Total Effective Xenoestrogen Burden in Serum Samples and Risk of Endometrial Cancer in the Spanish Screenwide Case-Control Study

Introduction Endometrial cancer ranks as the most common gynecological tumor in regions with a very high human development index. (1) The burden of this cancer is expected to increase worldwide [...]
Background: Endometrial cancer is a hormone-dependent cancer, and estrogens play a relevant role in its etiology. However, little is known about the effects of environmental pollutants that act as xenoestrogens or that influence estrogenic activity through different pathways. Objective: We aimed to assess the relationship between the combined estrogenic activity of mixtures of xenoestrogens present in serum samples and the risk of endometrial cancer in the Screenwide case-control study. Methods: The total effective xenoestrogen burden (TEXB) attributable to organohalogenated compounds (TEXB-[alpha]) and to endogenous hormones and more polar xenoestrogens (TEXB-[beta]) was assessed in serum from 156 patients with endometrial cancer (cases) and 150 controls by combining chemical extraction and separation by high-performance liquid chromatography with the E-SCREEN bioassay for estrogenicity. Results: Median TEXB-[alpha] and TEXB-[beta] levels for cases (0.30 and 1.25 Eeq pM/mL, respectively) and controls (0.42 and 1.28 Eeq pM/mL, respectively) did not significantly differ (p = 0.653 and 0.933, respectively). An inverted-U risk trend across serum TEXB- [alpha] and TEXB-[beta] levels was observed in multivariate adjusted models: Positive associations were observed for the second category of exposure in comparison to the lowest category of exposure [odds ratio (OR) =2.11 (95% CI: 1.13, 3.94) for TEXB-[alpha], and OR = 3.32 (95% CI: 1.62, 6.81) for TEXB-[beta]], whereas no significant associations were observed between the third category of exposure and the first [OR= 1.22 (95% CI: 0.64, 2.31) for TEXB-[alpha], and OR= 1.58 (95% CI: 0.75, 3.33) for TEXB-[beta]]. In mutually adjusted models for TEXB-[alpha] and TEXB-[beta] levels, the association of TEXB-[alpha] with endometrial cancer risk was attenuated [OR = 1.45 (95% CI: 0.61, 3.47) for the second category of exposure], as well as estimates for TEXB- [beta] (OR = 2.68; 95% CI: 1.03, 6.99). Most of the individual halogenated contaminants showed no associations with both TEXB and endometrial cancer. Conclusions: We evaluated serum total xenoestrogen burden in relation to endometrial cancer risk and found an inverted-U risk trend across increasing categories of exposure. The use of in vitro bioassays with human samples may lead to a paradigm shift in the way we understand the negative impact of chemical mixtures on human health effects. These results are relevant from a public health perspective and for decision-makers in charge of controlling the production and distribution of chemicals with xenoestrogenic activity. https://doi.org/10.1289/EHP13202