Role of PXR in EDC-induced cardiovascular disease

Project Summary Atherosclerotic cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide and recent large-scale human studies have implicated a link between exposure to endocrine disrupting chemicals (EDCs) and CVD. However, how exposure to EDCs and other environmental chemicals influences CVD risk is still poorly understood, and continues to hamper assessment of the health risks of EDC exposure. With the NIEHS funding support, we have identified many EDCs as potent agonists of the xenobiotic sensor pregnane X receptor (PXR). The identification of EDCs as PXR ligands has provided an important tool for the study of new mechanisms through which EDC exposure impacts disease. Our laboratory was the first to reveal the novel function of PXR in the regulation of atherosclerosis development, and has also demonstrated that widely-used EDCs including bisphenol A, dicyclohexyl phthalate, and tributyl citrate increase atherosclerosis and dyslipidemia through PXR signaling in various mouse models. Influences of the chemical environment on human health have become the subject of intense interest but very few studies in the EDC research field have focused on atherosclerosis development. My diverse scientific training in molecular biology, toxicology, pharmacology, and cardiovascular research has put me in a unique position to investigate how “gene-EDC interactions” affect atherosclerosis development and lipid homeostasis. This EDC-Induced CVD Revolutionizing Innovative, Visionary Environmental health Research Program (EICVD-RIVER) will allow me to investigate the broad scientific theme of the impact of EDC exposure on lipid homeostasis and atherosclerosis in adults and their offspring. EICVD-RIVER will address the following specific scientific questions: 1) How many common chemicals in plastic and other consumer products act as EDCs to modulate PXR activities? Can different EDC mixtures synergistically activate PXR? 2) Through which cell-specific mechanisms do EDCs induce dyslipidemia and atherosclerosis? 3) How does PXR regulate ceramide homeostasis to affect EDC- induced atherosclerosis? 4) Do microplastics have a Trojan Horse effect on EDC-induced atherosclerosis? Can they bring EDCs intracellularly to have synergistic or additive impact on PXR-mediated atherosclerosis? 5) Does paternal exposure to PXR agonistic EDCs affect the atherosclerosis development of the offspring? How does PXR signaling alter the sperm RNA code to increase CVD risk of the offspring? The proposed studies will contribute to our understanding of gene-EDC interactions in predisposing individuals and their offspring to CVD, and my expertise and experience are an ideal fit for the RIVER mechanism that supports a multi- dimensional long-term study of the proposed research.