Premature Estrogen Exposure Alters Endometrial Gene Expression to Disrupt Pregnancy in the Pig

Establishment and maintenance of pregnancy in the pig involve intricate communication between the developing conceptuses and maternal endometrium. Conceptus synthesis and release of estrogen during trophoblastic elongation are essential factors involved with establishing conceptus-uterine communication. The present study identified endometrial changes in gene expression associated with implantation failure and complete pregnancy loss after premature exposure of pregnant gilts to exogenous estrogen. Gilts were treated with either 5 mg estradiol cypionate (EC) or corn oil on d-9 and -10 gestation, which was associated with complete conceptus degeneration by d-17 gestation. Microarray analysis of gene expression revealed that a total of eight, 32, and five genes were up-regulated in the EC endometrium, whereas one, 39, and 16 genes were down-regulated, on d 10, 13, and 15, respectively. Four endometrial genes altered by EC, aldose reductase (AKR1B1), secreted phosphoprotein 1 (SPP1), CD24 antigen (CD24), and neuromedin B (NMB), were evaluated using quantitative RT-PCR and in situ hybridization. In situ hybridization localized gene expression for NMB, CD24, AKR1B1, and SPP1 in the luminal epithelium, and confirmed the expression patterns from RT-PCR analysis. The aberrant expression patterns of endometrial AKR1B1, SPP1, CD24, and NMB 3-4 d after premature estrogen exposure to pregnant gilts may be involved with conceptus attachment failure to the uterine surface epithelium and induction of endometrial responses that disrupt the establishment of a viable pregnancy.