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Record Count: 5
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header (Title, Principal Investigator, Institution, City, ST, Award Code, or
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DESCRIPTION (provided by applicant): 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.
DESCRIPTION (provided by applicant): This application for an R21 grant is designed to solidify an interdisciplinary team of basic and clinical researchers in the Center for Environmental Health Sciences at Mississippi State University for research into the environmental factors contributing to the higher mortality of cardiovascular disease (CVD) in the Deep South and among African Americans, and to position this team for participation in larger-scale on- going multi-institutional epidemiological studies. This health disparity in CVD is logically related to risk factors more prevalent in the South (which has a higher proportion of African Americans than other regions in the country.) The South is rural and highly agricultural, so the Southern populations would be expected to be routinely exposed to higher levels of pesticides than populations in many other regions. We hypothesize the following: The effects of pesticide exposure contribute to the development of CVD and are more pronounced in the African American population. Two enzymes that we have studied for many years because of their involvement in the detoxication of many pesticides are paraoxonase (PON1) and carboxylesterase (CaE). The former is known to be associated with HDL particles and the latter has recently been identified as a cholesteryl ester hydrolase that is involved in reverse cholesterol transport; therefore, both of these enzymes are involved in vascular health, and are potential biomarkers of susceptibility to CVD. We have experience biomonitoring urinary pesticide metabolites as an index of current pesticide exposure. We have developed a novel geospatial analysis of pesticide harvested crop records that predicts pesticide exposure to individuals for the previous 35 years of their lives. We have experience in cardiology and access to patients in a cardiology practice. We propose a pilot study to investigate the above listed parameters (i.e., PON1 and CaE in the blood and pesticide metabolites in the urine) of subjects recruited from the cardiology practice, and to calculate strength of associations among these factors, the degree of cardiovascular disease and the pesticide exposure estimated in the geospatial analysis model. This pilot study will be conducted following a year of planning, solidifying the interdisciplinary team, optimizing assays, and developing interactions with the project's consultants. The pilot study will position us to participate in a far more extensive study through interactions with our consultants at the University of Alabama at Birmingham. In addition, we anticipate that we will develop more simplified assay methods for PON1 and CaE that will be more amenable for use as a clinical biomarker.
DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of death in the U.S. today and has been so for the last century. Approximately 70 million Americans suffer from some form of cardiovascular disease and many require ongoing pharmacological therapy. Mississippi has the highest annual age-adjusted death rate from cardiovascular disease of any state in the U.S. Known risk factors for cardiovascular disease probably account for much of this disparity but other factors may be playing a role. Increasingly, the role of environmental toxicants in cardiovascular disease is being recognized. Mississippi has an agricultural based economy and much of the population resides in rural settings close to where crops are grown. This proximity results in the contact of the population with current use pesticides as well as legacy pesticides, those pesticides used in the past but persistent in the environment today. Recent studies have shown exposure to chlorpyrifos, an organophosphate insecticide, in utero can affect the adenylyl cyclase signaling pathway in cardiac myocytes. However, little is known about the effect of pesticides on the development, progression, and pharmacological treatment of cardiovascular disease. This grant proposes to examine the effects of two environmentally relevant pesticides, dieldrin and chlorpyrifos, on the rat cardiac proteome. Dieldrin is a legacy pesticide used extensively in the 1950's and 1960's (though currently banned in the U.S.) which is still present in soil samples from the Mississippi Delta region. Chlorpyrifos is a pesticide in current use. The goal of this grant is to identify proteins whose levels of transcription and/or post-translational modifications are altered by exposure to these two pesticides. The proteins thus identified will serve to direct further studies aimed at identifying the mechanism of toxicity of these pesticides. Our long-term objective is to better understand the extent to which commonly used pesticides and other environmental chemicals influence heart disease and its treatment.
