Cardiovascular disease (CVD) in its various forms is the leading cause of death in the United States. Reverse cholesterol transport is a mechanism by which cholesterol present in atherosclerotic plaques within arterial walls is transported to the liver via high density lipoprotein particles for excretion in bile. Recent studies have suggested that human cholesteryl ester hydrolase (CEH), an enzyme that metabolizes cholesteryl esters, plays an important role in the regulation of reverse cholesterol transport. This enzyme is identical to the carboxylesterase CES1. Our long term goal is to understand the role that environmental toxicants such as agricultural chemicals play in human disease. Three commonly used organophosphate (OP) insecticides will be used in this proposed study. The hypothesis to be tested is that exposure to OP insecticides will inhibit the CEH/CES1-catalyzed metabolism of cholesteryl esters, which could therefore increase the risk of developing atherosclerosis.
Three aims are proposed: (1) Determine the dose response curve for the oxons of chlorpyrifos, parathion, and methyl parathion that inhibit the cholesterol ester hydrolyzing activity of recombinant CEH/CES1 enzyme;(2) Determine the dose response curve for these same oxons with respect to inhibition of CEH/CES1 activity in a human monocyte/macrophage cell line (THP1);(3) Characterize the CEH/CES1 protein adducts formed after treatment of recombinant CEH/CES1 and THP1 cells with chlorpyrifos oxon. We will determine the potency of the active metabolites (oxons) of three environmentally relevant OP insecticides to inhibit CEH/CES1-catalyzed cholesteryl ester hydrolysis activity in a cell-free system and in cultured cells. Furthermore, we will identify the covalent adduct of the protein that inactivates enzyme function. Several environmental factors may increase the incidence of CVD in humans. The results from this study will provide preliminary insights into whether OP oxon metabolites can directly alter the structure-function of an enzyme involved in cholesterol metabolism, thus leading to an increased probability of a pathological outcome (i.e. atherosclerosis). These studies will determine if active metabolites (oxons) of three environmentally relevant organophosphate insecticides can interfere with cholesterol metabolism.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Academic Research Enhancement Awards (AREA) (R15)
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Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
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Nadadur, Srikanth
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Mississippi State University
Public Health & Prev Medicine
Schools of Veterinary Medicine
Mississippi State
United States
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Mangum, Lee C; Hou, Xiang; Borazjani, Abdolsamad et al. (2018) Silencing carboxylesterase 1 in human THP-1 macrophages perturbs genes regulated by PPAR?/RXR and RAR/RXR: down-regulation of CYP27A1-LXR? signaling. Biochem J 475:621-642
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Ross, Matthew K; Pluta, Kim; Bittles, Victoria et al. (2016) Interaction of the serine hydrolase KIAA1363 with organophosphorus agents: Evaluation of potency and kinetics. Arch Biochem Biophys 590:72-81
Matthews, Anberitha T; Lee, Jung Hwa; Borazjani, Abdolsamad et al. (2016) Oxyradical stress increases the biosynthesis of 2-arachidonoylglycerol: involvement of NADPH oxidase. Am J Physiol Cell Physiol 311:C960-C974
Mangum, Lee C; Borazjani, Abdolsamad; Stokes, John V et al. (2015) Organochlorine insecticides induce NADPH oxidase-dependent reactive oxygen species in human monocytic cells via phospholipase A2/arachidonic acid. Chem Res Toxicol 28:570-84
Matthews, Anberitha T; Ross, Matthew K (2015) Oxyradical Stress, Endocannabinoids, and Atherosclerosis. Toxics 3:481-498
Szafran, Brittany; Borazjani, Abdolsamad; Lee, Jung Hwa et al. (2015) Lipopolysaccharide suppresses carboxylesterase 2g activity and 2-arachidonoylglycerol hydrolysis: A possible mechanism to regulate inflammation. Prostaglandins Other Lipid Mediat 121:199-206
Ross, Matthew K; Borazjani, Abdolsamad; Mangum, Lee C et al. (2014) Effects of toxicologically relevant xenobiotics and the lipid-derived electrophile 4-hydroxynonenal on macrophage cholesterol efflux: silencing carboxylesterase 1 has paradoxical effects on cholesterol uptake and efflux. Chem Res Toxicol 27:1743-56
Ross, Matthew K; Matthews, Anberitha T; Mangum, Lee C (2014) Chemical Atherogenesis: Role of Endogenous and Exogenous Poisons in Disease Development. Toxics 2:17-34

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