PROJECT SUMMARY Preterm birth (PTB) and related intrauterine growth retardation (IUGR) affects 15 million babies a year globally (~11% of births) and is linked to chronic diseases in adulthood. Infection-mediated PTB is associated with ~40% of all PTBs, but not all maternal infections elicit PTB. The placenta is a primary mediator of this protection and expresses protective Interferons (e.g., IFNb) which play a critical role in placental immune regulation. Co-I Gil Mor has shown that downregulation of protective IFNb at the site of the placenta allows for a secondary bacteria insult to elicit an uncontrolled inflammatory reaction that would otherwise have been benign. Recent epidemiological and preclinical work shows that certain classes of environmental pollutants are immunosuppressive and can inhibit IFN signaling. Per-and poly fluoroalkyl substances (PFAS) are a class of ubiquitous man-made chemicals utilized for their surfactant properties in cookware, clothing, and carpets as well as in foams used by firefighters and are found in the environment as mixtures. A handful of model PFAS have been associated with preterm birth and decreased fetal growth. PFAS are established immunosuppressants have reproducibly been shown to be associated with decreased IFN signaling in mice or humans and have been linked to increased severity or incidence of infections. PFAS target the placenta and can decrease IFN signaling in trophoblasts, but mechanistic studies investigating the role of decreased IFN as it relates to increased susceptibility to a second hit during pregnancy are lacking. Thus, we hypothesize that PFAS exposure leads to dysregulation of type 1 (i.e., IFNb) and/or type 2 (IFNg) responses in the placenta and is responsible for a dysregulated inflammatory response to a secondary bacterial infection resulting in IUGR and PTB. IFN signaling can be regulated by modulating IFN levels at the site of infection, or through regulation of IFN receptors by post-translational modifications (PTMs), primarily by glycosylation. Biochemical labeling tools now exist that allow for spatial analysis of glycosylated proteins at the resolution of single cells. No group has used sugar labeling to track effects of PFAS on placental inflammation, especially as it relates to IFNs. This Katz award will allow Dr. Petriello, a toxicologist and early-stage investigator to transition to study inflammation within critical windows of susceptibility (pregnancy) and impacts on placental health and birth outcomes. For this Katz award we will expose pregnant mice to concentrations of PFAS previously shown to decrease IFN signaling as well as lead to IUGR, and then expose to a bacterial stressor which we predict will elicit preterm delivery. Our aims are: 1. To test the hypothesis that maternal exposures to PFAS lead to decreased IFN signaling and induce placental toxicity. 2. To test the hypothesis that N- and O-glycoprotein distribution is altered specifically in spongiotrophoblas...