Dioxin and Endometrial Progesterone Resistance

Kaylon L Bruner-Tran, Kaylon L. Bruner‐Tran, Ding T, Tianbing Ding, Kevin G. Osteen, Osteen KG
Seminars in reproductive medicine · 2010 · vol. 28(01) , pp. 059–068 · doi:10.1055/s-0029-1242995 · PMID:20104429 · PMC2875884 · W1979924696
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⚙ AI-generated summary by claude@2026-06, 2026-06-09 ⓘ

Developmental exposure to the environmental toxicant TCDD induces progesterone resistance in the mouse endometrium, a phenotype that persists across multiple generations.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 · read from full text ⓘ

The paper investigates how developmental exposure to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects progesterone action in the endometrium and whether this relates to mechanisms implicated in endometriosis development. In mouse studies, developmental TCDD exposure produces adult offspring with a progesterone-resistant endometrial phenotype that can persist across several generations. The authors emphasize that while progesterone resistance in endometriosis patients is considered speculative in terms of mechanism, their findings support the importance of elucidating TCDD-related reproductive effects involving endocrine and immune disruption, with the main caveat being uncertainty about how the mouse progesterone-resistance mechanism maps onto human endometriosis. Relevance to endometriosis: the abstract explicitly frames endometriosis as likely involving interactive endocrine and immune mechanisms and highlights TCDD’s potential contributory role in endometriosis development and progesterone resistance, even though the paper’s direct experimental focus is TCDD-driven progesterone resistance in mice rather than patient endometrium. This paper is centrally about endometriosis — it links TCDD exposure to progesterone resistance in an endometriosis-relevant reproductive phenotype in mice.

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Abstract

Development of endometriosis likely requires multiple, interactive mechanisms involving both the endocrine and immune systems. Environmental toxicants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are of particular interest as potential contributory agents in the development of this disease because they can disrupt both systems. Nevertheless, defining the potential role that environmental exposure to TCDD plays in the development of endometriosis requires a better understanding of how this toxicant affects the biological processes that promote the disease. Although the disease mechanism(s) responsible for progesterone resistance in the endometrium of endometriosis patients remains speculative, our studies indicate that developmental exposure of mice to TCDD leads to a progesterone-resistant phenotype in adult animals that can persist for several generations. These studies and others underscore the importance of developing a greater understanding of the mechanisms of TCDD action that relate to reproductive disorders such as endometriosis.
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Tcdd

As noted earlier, experimental primate studies as well as human observations have revealed that exposure to TCDD can disrupt pregnancy and lead to spontaneous abortion. 67 Pregnancy loss is not an unexpected reproductive consequence given that this toxicant is known to disrupt ovarian progesterone production 68 as well other important elements of endocrine and immune responses. 69 Whereas in vitro studies and some animal models continue to provide mechanistic clues suggesting that TCDD and similarly acting environmental toxicants may promote the development of endometriosis, 4 , 70 epidemiological studies of human populations have not consistently confirmed such a link. 71 Given that the development of endometriosis involves altered function of both the immune and endocrine systems, exposure to environmental toxicants is likely to be only one of several risk factors for this disease. A critical factor often overlooked in the study of environmental toxicants is the relative risk that exposures may play at different stages of life. Several recent studies in the field of environmental toxicology suggests that early life exposures to toxicants may epigenetically modify critical genes that can play a significant role in disease processes that only become evident later in adult life. 9 , 72 , 73 In regard to progesterone action, using a murine model, we have shown that in utero exposure to TCDD impacts the sensitivity of the reproductive tract to future toxicant exposures as well as creating a uterine phenotype that exhibits insensitivity to progesterone. 74 Interestingly, following a combination of in utero and prepubertal TCDD exposure, adult mice can exhibit either infertility or a failure to sustain pregnancy to term. 4 Even the surviving F2 and F3 offspring of TCDD-exposed mice (F1) are frequently found to exhibit reduced fertility, suggesting that toxicant-induced epigenetic changes may affect several generations. As shown in Fig. 2 , the F1 generation of mice exposed in utero to TCDD exhibit changes in global methylation compared with unexposed animals; in addition to these global epigenetic changes, a specific loss of progesterone receptor (PR) protein expression was observed. Significantly, although 80% of F1 mice exhibited these changes, 20% of mice at the F5 generation continued to exhibit altered global methylation and reduced PR protein expression. As shown in Fig. 3 , F1 mice that are able to attain pregnancy following in utero TCDD exposure are frequently found to exhibit a marked reduction in decidualization as noted on gestation day 7 (GD7) compared with control pregnant animals. These studies suggest that early-life exposures to TCDD can dramatically affect the function of the adult uterus, and that these affects can be passed to future generations. Certainly, if endometriosis in women is found to be a disease with developmental origins, studies attempting to link a woman’s adult body burden of toxicants with her disease status may not reveal the true relationship between toxicant exposure and disease risk. Because experimental models of development toxicant exposures cannot be conducted in humans, we must rely on prospective data collected from accidental population exposures (i.e., Seveso, Italy) as well as carefully controlled laboratory-based animal studies.

