The potential effects of a universal plasticizer alkylsulfonic phenyl ester on dyslipidemia and atherosclerosis

The National Institute of General Medical Sciences awarded the University of Nebraska $132,735 on July 27, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to investigate the potential effects of a universal plasticizer alkylsulfonic phenyl ester on dyslipidemia and atherosclerosis. The project examines whether the plasticizer, widely used in food packaging, medical tubing, and children's toys, activates the pregnane X receptor and contributes to atherosclerotic development through mechanisms similar to previously identified endocrine-disrupting chemicals. The research builds on preliminary data and animal models showing that PXR activation increases atherosclerotic development in LDLR-deficient and APOE-deficient mouse models, with implications for understanding cardiovascular disease risk from chemical exposure. Performance occurs at the University of Nebraska, Kearney, Nebraska, with a period of performance through May 31, 2030.

Abstract

Atherosclerotic cardiovascular disease (CVD) is the leading cause of mortality worldwide despite of advanced diagnosis and treatment. Our chemical environment has changed substantially in the past few decades, and recent large-scale human studies have implicated a novel link between exposure to endocrine disrupting chemicals (edcs) and CVD. Plastics have become an essential part in modern life, and plastic pollution is a significant environmental and health concern. Plastic-associated edcs including numerous plasticizers are produced in high volume and have been demonstrated to be associated with increased CVD risk in humans. However, the underlying mechanisms for the EDC-associated CVD are still poorly understood, making IT difficult to conduct rational exposure assessment. Many plastic-associated edcs including bisphenol a, phthalates, and phthalate substitutes have been previously identified as potent agonists of pregnane x receptor (PXR), which is a nuclear receptor activated by a variety of environmental chemicals, dietary steroids, and pharmaceutical agents. PXR functions as a xenobiotic sensor activating the expression of genes required for xenobiotic metabolism in the liver and intestine, two organs that play a central role in whole body lipid homeostasis. In addition to the role in xenobiotic metabolism, the atherogenic effect of PXR has been revealed in animal models. PXR has been shown to contribute to increased atherosclerotic development in atherosclerosis-prone low-density lipoprotein receptor-deficient (ldlr-/-) and apolipoprotein e-deficient (apoe-/-) mouse models. Our preliminary data suggests that PXR could be activated by a non-phthalate plasticizer, alkylsulfonic phenyl ester (ASE), which is widely used for food packing, medical tubing, and children's toys. However, IT is still unclear whether ASE could cause adverse atherogenic effects through PXR signaling. The objective of this project is to assess the potential risks of ASE in dyslipidemia and atherosclerosis. The central hypothesis is that ASE promotes lipid absorption by activating PXR signaling resulting in increased plasma lipid levels and atherosclerotic development. Three specific aims are proposed by our undergraduate research team to test this hypothesis: 1) what molecular mechanisms underly PXR activation by ASE? 2) how does acute ASE exposure affect lipid uptake and lipid profiles through PXR? 3) does chronic ASE exposure increase atherosclerotic development in atherosclerosis-prone apoe-/- mice via PXR signaling? The proposed studies are the first to explore the cellular and molecular mechanisms by which exposure to ASE activates human PXR and increases the risk of dyslipidemia and atherosclerosis. These studies are broadly translational and will provide strong evidence to inform future CVD risk assessment for the universal plasticizer ASE as well as other environmental chemicals. Our proposed project will benefit our undergraduate students by gaining meaningful cardiovascular research experience.