Abstract
In most mammals, labor is heralded by the withdrawal of progesterone. In humans, circulating progesterone levels increase as gestation advances while placental expression of progesterone receptor A (PR-A) declines. As a result of PR-A downregulation, the non-canonical NF-κB pathway is activated, an event implicated in triggering labor. Here, we sought to identify fetal-derived mediator(s) that represses placental PR-A in human placenta leading to activation of pro-labor signaling. Lipidomic profiling demonstrated enrichment of platelet-activating factor (PAF) in exosomes originating from the human fetus. Exposure of primary cytotrophoblasts to fetal exosomes from term pregnancies reduced PR-A expression by > 50%, and PAF also reduced PR-A message levels in a dose-dependent manner. Notably, fetal exosomes from preterm pregnancies had lower PAF levels and no effect on PR-A expression. Synthetic PAF-induced DNA methylation increases by 20% at the PR-A promoter, leading to recruitment of corepressors and downregulation of PR-A in cytotrophoblast. Furthermore, suppression of PR-A by PAF-stimulated expression of the pro-labor genes, corticotropin-releasing hormone (CRH) and cyclooxygenase-2 (COX-2), which was reversed by disruption of the DNA methyltransferases 3B and 3L. Taken together, PAF represents a novel fetal-derived candidate for initiation of labor by stimulating methylation and repression of PR-A and activating pro-labor signaling in trophoblast.