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Record Count: 33
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DESCRIPTION (provided by applicant): This project pursues the hypothesis that lifetime cumulative exposure to ambient air pollution is associated with sonographically measured carotid intima-media thickness (CIMT) at age 18-20. CIMT is an established marker of subclinical atherosclerosis - the primary pathogenic process of cardiovascular diseases (CVD). CIMT gradually increases from birth to death and is associated with subclinical inflammation at all ages, and is a strong determinant of CVD. Ambient air pollution is associated with cardiovascular mortality and morbidity and is a cause of pulmonary and systemic inflammation - a hallmark of atherosclerosis. Significant associations between air pollution and CIMT have been reported in adults. Long-term exposure to air pollution also adversely affects lung function (LF) which is a strong predictor of CVD mortality. Both pulmonary and systemic inflammation is an important correlate of poor LF. Poor LF also modifies the distribution and uptake of pollutants in the respiratory tract, leading to higher tissue dose. Given systemic inflammation affecting CIMT, LF and dyslipidemia, low LF, high C-reactive protein (CRP) and high lipids (LDL) these markers will be used to those most susceptible to atherogenic effects of air pollution. CIMT, lifetime residential history, cardio-respiratory covariates, LF, LDL and CRP will be assessed among 800 non-smoking USC College students with lifetime California residencies. Statewide air pollution monitoring information will be assembled to interpolate monthly fine particulate matter (PM2.5), nitrogen- dioxide (NO2) and ozone (O3) concentrations to each residence across lifetime. Concentrations will be weighted by activity levels and time spent indoors and outdoors to individually derive estimates of lifetime exposure. The association between exposure and CIMT and the interaction with LF, CRP and LDL will be investigated with multivariate regressions, tests for interactions, and structural equation modeling. The American Heart Association recommends focusing on prevention of atherosclerosis in early life. Air pollutants represent ubiquitous inflammatory exposures, and millions of young Americans live in areas that exceed current government standards. Small differences in CIMT and LF at a young age translate into clinically relevant diseases, including CVD - the leading cause of mortality in the U.S.
DESCRIPTION (provided by applicant): Benzo[a]pyrene (BaP) is an environmental pollutant. Besides inducing cancers in humans, BaP has been shown to promote the development of atherosclerosis, which is the primary cause of coronary heart disease and stroke. The mechanism underlying the atherogenic action of BaP remains unknown. A currently popular theory postulates atherosclerosis as an inflammatory process driven by reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. BaP has been shown to increase intracellular ROS. Thus, the project described herein hypothesizes that generation of ROS in vascular cells is a key mechanism by which BaP promotes atherogenesis. Our laboratory has generated mouse models that overexpress Cu/Zn-superoxide dismutase (Cu/Zn-SOD) or catalase alone, or both Cu/Zn-SOD and catalase. Cu/Zn-SOD is a protein that converts superoxide to hydrogen peroxide, while catalase destroys hydrogen peroxide by converting it to water. As the relative contribution of different ROS to atherosclerosis might vary, our animal models provided a valuable tool for testing the role of superoxide and hydrogen peroxide in BaP-induced atherosclerosis. The transgenic mice overexpressing Cu/Zn-SOD and/or catalase have been crossbred into the apolipoprotein E (ApoE)-deficient mice, which spontaneously develop atherosclerotic lesions with morphological features closely resembling the atherosclerotic lesions that occur in humans. In this project, the ApoE-deficient mice, with or without overexpression of Cu/Zn-SOD and/or catalase, will be treated with BaP. We will determine: (1) whether overexpression of antioxidant enzymes inhibits BaP-induced atherogenesis and reduces the accumulation of inflammatory cells within the atherosclerotic lesions, (2) whether overexpression of antioxidant enzymes reduces BaP-induced accumulation of oxidized lipids and nitrotyrosine in the arterial wall, and (3) whether overexpression of antioxidant enzymes reduces BaP-induced atherogenic events in vascular cells, and inhibits BaP-induced gene expression and transcriptional factor activation. If our hypothesis described above is correct, BaP-induced atherosclerotic lesions will be smaller in mice overexpressing Cu/Zn-SOD and/or catalase, which will correlate to a decreased oxidative injury in the arterial wall and/or a reduced response of vascular cells to BaP.