Crisp Terms/Key Words: two dimensional gel electrophoresis, protein quantitation /detection, proteomics, environmental exposure, environmental toxicology, protein structure function, posttranslational modification, protein biosynthesis, pesticide biological effect, heart function, heart disorder, gene expression, pathologic process, cardiovascular disorder epidemiology, cardiovascular disorder chemotherapy, laboratory rat
DESCRIPTION (provided by applicant): Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants that are a human health concern because they are implicated in human cancers and endocrine disruption. The fish Fundulus heteroclitus will be used as a model organism to investigate the central hypothesis that CYP1B and/or CYP19 are involved in the molecular mechanisms of benzo(a)pyrene-mediated toxicity. The Specific Aims are to:
1) Assess the respective roles of CYP1B and CYP19s in BaP and estrogen metabolism and estrogen synthesis with in vitro recombinant systems,
2) Determine the extent, to which BaP-induced CYP1 B-mediated metabolism is important in genotoxicity. Aim 2.1: In adult fish following BaP exposure, the relationship between tissue specific CYP1B expression, toxic metabolite formation, DNA adducts and oxidative stress will be quantitated. Aim 2.2: Determine how egg or larval BaP-exposure affects CYP1B expression and associated toxicological endpoints. Aim 2.3: Determine how CYP1B and CYP19 are up-regulated in tumor tissues in exposed fish.
3) Measure the association between BaP-induced changes in aromatase and Fundulus reproductive or developmental success.
Aim 3.1: Determine if maternal BaP-exposure decreases reproductive success.
Aim 3.2: Determine if and how egg and larval BaP exposures alter aromatase expression and if this is correlated with developmental deficiencies. Successful completion of these Aims will provide a greater molecular understanding of these important P450 genes and their role in the mechanisms of action of PAHs. This research will further define the utility of Fundulus as a model organism for studying PAH-associated toxicities and in the development of human CYP19 or CYP1 B-related therapeutics.
DESCRIPTION (provided by applicant): Sodium methyldithiocarbamate (SMD, also called metam sodium) is the third most abundantly used conventional agricultural pesticide in the U.S. It spontaneously breaks down to form methylisothiocyanate MTC), which has been classified a toxic air contaminant by the California EPA and which shares some immunomodulatory actions, with SMD. Both SMD and MITC alter toll-like receptor signaling in mouse peritoneal macrophages and cause substantial increases in the concentration of IL-10 and substantial decreases in IL-12 (and other pro-inflammatory cytokines and chemokines) in mice treated with bacterial lipopolysaccharide (IPS). SMD also substantially reduces innate resistance to Escherichia coli peritonitis in mice. A number of other chemicals and drugs cause increased expression of IL-10 and decreased expression of IL-12. Because these changes would tend to decrease innate immunity, understanding the mechanisms by which SMD and MITC affect these parameters has broad implications for human health, even for persons not exposed to SMD or MITC. This project will test the following hypothesis: SMD alters signaling through TLR4 to decrease the production of IL-12 and to increase IL-10 production by altering cellular redox balance, altering copper availability, and inducing stress mediators. These effects play key roles in decreasing innate resistance to infection with E. coli. Three aims will be used to test the hypothesis of this project: Specific Aim 1- Determine the mechanism(s) by which SMD and MITC increase LPS-induced IL-10 production and decrease LPS-induced IL-12 production by peritoneal macrophages. Specific Aim 2- Determine the mechanism(s) by which SMD alters activation of upstream kinases involved in IL-10 and IL-12 expression and determine the role of increased IL-10 expression in the SMD and MITC-induced decreases in IL-12 expression. Specific Aim 3- Determine the role of each of the mechanisms evaluated in Aims 1 and 2 in the decreased resistance to E. coli peritonitis in SMD or MITC treated mice. In each Aim the mechanisms to be investigated are those noted in the hypothesis (altered redox balance, altered copper availability, and induction of stress mediators). In Aim 3, mathematical models will be developed to predict or describe the relationships between changes in signaling, gene expression, and host resistance. These results will represent a new (systems biology) approach to immunotoxicology. These results will allow mechanism based risk assessment for SMD and MITC for the first time. It is also expected that the detailed study of three important mechanisms of action, which will be examined in each aim, can be generalized to other situations or toxicants that alter these parameters.