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 ($\text{TEXB-}\alpha$) and to endogenous hormones and more polar xenoestrogens ($\text{TEXB-}\beta$) 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 $\text{TEXB-}\alpha$ and $\text{TEXB-}\beta$ levels for cases (0.30 and $1.25\text{Eeq pM}/\mathrm{mL}$, respectively) and controls (0.42 and $1.28\text{Eeq pM}/\mathrm{mL}$, respectively) did not significantly differ ($p=0.653$ and 0.933, respectively). An inverted-U risk trend across serum $\text{TEXB-}\alpha$ and $\text{TEXB-}\beta$ 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 [$\text{odds ratio}\left(\text{OR}\right)=2.11$ (95% CI: 1.13, 3.94) for $\text{TEXB-}\alpha$, and $\text{OR}=3.32$ (95% CI: 1.62, 6.81) for $\text{TEXB-}\beta$], whereas no significant associations were observed between the third category of exposure and the first [$\text{OR}=1.22$ (95% CI: 0.64, 2.31) for $\text{TEXB-}\alpha$, and $\text{OR}=1.58$ (95% CI: 0.75, 3.33) for $\text{TEXB-}\beta$]. In mutually adjusted models for $\text{TEXB-}\alpha$ and $\text{TEXB-}\beta$ levels, the association of $\text{TEXB-}\alpha$ with endometrial cancer risk was attenuated [$\text{OR}=1.45$ (95% CI: 0.61, 3.47) for the second category of exposure], as well as estimates for $\text{TEXB-}\beta$ ($\text{OR}=2.68$; 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.

Figure 1.

Generalized additive models for serum levels of TEXB of (A) $\mathrm{\alpha }$ and (B) $\mathrm{\beta }$ fractions and endometrial cancer with 2 degrees of freedom among participants in the Screenwide case–control study ($n=303$), 2017–2021. Generalized additive models adjusted for age ($<60$, 60–69, $\ge 70$ y), education (high school or below, some college, college or above), BMI ($<25$, 25–29.9, $\ge 30{\mathrm{kg}/\mathrm{m}}^2$), use of hormonal contraceptives (ever, never), parity (0, 1–2, $\ge 3$), past history of cancer (no, yes), and the other fraction of TEXB ($<\text{LOD}$, below median, above median). Median for $\text{TEXB-}\mathrm{\alpha }=5.72\times {10}^{-1}$ and median for $\text{TEXB-}\mathrm{\beta }=1.79$ Eeq pM/mL. Smooth estimates are represented in solid lines and 95% confidence intervals in dashed lines. Numeric data can be found in Excel Tables S1(alpha) and S2 (beta). Note: BMI, body mass index; LOD, limit of detection; TEXB, total effective xenoestrogen burden; $\text{TEXB-}\mathrm{\alpha }$, TEXB of the alpha fraction (represents the combined estrogenic effect of mixtures of lipophilic organohalogenated xenoestrogens); $\text{TEXB-}\mathrm{\beta }$, TEXB of the beta fraction (represents the combined estrogenic activity of endogenous hormones and more polar xenoestrogens).

Figure 2.

Odds ratios (ORs) for endometrial cancer comparing categories (above and below the median compared with below the LOD) of TEXB of $\mathrm{\alpha }$ and $\mathrm{\beta }$ fractions by subgroups, among participants in the Screenwide case–control study ($n=303$), 2017–2021. Numbers of participants in each category are provided for controls (Co) and cases (Ca). Logistic models adjusted for age ($<60$, 60–69, $\ge 70$ y), education (high school or below, some college, college or above), BMI ($<25$, 25–29.9, $\ge 30{\mathrm{kg}/\mathrm{m}}^2$), use of hormonal contraceptives (ever, never), parity (0, 1–2, $\ge 3$), past history of cancer (no, yes), and the other fraction of TEXB ($<\text{LOD}$, below median, above median). Median for $\text{TEXB-}\mathrm{\alpha }=5.72\times {10}^{-1}$ and median for $\text{TEXB-}\mathrm{\beta }=1.79$ Eeq pM/mL. Results for normal BMI are omitted owing to the limited number of participants in the case categories. All $p$-interactions $>0.05$. Note: BMI, body mass index; CI, confidence interval; HC, hormonal contraception; PMH, postmenopausal hormone use; LOD, limit of detection; Ref, reference; TEXB, total effective xenoestrogen burden; $\text{TEXB-}\mathrm{\alpha }$, TEXB of the alpha fraction (represents the combined estrogenic effect of mixtures of lipophilic organohalogenated xenoestrogens); $\text{TEXB-}\mathrm{\beta }$, TEXB of the beta fraction (represents the combined estrogenic activity of endogenous hormones and more polar xenoestrogens).