Summary/Perspective

Although endometriosis is defined rather simply as the presence of both glandular and stromal elements of endometrial tissue at an ectopic site, the biological triggers for the development of clinically significant disease in only certain women remain unclear. Most investigators involved in endometriosis research suspect that multiple interactive mechanisms involving both the endocrine and immune systems are likely involved in the pathogenesis of this disease. Therefore, defining the potential role that environmental exposure to TCDD plays in the development of endometriosis will require a better understanding of how this environmental toxicant affects the biological triggers that promote the disease process. To approach such an understanding, our research group has used human endometrial tissues and cells and various in vitro models as well as an experimental endometriosis model. In initial experiments, we found that even brief TCDD exposure can disrupt progesterone action related to regulation of several members of the endometrial MMP system. As we continued to explore the action of TCDD exposure on otherwise normal endometrial tissue and cells, we found that exposure to this toxicant disrupts MMP regulation by inhibiting normal progesterone-mediated patterns of stromal-epithelial communication. Given the established role of MMPs in endometrial tissue breakdown and repair, it is not surprising that TCDD also acts to increase the invasive behavior of human endometrium in our experimental endometriosis model. In general, we find that exposure of human endometrium to TCDD acts to promote a similar progesterone-resistant endometrial phenotype that we and others have observed in tissues acquired from women with endometriosis. Although the disease mechanism(s) responsible for progesterone resistance in the endometrium of endometriosis patients remains speculative, we have also found that developmental exposure of mice to TCDD leads to a progesterone-resistant phenotype in adult animals that can persist for several generations. At this juncture, whether experimental TCDD exposure models reflect a potential relationship of environmental toxicants to the patho-genesis of endometriosis in humans remains unclear. Nevertheless, laboratory-based studies with TCDD and other environmental toxicants are beginning to reveal important information about the potential role of the environment on not only endometriosis but other reproductive disorders as well. In particular, the potential that early-life exposure to environmental toxicants may affect our reproductive health for generations deserves more attention.

