Per- and poly-fluoroalkyl substances (PFAS) in pregnancy vascular and placental dysfunction

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ABSTRACT Pregnancy-induced vascular adaptations, adequate placental vascularization, and optimal flux of nutrients across the placenta to the fetus are critical to support fetal growth. Disruption in one or more of these processes leads to fetal growth restriction (FGR). FGR affects up to 15% of all newborns, and no treatment is available. The cause of FGR is not known, but the environmental exposure to per- and poly-fluoroalkyl substances (PFAS) and its bioaccumulation in the placenta may hold important keys to understanding the origins of the disease and the underlying causes of maternal organ dysfunction. Perfluorooctane sulfonate (PFOS), a legacy PFAS, is the most produced and well studied PFAS. Elevated maternal PFOS is shown to be associated with maternal vascular dysfunction and FGR in humans. Whether this increase in PFOS is directly involved in endothelial dysfunction and manifestations of FGR is unknown. Our pilot studies show that elevated PFOS in pregnant rats increases maternal blood pressure, blunts endothelial function, and decreases in placental size, VEGF expression, and nutrient transport. Based on these findings, we hypothesize that elevated PFOS levels impair maternal cardiovascular function and reduce placental vascularization and flux of nutrients to lead to FGR. We will examine this premise in 3 aims employing in vivo animal studies, ex vivo tissue-level functional analysis and in vitro molecular analyses. Aim 1 will first establish the functional effects of elevated PFOS on systemic blood pressure and uterine artery blood flow and define the PFOS-mediated signaling. To test the PFOS-mediated vascular mechanisms, EDHF, NO, and PGI2 relaxation pathways will be determined. Also, the expression of eNOS and its activity state—signaling components of EDHF and PGI2 pathways as well as nitrate/nitrite and PGI2 production and changes in membrane potential—will be measured. Then translational studies will test whether PFOS affects the endothelial pathways and mechanisms in pregnant women by examining the effects in isolated omental and placental vessels. Aim 2 will examine placental vascular effects. We will determine if elevated PFOS decreases growth, diameter, and length of spiral arteries, central arterial canals, fetoplacental arterial branches, and umbilical arteries. We will also measure the expression of pro- and anti-angiogenic factors in the placenta, and then determine if PFOS disrupts signaling mechanisms in endothelial cells isolated from pregnant women. Aim 3 will examine placental nutrient transport effects. We will determine if elevated PFOS decreases glucose, amino acid, and fatty acid transport across the placenta to the fetus and measure the expression of nutrient transporters in the placenta. Then, determine if PFOS disrupts nutrient transport in pregnant women by examining the effects in primary trophoblasts. These results are expected to have an important impact because they will contribute substantively to a mechanism-based understanding of PFOS's role in pregnancy complications and alert environmental agencies to devise policies to curtail PFOS exposure to reproductive-age women.