Endocrine Disrupting Chemicals, PXR and Atherosclerosis

  • Zhou, Changcheng (PI)

Grants and Contracts Details


Despite enormous research efforts and advances in treatments in the past few decades, atherosclerosis is still a major health problem in the United Sates and around the world. The etiology of atherosclerosis is complex, involving a mix of genetic and environmental factors interacting with each other over years. While recent studies utilizing genome wide association have revealed many new genes involved in atherosclerosis, the study of “gene-environment interactions” related to cardiovascular disease has lagged far behind. In addition to the obvious contributions of diet and lifestyle to the high incidence of atherosclerosis, recent findings have implicated a link between exposures to endocrine disrupting chemicals (EDCs) and cardiovascular disease. However, the roles of EDCs in the etiology of atherosclerosis are poorly understood. Many EDCs including bisphenol A (BPA), alkylphenols, phthalates, polychlorinated biphenyls (PCBs), organochlorine, and organophosphate can activate a xenobiotic receptor pregnane X receptor (PXR). PXR is a nuclear hormone receptor activated by a diverse array of endogenous hormones, dietary steroids, pharmaceutical agents, and xenobiotic compounds. PXR functions as a xenobiotic sensor to coordinately regulate xenobiotic metabolism in the liver and intestine. More recently, we found that in atherosclerosis sensitive apolipoprotein E deficient (ApoE-/-) mice chronic PXR activation decreased HDL cholesterol levels and increased atherosclerosis. Furthermore, PXR activation significantly altered expression of atherosclerosis modifier genes in the liver. We hypothesize that long-term exposure to EDCs that can activate PXR may lead to aberrations of lipid homeostasis and increased atherosclerosis. To test this hypothesis, we propose to 1) investigate the species-specific role of PXR in atherosclerosis; 2) determine the contribution of PXR towards the atherogenic effects of PXR-related EDCs using knockout and transgenic humanized mice; and 3) explore the anti-atherogenic potential of the human PXR antagonist sulforaphane. Taken together, the proposed research may reveal an important molecular mechanism by which EDCs induce metabolic disorders and atherosclerosis. The discovery and pharmacological development of new PXR modulators might represent an innovative approach to prevent EDC-elicited atherogenesis.
Effective start/end date2/1/106/30/11


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