Endocrine disruptor mediated activation of PXR causes dyslipidemia

The goal of this project is to investigate a novel mechanism linking endocrine disrupting chemical (EDC) exposure and hyperlipidemia. The pregnane X receptor (PXR) is a nuclear receptor activated by numerous drugs, xenobiotic and dietary chemicals. Many endocrine disrupting chemicals (EDCs) activate PXR, including organochlorine and organophosphate pesticides, alkylphenols, phthalates, polychlorinated biphenyls (PCBs), bisphenol A (BPA) and its analogs. 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 hypercholesterolemia in wild-type (WT) 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 and increase 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 espouse 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.