Placental molecule secretions measured in early pregnancy are targets of endocrine disruption and are indicators of sex-specific fetal development.

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

The proposed project will use information from the placenta in early pregnancy (also called the gestational sac (GS)) to estimate environmental risks to the health of the newborn. According to population-wide biomonitor- ing studies, fetuses in the U.S. are exposed to a long list of endocrine disrupting chemicals (EDCs) that enter our bodies primarily through packaged and processed food and personal care product use. EDCs, such as phthalates and perfluoroalklyl chemicals (PFCs), can alter developmental pathways in the rodent fetus with consequences for the genitalia, brain, immune system, and body mass index. We have established a relation- ship using epidemiologic and experimental methods between phthalate exposures, sex-specific disruption of a placental hormone called human chorionic gonadotropin (hCG), and the distance between the anus and the genitalia in the newborns. Anogenital distance (AGD) is a marker of hormonal actions in utero and is predictive of fertility in the adult. Hence, we have offered a novel conceptual framework for the role of the early placenta or the gestational sac (GS) in endocrine disruption. We theorize that the role of the GS is distinct from the pla- centa proper, which forms at 10 weeks when maternal perfusion and nutrient transport begins. In this project we will extend this model to ask the question if the phthalate-hCG-genital relationship can be generalized to a) a class of persistent EDCs that also enter our bodies from processed and packaged food; b) a set of 5 other candidate molecules that are synthesized and secreted by the placenta and correlated with hCG; and c) other endpoints in the neonate that reflect sex-specific development. First, we will measure the real-time relationship between maternal exposures to endocrine disrupting compounds (EDC) in the earliest stage of pregnancy and their correlation with hormones and other molecules that are secreted and/or regulated by the GS. Secondly, we will measure outcomes in the male and female newborns that indicate differences in genital development, birth size, and adiposity or prenatal programming of obesity and other metabolic disorders. The outcomes in the neonates were selected, as they are predictive of longer-term health outcomes in the child and in the adult. Using statistical techniques, we will determine if the first trimester placental response to EDCs mediated the overall `effect' of the EDC exposure on neonatal outcomes. Thirdly, we will analyze the placental tissue (sam- pled at delivery) transcriptome for the global expression of coding and non-coding RNA levels. We will test the correspondence between the placental molecular signature (by sex and by phthalate) at the end of pregnancy with the placental secretion profile in early pregnancy. With these same data, we will test a hypothesis from our pilot studies on a specific type of epigenetic regulation of the transcriptome that may explain on a molecular level how phthalates induce a sex-specific response in the placenta. By testing a unified theory on the role of the GS, we will contribute to innovation in strategies to identify obstetric and developmental risks at early time points in pregnancy, and possibly within a timeframe to reduce risks to the child.