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

全氟烷基物质和多氟烷基物质 (PFAS) 与妊娠血管和胎盘功能障碍的关系

基本信息

批准号：
10593111
负责人：
SATHISH KUMAR
金额：
$ 34.39万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-16 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593111
关键词：
Adult Affect Age Amino Acids Angiogenesis Inhibitors Angiogenic Factor Animals Area Arteries Biological Monitoring Blood Pressure Blood Vessels Blood flow Cardiovascular Physiology Cell Separation Cells Chemicals Developed Countries Development Diameter Disease Doppler Ultrasound Economic Burden Endothelial Cells Endothelium Environmental Exposure Epoprostenol Equilibrium Essential Fatty Acids Etiology Exhibits Exposure to Failure Family Fetal Growth Fetal Growth Retardation Fetal health Fetus Functional disorder Future Glucose Growth Health Human Hypertension Impaired cognition Impairment In Vitro Intervention Length Life Measures Mediating Membrane Potentials Mesentery Metabolic Metabolic syndrome Modeling Molecular Analysis Mothers Myography National Institute of Environmental Health Sciences Nature Neurologic Newborn Infant Nitrates Nitrites Nutrient Organ Outcome Pathway interactions Perfusion Perinatal Care Pilot Projects Placenta Policies Poly-fluoroalkyl substances Potassium Channel Pregnancy Pregnancy Complications Pregnant Women Process Production Public Health Radioactive Tracers Rattus Relaxation Research Priority Resistance Risk Risk Assessment Role Signal Pathway Signal Transduction Spiral Artery of the Endometrium Structure of umbilical artery System Systemic blood pressure Telemetry Testing Time Tissues Toxic effect Uterus Vascular Diseases Vascular Endothelial Growth Factors Vascularization Vasodilation Water Woman Work angiogenesis bioaccumulation blood pressure elevation channel blockers clinical care consumer product endothelial dysfunction environmental agent fatty acid transport fetal hemodynamics high risk human tissue in vivo knock-down microCT mother nutrition offspring overexpression perfluorooctane sulfonate perinatal morbidity pregnant programs reproductive sex translational study trophoblast

项目摘要

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.

抽象的妊娠引起的血管适应、充足的胎盘血管化和最佳的营养通量穿过胎盘到达胎儿对于支持其中一种或多种的胎儿生长至关重要。过程会导致胎儿生长受限 (FGR)，影响高达 15% 的新生儿，且目前尚无治疗方法。 FGR 的原因尚不清楚，但环境暴露于全氟烷基和多氟烷基。物质（PFAS）及其在胎盘中的生物蓄积可能是了解疾病的起源和母体器官功能障碍的根本原因。 (PFOS) 是一种传统的 PFAS，是生产最多且研究最多的 PFAS。 PFOS 的增加是否与母体血管功能障碍和 FGR 直接相关。与内皮功能障碍有关的 FGR 的表现尚不清楚，我们的初步研究表明，其升高。怀孕大鼠中的全氟辛烷磺酸会增加母体血压，削弱内皮功能，并降低根据这些发现，我们发现了胎盘大小、VEGF 表达和营养转运。 PFOS 水平升高会损害母体心血管功能并减少胎盘血管化和血流量我们将通过体内、离体动物研究的 3 个目标来检验这一前提。组织水平功能分析和体外分子分析将首先确定其功能效应。 PFOS 对全身血压和子宫动脉血流量的影响，并定义 PFOS 介导的为了测试 PFOS 介导的血管机制，将研究 EDHF、NO 和 PGI2 松弛途径。此外，还确定了 eNOS 的表达及其活性状态——EDHF 和 PGI2 的信号成分。将测量途径以及硝酸盐/亚硝酸盐和 PGI2 的产生以及膜电位的变化。然后转化研究将测试 PFOS 是否影响血管内皮细胞通路和机制目标 2 将通过检查对孕妇的孤立网膜和胎盘血管的影响进行检查。我们将确定 PFOS 升高是否会降低胎盘血管的生长、直径和长度。螺旋动脉、中央动脉管、胎儿胎盘动脉分支和脐动脉。测量胎盘中促血管生成因子和抗血管生成因子的表达，然后确定 PFOS 是否存在破坏从孕妇体内分离出的内皮细胞的信号传导机制。目标 3 将检查胎盘。我们将确定 PFOS 升高是否会降低葡萄糖、氨基酸和脂肪酸。穿过胎盘转运至胎儿并测量胎盘中营养转运蛋白的表达。然后，通过检查对初级儿童的影响，确定 PFOS 是否会扰乱孕妇的营养运输。这些结果预计将产生重要影响，因为它们将做出贡献。实质性地基于机制了解 PFOS 在妊娠并发症中的作用并发出警报环境机构制定政策减少育龄妇女接触全氟辛烷磺酸。