1142292808
Developmental exposure of mice to dioxin exhibit endometrial dysfunction which mimics endometrium from women with endometriosis

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Abstract

Problem:  The environmental contaminant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) has been suggested to play a role in the etiology of endometriosis, but whether women develop this disease due to a prior exposure to endocrine disruptors is difficult to ascertain. Several studies have failed to demonstrate a link between adult TCDD exposure and the development of endometriosis, but we suspect it is the very early exposures that may be most relevant to alterations in adult tissue function. To this end, we have recently developed a mouse model in which we can examine the impact of developmental TCDD exposure on the adult uterus. The endometrial phenotype of these mice is markedly similarly to the phenotype found in women with endometriosis.

Method of Study:  TCDD was administered to mice at multiple developmental stages (in utero, prepubertal and pubertal). Adult mice were ovariectomized and treated with either estradiol (E2) or with E2 and progesterone (P4). The uteri were collected and PR expression examined by immunohistochemistry. As an indicator of P4 responsiveness, tissues were further examined for expression of TGF-β2. Human endometrial samples from women with and without endometriosis were similarly examined for PR and TGF-β2 expression.

Results:  Minimal uterine expression of PR and TGF-β2 was observed in TCDD exposed mice while control mice demonstrated abundant expression of both proteins. Analysis of normal human endometrium revealed intense staining for both PR and TGF-β2 during the P4-dominated secretory phase while these proteins were greatly diminished in tissues from women with endometriosis.

Conclusions:  A reduced responsiveness to P4 has recently been demonstrated in women with endometriosis. Although development of endometriosis is likely multifactorial, our studies are consistent with a role of in utero/developmental exposure to TCDD in the pathophysiology of this disease.

Acknowledgement:  This work was supported by NIEHS # R21ES12298 and The Endometriosis Association.

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