Endometriosis is a complex and persistent disease, which most often develops following retrograde menstruation and ectopic establishment of endometrial fragments. Ectopic growth is an invasive event, which mimics cancer metastasis, and women with endometriosis appear to have an increased risk for the development of certain neoplasms. Estrogen exposure predisposes development of endometriosis, while progesterone exposure, either therapeutically or during pregnancy, may lower a woman's risk of the disease. Exposure to dioxin (TCDD:2,3,7,8 tetrachlorodibenzo-p-dioxin), an endocrine and immune disrupting toxin increased the rate of spontaneous endometriosis in an exposed primate colony and, at autopsy revealed aggressive endometriosis in exposed animals. Although an association between TCDD and the development of endometriosis in women remains speculative, our studies using a mouse model of endometriosis has revealed TCDD treatment is associated with increased expression of matrix metalloproteinases (MMPs) and a more aggressive disease. A potential mechanism of TCDD action associated with endometriosis is as an inhibitor of transforming growth factor-132, an essential tissue factor for normal embryonic development as well as MMP regulation in adult tissues. In order to assess the possibility that in utero or neonatal exposure to TCDD may permanently alter steroid-mediated regulation of MMPs later in life, we propose the development of in vivo and in vitro murine (mouse) models in which to explore MMP regulation. Although mice do not spontaneously develop endometriosis, recent data suggest the disease may have an origin in defective steroid sensitivity in the uterus. Identifying the mechanisms by which fetal/neonatal TCDD disrupts steroid-mediated MMP regulation in the adult mouse uterus will provide insight into the potential role of toxin exposure in the development of endometriosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES012298-01
Application #
6647350
Study Section
Special Emphasis Panel (ZRG1-REB (50))
Program Officer
Heindel, Jerrold
Project Start
2003-05-05
Project End
2006-03-31
Budget Start
2003-05-05
Budget End
2004-03-31
Support Year
1
Fiscal Year
2003
Total Cost
$151,000
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Bruner-Tran, Kaylon L; Gnecco, Juan; Ding, Tianbing et al. (2017) Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: Translating lessons from murine models. Reprod Toxicol 68:59-71
Bruner-Tran, Kaylon L; Yeaman, Grant R; Crispens, Marta A et al. (2008) Dioxin may promote inflammation-related development of endometriosis. Fertil Steril 89:1287-98
Nayyar, Tultul; Bruner-Tran, Kaylon L; Piestrzeniewicz-Ulanska, Dagmara et al. (2007) Developmental exposure of mice to TCDD elicits a similar uterine phenotype in adult animals as observed in women with endometriosis. Reprod Toxicol 23:326-36
Igarashi, Toshio M; Bruner-Tran, Kaylon L; Yeaman, Grant R et al. (2005) Reduced expression of progesterone receptor-B in the endometrium of women with endometriosis and in cocultures of endometrial cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fertil Steril 84:67-74
Osteen, Kevin G; Bruner-Tran, Kaylon L; Eisenberg, Esther (2005) Reduced progesterone action during endometrial maturation: a potential risk factor for the development of endometriosis. Fertil Steril 83:529-37