Perinatal Exposure to Bisphenol A and Diethylstilbestrol Programs Endometriosis Related Gene Expression in the Mouse Uterus.

Endometriosis is a chronic painful disease that is thought to occur when retrograde menstruation places shed endometrial tissue in the peritoneal cavity where in then implants and invades surrounding tissue. Although retrograde menstruation is thought to occur in up to 90% of women, only 10% of women develop endometriosis. Not only is endometriosis is an estrogen dependent disease in adulthood but the fetal estrogen environment is also associated with the risk of developing endometriosis in women. Conditions during pregnancy associated with high estrogen levels have been correlated with increased risk of endometriosis in adulthood. For example, women whose mothers took the pharmaceutical xenoestrogen DES during their pregnancy have an 80% increased risk of endometriosis. Conversely, maternal smoking, which inhibits placental aromatase expression and results in decreased fetal estrogens, is associated with a four-fold decrease in adult endometriosis risk. In order to better understand the role that developmental xenoestrogen exposure has on programming endometriosis related gene expression, we performed two separate experiments in which we used a mouse model of developmental exposure followed by surgical induction of endometriosis in adulthood. Following perinatal exposure to bisphenol A (BPA) and DES, endometriosis was surgically induced by autotransplantation of endometrial tissue to the arterial cascade of the intestinal mesentery in adulthood. Altered gene expression was assessed with both a global and targeted approach. Developmental exposure to DES and BPA altered the expression of a number of genes as measured by next generation sequencing (RNA-Seq): 22 and 26 genes were upregulated in adulthood and nine and four down regulated by DES and BPA respectively. Interestingly, only 11 genes were altered by both chemicals. In a targeted analysis, the expression of five endometriosis related genes was assessed in the eutopic uterine tissue and endometriotic lesions by real time RT-PCR. Developmental exposure to DES altered the expression of three genes in the eutopic uterus: the expression of Cxcl5 and Ltf was increased and Spp1 tended to be increased in both experiments. Developmental exposure to BPA tended to alter the expression of these genes also. Taken together, these results suggest that developmental exposure to bisphenol A and other xenoestrogens at current environmentally relevant levels may alter the risk for endometriosis in women.