DEVELOPMENTAL EXPOSURE TO XENOBIOTIC ESTROGENS PERMANENTLY PROGRAMS EXPRESSION OF EXTRACELLULAR MATRIX AND ADHESION MOLECULES IN A MOUSE ENDOMETRIOSIS MODEL

Abstract

Estrogens have permanent developmental effects in the fetus. Our lab is investigating the potential for xenobiotic estrogens to program endometriosis-related genes during fetal development. It has recently been reported that women exposed in utero to the synthetic estrogen diethylstilbesterol (DES) had an 80% increased incidence of endometriosis, an estrogen dependent disease characterized by the growth of ectopic endometrium. Additionally fraternal twins, who are exposed to 60–80% increased levels of circulating estrogens in utero, have a 70% increased incidence of endometriosis. We therefore hypothesized that developmental estrogen exposure would result in the exacerbation of endometriosis in adulthood in a mouse model of surgically-induced endometriosis. In a preliminary study we found that developmental DES exposure resulted in 55% larger endometriotic lesions in adulthood. To investigate mechanisms that led to the exacerbation of endometriosis we examined the ability of developmental DES to alter proliferation and program extracellular matrix and adhesion molecule gene expression in endometriotic lesions. Methods: Pregnant female mice were given a daily oral dose of 0.1 microg/kg DES or vehicle control on gestation days 11–17. When mice exposed in utero reached adulthood, endometriosis was surgically induced by autotransplantation of uterine tissue to the intestinal mesentery. After 4 weeks, mice were euthanized and eutopic and ectopic endometrium were collected. Results: Proliferation was significantly greater in endometriotic lesions from DES developmentally treated mice compared to control treated mice as detected by immunolocalization of the nuclear proliferation marker Ki67. To examine potential developmental programming of adult gene expression, an extracellular matrix and adhesion molecule pathway specific microarray was used. Overall, 19% (21 out of 113) of extracellular matrix and adhesion molecule genes were up-regulated and only 3% (3 out of 113) were down-regulated in endometriotic lesions from developmentally DES exposed mice compared to control treated mice. Upregulated genes included several procollagens, integrins, laminins, matrix metallopeptidase 12, fibronectin, and periostin. Downregulated genes included synaptotagmin 1, thrombospondin 1, and tissue inhibitor of metalloproteinase 4. These results indicate that developmental xenoestrogen exposure may program the fetus and result in a more favorable environment for the growth of ectopic endometriotic lesions by increasing the expression of genes for extracellular matrix and adhesion molecules that are necessary for tissue re-modeling and endometriotic lesion growth. (platform)