PROTECT Identifies Biological Mechanisms Linking Exposure to Toxic Chemicals and Preterm Birth

Project 2 investigators are conducting innovative studies with human placenta and extraplacental membranes (which form the fetal compartment) to better understand the relationship between exposure to toxicants and preterm birth. Because immune cells such as macrophages can be important sources of reactive oxygen species as well as mediators of pro-inflammatory responses relevant to labor onset, we conducted experiments with macrophages isolated from human placenta. We found that exposure to the phthalate metabolite mono-2-ethylhexyl phthalate (MEHP) stimulated release of prostaglandins from macrophages. Release of prostaglandin E2 (PGE2) was dependent of increased mRNA and protein expression of cyclooxygenase-2 (COX-2), a key prostaglandin synthesis enzyme (Fig 1; Tetz et al., 2015). Because PGE2 is well recognized as an important mediator of labor, toxicant-stimulated release of PGE2 may contribute to premature labor onset. By working with freshly isolated macrophages, we build on our previous findings that MEHP stimulates increased reactive oxygen species generation, oxidative DNA damage, and gene expression of COX-2 in a human placental cell line (HTR-8/SVneo; Tetz, Cheng et al., 2013). These studies support PROTECT epidemiologic findings that phthalate exposure is associated with increased odds of preterm birth.

Fig. 1: A) Model showing proposed relationship of MEHP effects on placental macrophages and preterm birth. B) MEHP-stimulated expression of the prostaglandin synthesis enzyme COX-2 in human placental macrophages. C) MEHP-stimulated release of PGF2α in human placental macrophages. N = 3-4 women. *p < 0.05, **p < 0.01, compared to solvent controls.