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

Abstract

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 ( ) and to endogenous hormones and more polar xenoestrogens ( ) 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 and levels for cases (0.30 and , respectively) and controls (0.42 and , respectively) did not significantly differ ( and 0.933, respectively). An inverted-U risk trend across serum and 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 [ (95% CI: 1.13, 3.94) for , and (95% CI: 1.62, 6.81) for ], whereas no significant associations were observed between the third category of exposure and the first [ (95% CI: 0.64, 2.31) for , and (95% CI: 0.75, 3.33) for ]. In mutually adjusted models for and levels, the association of with endometrial cancer risk was attenuated [ (95% CI: 0.61, 3.47) for the second category of exposure], as well as estimates for ( ; 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

Invited Perspective: Closing the Loop of Nonmonotonicity—from Natural Hormones in Experimental Endocrinology to Endocrine Disruptors in Epidemiology

“…in this issue of Environmental Health Perspectives , which revealed for the first time an inverted-U risk trend between total effective xenoestrogen burden (TEXB) levels in serum and endometrial cancer. 1 These findings involved levels of both the (nonpolar) and (polar) fractions; the latter includes endogenous hormones such as estradiol and xenoestrogens such as bisphenol A (BPA).…”

“… 4 , 5 While our group continued to work on theoretical and experimental biology using cell cultures and animal models, Olea and Fernández returned to Spain, where they optimized the total xenoestrogen burden methodology and applied it to biomonitoring of environmental exposure in human tissues 7 and in epidemiological studies of breast cancer, 8 hypospadias, 9 cryptorchidism, 9 and now endometrial cancer. 1 Meanwhile, Kortenkamp’s group published the first of a long series of articles addressing mixture effects from combinations of xenoestrogens, each at a level that produced no effect alone. 10 …”