Developmental exposure of mice to TCDD elicits a similar uterine phenotype in adult animals as observed in women with endometriosis

Abstract

Whether environmental toxicants impact an individual woman's risk for developing endometriosis remains uncertain. Although the growth of endometrial glands and stroma at extra-uterine sites is associated with retrograde menstruation, our studies suggest that reduced responsiveness to progesterone may increase the invasive capacity of endometrial tissue in women with endometriosis. Interestingly, our recent studies using isolated human endometrial cells in short-term culture suggest that experimental exposure to the environmental contaminant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) can alter the expression of progesterone receptor isotypes. Compared to adult exposure, toxicant exposure during development can exert a significantly greater biological impact, potentially affecting the incidence of endometriosis in adults. To address this possibility, we exposed mice to TCDD at critical developmental time points and subsequently examined uterine progesterone receptor expression and steroid responsive transforming growth factor-β2 expression in adult animals. We find that the uterine phenotype of toxicant-exposed mice is markedly similarly to the endometrial phenotype of women with endometriosis. KeywordsDioxin; TCDD; Progesterone; Progesterone receptor; TGF-β2; Endometrium; Endometriosis; Development; Fetal origin 1.IntroductionPolychlorinated dibenzo-p-dioxins, generally called dioxins, are a family of chlorinated aromatic hydrocarbons that accumulate as ubiquitous contaminants in our environment. In human populations, ingestion of contaminated food is the primary source of dioxin exposure [1][2][3]. These chemicals are resistant to degradation and, due to their lipophilic nature, bioaccumulate and biomagnify at higher levels within the food chain [4]. Among the numerous dioxin-like environmental contaminants, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is often considered to be the prototypical disruptor of steroid action within endocrine sensitive tissues, affecting steroid receptor levels as well as steroid metabolism and serum transport [5][6][7]. In addition to dramatically affecting the endocrine system, TCDD exposure also impacts the expression of multiple cellular signaling systems that regulate key elements of the immune In opposition to the role of estrogen as a risk factor for endometriosis, progesterone may play a critical role in protecting a woman from the development and progression of this disease. For example, progesterone exposure during pregnancy, or exogenous therapy with various progestins, has been associated with disease regression in some women [19]. Nevertheless, reduced progesterone responsiveness has been noted in the eutopic endometrium of women with endometriosis, correlating with an altered expression of progesterone receptor (PR) isotypes [20]. In the endometrium of endometriosis patients, reduced levels of PR-B expression relative to PR-A likely explains the altered expression of progesterone-responsive genes that we and others have recently described during endometrial diff...

Dioxin may promote inflammation-related development of endometriosis

“…Additionally, evidence from a number of laboratories indicates that an early developmental exposure to a toxicant actually increases an individual's sensitivity to a second, later exposure (39,40). It is important to note that the offspring of mice in our study (38) exhibited altered PR expression and disrupted fertility for at least three generations without additional toxicant exposure (41), suggesting that an inheritable, epigenetic alteration had occurred.…”

Environmental immune disruption: a comorbidity factor for reproduction?

“…TCDD treatment of human endometrial cells results in reduced expression of progesterone receptor B and increased expression of MMPs similar to endometrial tissues from women with endometriosis (31). Developmental exposure to TCDD in mice results in altered expression of uterine progesterone receptors similar to endometrial tissues from women with endometriosis (32).…”

Reproductive medicine and inheritance of infertility by offspring: the role of fetal programming

“…Fetal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice promotes growth in endometriotic implants during adult life (158). Several mechanisms of action have been suggested for these endocrine disruptors to promote endometriosis: [1] alteration of the hormonal milieu, in that TCDD reduces estradiol levels in vitro and in vivo and induces degradation of estrogen receptor a and progesterone receptors (159)(160)(161); [2] alteration of the immune function (162); and [3] activation of specific cell-signaling pathways (163). In a prospective cohort study, Missmer et al (164) reported an increased risk of endometriosis in DES-exposed women (relative risk [RR] 1.8; 95% CI, 1.2-2.8) and in women born as one of the fetuses of a multiple gestation (RR 1.7; 95% CI, 1.2-2.5).…”