The goal of this project is to investigate a novel mechanism linking exposure to endocrine disrupting chemicals (EDCs) with dyslipidemia and cardiovascular disease. The pregnane X receptor (PXR) is a nuclear receptor activated by numerous drugs, xenobiotic and dietary chemicals. Many EDCs activate PXR, including organochlorine and organophosphate pesticides, alkylphenols, phthalates, polychlorinated biphenyls, bisphenol A and its analogs. However, the role of PXR in mediating the pathophysiological effects of EDCs in humans and animals remains elusive. Mounting evidence implicates EDC exposure in the development of chronic human diseases but the contribution of these EDCs to the etiology of cardiovascular disease (CVD), obesity, and diabetes is poorly understood. We have recently revealed the pro-atherogenic effects of PXR in animal models and demonstrated that chronic PXR activation induces hyperlipidemia in wild-type mice and increases atherosclerosis in atherosclerosis-prone apolipoprotein E deficient (ApoE-/-) mice. Our central hypothesis is that EDCs which activate PXR will lead to hyperlipidemia and accelerated atherosclerosis in mice, thereby increasing the risk of CVD in exposed individuals. We propose the following specific aims to test this hypothesis: 1) What are the molecular mechanisms through which intestinal PXR activation induces hyperlipidemia? 2) How does exposure to FDA-approved phthalate substitute plasticizers elevate plasma lipid levels in mice? 3) Is EDC-mediated PXR activation necessary and sufficient to increase atherosclerosis development in ApoE-/- mice? Our research will establish the role of PXR in linking exposure to EDCs with hyperlipidemia and CVD, and will provide novel mechanistic links explaining how EDC exposure causes atherogenic effects. These studies are broadly translational and will provide strong evidence to inform future risk assessment for EDCs.

Public Health Relevance

Cardiovascular disease is the leading cause of death worldwide and can be caused by genetic and environmental factors. The proposed studies will investigate the mechanisms through which exposure to certain environmental chemicals leads to hyperlipidemia and cardiovascular disease. These studies will provide important new information about underlying causes of cardiovascular disease and strong evidence to inform future risk assessment for environmental chemicals.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Heindel, Jerrold
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University of Kentucky
Schools of Medicine
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Wang, Fang; Liu, Zun; Park, Se-Hyung et al. (2018) Myeloid ?-Catenin Deficiency Exacerbates Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice. Arterioscler Thromb Vasc Biol 38:1468-1478
Memetimin, Hasiyet; Li, Dong; Tan, Kaiyuan et al. (2018) Myeloid Specific Deletion of Thrombospondin 1 Protects Against Inflammation and Insulin Resistance in Long-term Diet-induced Obese Male Mice. Am J Physiol Endocrinol Metab :
Sui, Yipeng; Park, Se-Hyung; Wang, Fang et al. (2018) Perinatal Bisphenol A Exposure Increases Atherosclerosis in Adult Male PXR-Humanized Mice. Endocrinology 159:1595-1608
Sui, Yipeng; Liu, Zun; Park, Se-Hyung et al. (2018) IKK? is a ?-catenin kinase that regulates mesenchymal stem cell differentiation. JCI Insight 3:
Helsley, Robert N; Zhou, Changcheng (2017) Epigenetic impact of endocrine disrupting chemicals on lipid homeostasis and atherosclerosis: a pregnane X receptor-centric view. Environ Epigenet 3:
Helsley, Robert N; Sui, Yipeng; Park, Se-Hyung et al. (2016) Targeting I?B kinase ? in Adipocyte Lineage Cells for Treatment of Obesity and Metabolic Dysfunctions. Stem Cells 34:1883-95
Park, Se-Hyung; Liu, Zun; Sui, Yipeng et al. (2016) IKK? Is Essential for Adipocyte Survival and Adaptive Adipose Remodeling in Obesity. Diabetes 65:1616-29
Zhou, Changcheng (2016) Novel functions of PXR in cardiometabolic disease. Biochim Biophys Acta 1859:1112-1120
Cui, Wenpeng; Maimaitiyiming, Hasiyeti; Zhou, Qi et al. (2015) Interaction of thrombospondin1 and CD36 contributes to obesity-associated podocytopathy. Biochim Biophys Acta 1852:1323-33
Sui, Yipeng; Helsley, Robert N; Park, Se-Hyung et al. (2015) Intestinal pregnane X receptor links xenobiotic exposure and hypercholesterolemia. Mol Endocrinol 29:765-76

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