Impact of Per/Polyfluoroalkyl pollutants on vascular disease mechanisms

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Project Summary/Abstract Per- and polyfluoroalkyl substances (PFAS) are manmade chemicals that are extensively used in industrial and consumer products such as stain- and water-repellent fabrics, food contact materials, polishes, waxes, paints, and foams. PFAS have exceptionally long half-lives, can bio-accumulate in humans, and are omnipresent in the environment including our food and drinking supplies. This proposal will focus on the growing evidence that PFAS exposures are associated with negative health outcomes and may play a role in the pathogenesis of cardiovascular diseases. Our preliminary data show that PFAS disrupt key physiological functions of human blood vessels by impairing arteriolar vasomotor function and angiogenesis. In this application, we will seek to characterize, to our knowledge for the first time, causal pathophysiological actions of diverse classes of PFAS toxicants upon the human vascular system. To achieve our objectives, we will employ complementary approaches harnessing physiological studies of vasodilator function and angiogenesis, and mouse models tailored to human-relevant conditions and chronic exposure scenarios to gain novel insights into mechanisms of PFAS-mediated vascular disease. In Aim 1, we will characterize the effects of PFAS pollutants on the human adipose tissue microvasculature by examining endothelium-dependent and –independent vasodilator responses using videomicroscopy in live intact arterioles, and perform angiogenic assays from human fat biopsies collected during elective surgical procedures in 50 male and female subjects. We will test the hypothesis that select PFAS have negative effects upon the human vascular system. Aim 2 will investigate the ability of specific PFAS, using chronic, low-dose, human-relevant exposure scenarios to induce the development of vascular dysfunction and atherosclerosis in male and female mouse models that express the human PPARα gene and fed an American diet. We will test the hypothesis that long-term exposure of select PFAS toxicants can impair vascular function and induce atherosclerosis in vivo. Our approach includes a diverse complementary team involving clinical cardiovascular (Dr. Gokce) and environmental toxicology (Dr. Schlezinger) expertise, and combines studies of physiology utilizing live human biospecimens, molecular toxicology, and an in vivo murine chronic exposure model to study acute and long-term effects of PFAS upon the vasculature. The overall project tackles an unmet clinical need for innovative research as outlined by the recently established PFAS Commitments to Action Strategic Roadmap (2021-2024) by the EPA, for understanding how PFAS pollutants can play causal roles in mediating human disease. This overall project is positioned to move the field forward, and may lead to the identification of new interventions and public health approaches to mitigate toxicant-induced cardiovascular diseases.