Progesterone Mediated

In contrast to the influence of estrogen on the development of endometriosis, a woman’s exposure to progesterone during pregnancy is a well-recognized negative risk factor for the development of endometriosis. Therefore, understanding the various ways an environmental toxicant that disrupts progesterone action might influence the development of endometriosis requires that we first consider critical elements of endometrial biology related to progesterone action. Although the earliest signs of menstruation are noted quite rapidly as a consequence of progesterone withdrawal, the stages of progesterone-mediated endometrial maturation occur relatively slowly over a period of nearly a week as the endometrium prepares for the invasive process of implantation and placentation. 23 – 25 Establishing pregnancy is a biologically complex process, and progesterone must orchestrate the cooperative behavior of the multiple cell types that normally populate the maternal-fetal interface. 26 – 29 Importantly, after successful establishment of the hemochorial placenta, progesterone continues to exert a critical influence on multiple endometrial cell types, and the stability of the maternal-fetal interface requires the action of this steroid throughout pregnancy. Thus it is the specific lack of continued progesterone support to the endometrium that triggers the initiation of the inflammatory-like process leading to tissue breakdown and menstruation. 30 Significantly, in the absence of pregnancy or medical intervention, this unique pattern of endometrial growth, differentiation, and tissue breakdown can repeat itself >400 times over a woman’s reproductive life. Assuming that Sampson’s retrograde menstruation theory is correct, it seems remarkable that the development of endometriosis is not even more common. The simple fact that not all menstruating women have symptomatic endometriosis likely indicates that numerous factors, in addition to retrograde menstruation, are required for the development of clinically significant disease. Although retrograde menstruation allows for the mechanical transfer of endometrial tissue to the peritoneal cavity, it is the invasive behavior of the endometrial fragments within the peritoneal microenvironment that ultimately determines whether or not tissue fragments survive and grow at an ectopic site. Using an experimental model of endometriosis, our studies have shown that the progesterone-resistant endometrial phenotype observed in endometriosis patients is associated with an increased capacity for invading the peritoneal wall, obtaining a vasculature, and growing in the peritoneum of immunocompromised nude mice. 4 Approximately 3 weeks of ovarian steroid priming is required to achieve optimal endometrial maturation and the opening of the “window of receptivity” requisite for successful nidation; therefore, menstruation marks a failed attempt to establish pregnancy. Following menstruation, estradiol production by ovarian follicles is responsible for a variable period of endometrial regrowth; however, the timing of endometrial maturation is more predictable in response to the increased production of progesterone by the post-ovulatory corpus luteum. Within the fundus region of the endometrium, researchers have shown that estrogen and progesterone receptors exhibit a distinctive, cell-specific distribution pattern that largely reflects the changing levels of ovarian steroid production. 31 , 32 Within the functionalis region of the endometrium, ligand-bound steroid receptors mediate the transcriptional activation of specific genes coding critical proteins that subsequently promote changes in endometrial proliferation, morphology, and biochemistry across each phase of the menstrual cycle. Estradiol receptor levels peak during the late proliferative stage of the cycle, whereas progesterone receptor levels are highest somewhat later during the early secretory phase. 31 Although in vivo and in vitro studies have shown that ovarian steroids can directly impact specific steroid-responsive genes in both endometrial stromal and epithelial cells, 33 the expression of progesterone receptors in epithelial cells have been shown to be significantly reduced as the endometrium matures near the time of implantation. 34 Loss of progesterone receptors in differentiating epithelial cells suggests that the specialized fibroblasts within the stroma of the endometrium are likely the primary cells remaining fully responsive to ovarian steroids during the midsecretory phase of the menstrual cycle. 35 Therefore, appropriate stromal-epithelial communication via secondary paracrine signals becomes increasingly critical for progesterone-mediated endometrial preparation for pregnancy. 36 , 37 As relatively undifferentiated endometrial fibroblasts mature, they exhibit a remarkable transformation into decidual cells, producing a variety of progesterone-sensitive paracrine factors necessary for the appropriate differentiation of adjacent epithelial cells as well as other cells within the rich endometrial stroma. 26 , 38 , 39 The complete cellular makeup of uterine decidual tissue is complex, and careful analysis has revealed interactive specialized fibroblast cells, an abundant vascular supply and numerous invasive cells of hemopoietic origin. Cells of hemopoietic origin residing within the decidua include leukocytes and macrophages that, in humans, can ultimately make up 40% of the decidual cell population. 40 The origins and specialized functions of various cells migrating into the human decidua remain to be determined due to the involvement of many different cell types as well as the ethical considerations that restrict the study of early human pregnancy. However, toxicant-mediated disruption of the differentiated function of the specialized endometrial fibroblasts as we have shown in vitro 41 is likely a central component of the recognized ability of accidental TCDD exposure to disrupt human pregnancy. 42

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometrium Environmental Pollutants Polychlorinated Dibenzodioxins Progesterone Animals Endometriosis Endometriosis Endometrium Endometrium Environmental Exposure Environmental Pollutants Female Humans Mice Polychlorinated Dibenzodioxins Progesterone Receptors, Progesterone Receptors, Progesterone Receptors, Progesterone

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