Altered Lipid Metabolism: A Novel Mechanism of Maternal Blood PFAS and Preeclampsia Pathogenesis

Abstract

Pregnancy-induced hypertension, commonly known as preeclampsia, complicates nearly 3-5% of all pregnancies and is responsible for 10-25% of all maternal deaths and approximately 500,000 infant deaths worldwide. Recent work has identified a strong association between exposure to per- and polyfluoroalkyl substances (PFAS), a persistent and pervasive environmental contaminant, and an array of adverse pregnancy and birth outcomes, including preeclampsia; however, little is known about the pathophysiological mechanisms linking exposure to disease progression. As known peroxisome proliferator-activators receptor (PPAR) agonists, PFAS have been shown to disrupt lipid metabolism, leading to lipid abnormalities and increased risk of metabolic diseases. In an effort to better understand the influence of lipid metabolism dysfunction in the context of PFAS exposure and adverse pregnancy outcomes, this research aims to elucidate the mechanisms by which PFAS may disrupt lipid profiles during pregnancy and in placental trophoblasts. By integrating cell-based assays with multi-omic and epidemiological methods, this work provides critical insights into how PFAS exposure impacts complex biological pathways. The overall objective of our research is to evaluate the effect of PFAS exposure on lipid metabolism and related mechanisms associated with placental dysfunction that may lead to preeclampsia during pregnancy. We hypothesized that PFAS exposures during pregnancy induce significant alterations in lipid metabolism that contribute to preeclampsia pathogenesis via modifications in PPAR signaling. We examined these influences in three aims, designed to (1) identify lipid species associated with maternal blood PFAS concentrations across multiple gestational timepoints in the Michigan Mother Infant Pairs (MMIP) birth cohort, (2) evaluate PPARα and PPARγ lipid receptor binding in two placental trophoblast cell models, extravillous trophoblasts (HTR8/SVneo) and syncytiotrophoblasts (BeWo), following exposures to biologically relevant concentrations of PFOA, PFHxS, and a PFAS mixture, and (3) investigate the changes in gene expression and lipids in placental trophoblasts exposed to PFHxS and PFAS mixtures. In the first aim of this dissertation, we identified an association between maternal PFHxS and altered sphingomyelin (SM) and diacylglycerol (DG) concentrations in the first trimester samples. These changes, occurring in uncomplicated pregnancies and in the presence of very low circulating PFAS levels, further support the significance of lipid modifiable pathways as potential targets of PFAS exposure in pregnancy. In aim 2, we were the first to identify a strong propensity for PFHxS and PFOA to bind to PPARγ in placental syncytiotrophoblasts at concentrations as low as those in the average U.S. adult. Interestingly, no consistent increase in PPARα competitive binding was observed in either cell type following exposure, potentially indicating non-PPAR-related targets of PFAS. In the final aim, we describe significant alterations in both lipid concentrations and gene expression that differed depending on the cell type exposed, with HTR8/SVneo extravillous trophoblasts disproportionately impacted by PFAS exposure. Of note, HTR8/SVneo cells had an increase in expression of acylcarnitines alongside modifications in certain genes such as FN1, LRP1, AHNAK, HSPG2, UBR4, and SACS, some of which may be regulated by PPARs. The transcriptomics and lipidomics results emphasize the influence of PFAS at the cellular level involving modifications in lipid metabolism, apoptosis, extracellular matrix integrity, trophoblast motility/growth, autophagy, and intracellular trafficking. Cumulatively, these research aims incorporate a multi-faceted approach to understanding the impact of PFAS on lipid metabolism and placental cell health and can aid in improving our understanding of the biomolecular changes contributing to the pathogenesis of adverse pregnancy outcomes, including preeclampsia.