Document text
Principal Investigator: SATHISH KUMAR
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $343,881
Funding agency: National Institute of Environmental Health Sciences
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.
Terms: <0-4 weeks old><21+ years old><Adult><Adult Human><Affect><Age><Amino Acids><Angiogenesis Antagonists><Angiogenesis Blockers><Angiogenesis Factor><Angiogenesis Inhibitors><Angiogenetic Antagonists><Angiogenetic Inhibitors><Angiogenic Antagonists><Angiogenic Factor><Angiogenic Inhibitors><Angiostatic Agents><Animals><Anti-Angiogenetic Agents><Anti-Angiogenic Agents><Anti-Angiogenic Drugs><Antiangiogenesis Agents><Antiangiogenic Agents><Antiangiogenic Drugs><Area><Arteries><Biological Monitoring><Blood Pressure><Blood Vessels><Blood flow><Body Tissues><Cardiovascular Physiology><Causality><Cell Body><Cell Communication and Signaling><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cells><Cells Placenta-Tissue><Chemicals><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Common Rat Strains><D-Glucose><Developed Countries><Development><Dextrose><Diameter><Disease><Disorder><Disturbance in cognition><Doppler Ultrasound><Dysfunction><Economic Burden><Endothelial Cells><Endothelium><Environmental Exposure><Epoprostenol><Equilibrium><Essential Fatty Acids><Etiology><Exhibits><Exposure to><Failure><Family><Fetal Growth><Fetal Growth Restriction><Fetal Growth Retardation><Fetal health><Fetus><Functional disorder><Future><Generalized Growth><Gestation><Glucose><Growth><Health><Human><Hydrogen Oxide><Hypertension><IUGR><Impaired cognition><Impairment><In Vitro><Industrialized Countries><Industrialized Nations><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intrauterine Growth Retardation><K channel><Length><Life><Maternal Nutrition><Maternal diet><Measures><Mediating><Membrane Potentials><Mesenteric><Mesentery><Metabolic><Metabolic syndrome><Modeling><Modern Man><Molecular Analysis><Mothers><Myography><NIEHS><NO3-><National Institute of Environmental Health Sciences><Nature><Neovascularization Inhibitors><Neurologic><Neurological><Newborn Infant><Newborns><Nitrates><Nitrites><Normal Placentoma><Nutrient><Organ><Outcome><PFAS><PGI2><Pathway interactions><Perfusion><Perinatal Care><Physiopathology><Pilot Projects><Placenta><Placenta Embryonic Tissue><Placentome><Policies><Poly-fluoroalkyl substances><Potassium Channel><Potassium Ion Channels><Pregnancy><Pregnancy Complications><Pregnant Women><Process><Production><Prostaglandin I2><Public Health><Radioactive Tracers><Rat><Rats Mammals><Rattus><Relaxation><Research Priority><Resistance><Resting Potentials><Risk><Risk Assessment><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Spiral Artery><Spiral Artery of the Endometrium><Structure of umbilical artery><System><Systemic blood pressure><Telemetries><Telemetry><Testing><Time><Tissue Growth><Tissues><Toxic effect><Toxicities><Transmembrane Potentials><Umbilical Arteries><Uterus><VEGF><VEGFs><Vascular Diseases><Vascular Disorder><Vascular Endothelial Growth Factors><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vascularization><Vasodilatation><Vasodilation><Vasorelaxation><Water><Woman><Work><X-ray microtomography><Xray microtomography><adulthood><ages><aminoacid><angiogenesis><antiangiogenic><balance><balance function><bioaccumulation><biological signal transduction><biomonitoring><blood pressure elevation><blood vessel disorder><cardiovascular function><causation><cell sorting><channel blockers><clinical care><cognitive dysfunction><cognitive loss><complications during pregnancy><consumer product><developed country><developed nation><developed nations><developmental><disease causation><elevated blood pressure><endothelial dysfunction><environmental agent><expectant mother><expecting mother><fatty acid transport><fetal><hemodynamics><high blood pressure><high risk><human tissue><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><impaired fetal growth><in vivo><increase in blood pressure><increased blood pressure><interventional strategy><intra-uterine growth><intra-uterine growth restriction><intra-uterine growth retardation><intrauterine growth><intrauterine growth restriction><knock-down><knockdown><maternal nutrition during pregnancy><micro CT><micro computed tomography><microCT><microtomography><mother nutrition><newborn child><newborn children><nitrate><offspring><ontogeny><overexpress><overexpression><pathophysiology><pathway><perfluorinated alkyl substances><perfluoro octane sulfonate><perfluoro-octane sulfonic acid><perfluoroalkyl substances><perfluoroalkylated substances><perfluorooctane sulfonate><perfluorooctane sulfonic acid><perfluorooctanesulfonate><perfluorooctanesulfonic acid><perinatal morbidity><pilot study><polyfluorinated alkyl substances><polyfluoroalkyl substances><pregnancy-related complications><pregnant><pregnant mothers><prenatal growth disorder><programs><prostaglandin X><reproductive><resistant><sex><social role><telemetric><translational study><trophoblast><vascular><vascular dysfunction><vasculopathy><womb>