polychlorinated biphenyls (PCBs), a family of persistent and bioaccumulative industrial compounds widely used until the 1980s, have been the pollutants principally investigated as to their possible role in the disease onset or progression. In the general population, diet accounts for over 90% of total exposure to dioxins and PCBs. PCBs comprise 209 different congeners which, according to the structure, are grouped into 12 dioxin-like PCB (DL-PCB) congeners, with no or only one chlorine in the ortho position, and non-dioxin-like PCBs (NDL-PCBs), characterized by the presence of two or more chlorines in the ortho positions. The latter are normally much more abundant than DL-PCBs in environmental, food, and human specimens. The most abundant congeners in human tissues include NDL-PCBs 28, 52, 101, 138, 153, and 180—referred to as ‘‘indicators’’ (Appel 2003) because conventionally they are used to estimate the overall PCB content in specimens of biological origin (EFSA 2005)—along with a few others such as DL-PCB-105, DL-PCB-118, DL-PCB-156, and DL-PCB-167, and NDL-PCB-170, PCB-138, PCB-153, and PCB-180, are prevalent in all human tissues and account for 50–80% of total PCB content in serum (Glynn et al. 2000). DL-PCBs have been the first PCB congeners to be considered in association with endometriosis because, as dioxins, they bind to the aryl hydrocarbon receptor (AhR) and elicit the same spectrum of toxic activities through the same mechanism of action. Indeed, DL-PCBs, rather than dioxins, were suggested to be associated with an endometriotic effect (Rier et al. 2001) when blood samples from exposed monkeys were analyzed years after the experiment was completed and significant concentrations of these compounds were detected, possibly originating from contaminated food. On the epidemiologic side, several studies have been conducted to investigate the potential relationship between endometriosis and dioxins and/or PCBs, including the non-dioxin-like congeners, but their results are conflicting. Major differences in study design, analytical methods, and the number and kinds of congeners measured make comparability (if any) between different studies limited, as recently discussed by some authors (Anger and Foster 2008; Heilier et al. 2008). In the last decade, the hypothesis of a correlation between the disease and environmentally persistent organohalogenated compounds has been extended to include other organohalogenated pollutants present in human tissues such as polybrominated biphenyls (PBBs) (Hoffman et al. 2007), hexachlorobenzene (HCB), and 1,1-dichloro-2,2-bis(4-chlorophenyl)-ethene (p,p′-DDE) (Lebel et al. 1998; Tsukino et al. 2005), all characterized by endocrine-disrupting and immunotoxic activity (Agency for Toxic Substances and Disease Registry 2002; Blanck et al. 2000; Davis et al. 2005; Foster et al. 1992, 1995; Halloway et al. 2005; Reed et al. 2007; Windham et al. 2005). No significant association for these pollutants has been evidenced in the studies performed to date. In previous studies carried out to investigate a possible association between organochlorinated compounds and endometriosis, we found significantly higher concentrations of some of the most abundant PCBs and higher concentrations of p,p′-DDE, in women affected by the disease (Porpora et al. 2006; Quaranta et al. 2006). We also observed that such increased concentrations were associated with altered natural killer (NK) immune responses (Quaranta et al. 2006). On the contrary, no increase in blood concentrations of dioxin-like chemicals (PCDDs, PCDFs, and the sum of the 12 DL-PCBs) was observed in women affected by the disease at different degrees (De Felip et al. 2004). The present study was funded by Italy’s Ministry of Health and National Institute for Health in the context of research activities aimed to characterize the risk for women’s reproductive health from exposure to persistent organic pollutants of environmental origin. It is the largest study carried out in Italy on the possible association between endometriosis and persistent organochlorinated pollutants of high toxicologic relevance.