DESCRIPTION: (provided by applicant) Heart disease is the leading cause of death and hospitalization among the elderly population, which makes the identification of preventable causes for heart disease morbidity and mortality a major goal of epidemiologic research. Numerous studies have shown associations of outdoor particulate matter (PM) air pollution with cardiovascular hospital admissions and mortality. The causal pollutant components and physiologic mechanisms for these associations are not fully understood. There is evidence that airway inflammation resulting from airway deposition of ultrafine particles (< 0.1 mu/m in diameter) could lead to an increase in thrombogenic and inflammatory activity in the blood, and to a disturbance in cardiovascular function, resulting from oxidant stress responses at extra-pulmonary sites, including the vascular endothelium of the heart. This is expected to increase the risk of adverse cardiovascular outcomes, particularly in people with underlying coronary heart disease (CHD). We propose to conduct a panel study with repeated measurements to evaluate acute cardiovascular and respiratory health effects of ultrafine PM personal, indoor and outdoor exposures. Over seven month periods, we will follow 72 nonsmoking elderly individuals with CHD living in areas with high air pollution levels in the Los Angeles Air Basin of California. The design will maximize the utility of intensive exposure assessments by measuring multiple interrelated clinical, physiological and biochemical outcomes. The specific aims will address the following hypotheses: 1) Exposure to ultrafine particles will be associated with increased circulating biomarkers of inflammation and thrombosis, increased blood pressure, adverse cardiac clinical outcomes, and increases in a biomarker of airway inflammation, exhaled nitric oxide; and 2) These associations will be stronger for measurements of particle components and certain ambient sources thought to influence inflammatory processes through oxidant damage. We will also evaluate relationships of outcomes with accumulation mode PM (0.18-2.5 mu/m) and coarse mode PM (2.5-10 fm). We will assess whether estimates of association for predicted (adjusted) personal or indoor exposure to ultrafine or accumulation mode PM of outdoor origin are stronger than estimates of association for unadjusted (raw) personal or indoor exposures. Results of this study will advance knowledge on the cardiovascular and respiratory effects of ultrafine particles. Our results are expected to clarify findings in the literature of associations between ambient particulate air pollution (PM10 and PM2.5) and severe cardiovascular outcomes, including mortality and hospital admissions.
Crisp Terms/Key Words: patient oriented research, outcomes research, clinical research, comorbidity, nitric oxide, pollution related respiratory disorder, longitudinal human study, particle, oxidizing agent, tumor necrosis factor alpha, interleukin 6, interleukin 1, human subject, electrocardiography, coronary disorder, inflammation, blood pressure, thrombosis, blood test, biomarker, air sampling /monitoring, air pollution, human old age (65+)
DESCRIPTION (provided by applicant): Air pollution and cardiovascular disease mortality are clearly linked, yet population-based studies of air pollution and arrhythmogenesis have not been conducted in women. Moreover, extant studies have not evaluated whether acute, pro-arrhythmic effects of exposure to ambient air pollutants are modified by three potentially important markers of the environmental, socioeconomic and clinical context within which such exposures ostensibly increase cardiovascular risk in women: chronic exposure status, neighborhood of residence, and disease-specific susceptibility factors for sudden death. We will investigate these issues in an ethnically diverse population of 68,133 post-menopausal women aged 59-70 years from the 40 clinical centers and their satellites participating in the baseline examination of the Women's Health Initiative clinical trial (WHI, 1993-1998). We will estimate exposure to criteria pollutants (PM10; NO2; SO2; CO; 03) in ambient air at geocoded participant addresses using validated, spatial models that rely on pollutant concentrations recorded at adjacent fixed-site monitors in the U.S. Environmental Protection Agency Aerometric Information Retrieval System. Spatially interpolated exposures will take the form of average pollutant concentrations on the day of, and for the 1, 2 & 3 days and 1, 2 & 3 years preceding the baseline examination and year three follow-up. We will reliably evaluate autonomic function, atrioventricular conduction, ventricular depolarization, ventricular repolarization and ectopy from resting, standard 12-lead ECGs recorded at the WHI examinations. After removing seasonal variations and long-term trends, and in addition, adjusting for demographic and meteorological covariates, we will explore the putative association between air pollutants and ECG measures. Then we will determine whether the associations are modified by chronic exposure status, socioeconomic characteristics of geographic regions in which participants live, and clinical risk factors for sudden cardiac death using Bayesian, hierarchical models. Lastly, we will assess sensitivity of our findings to adjustment for exposure measurement error arising from spatial interpolation of personal exposures from ambient concentrations of air pollutants. Our ancillary study will thereby evaluate the biologically relevant proarrhythmic mechanisms and contextual features linking ambient air pollution to cardiovascular disease morbidity and mortality in a large, ethnically and geographically diverse group of postmenopausal women. In doing so, it will improve understanding of associations between airborne pollutants and cardiovascular disease mortality, facilitate assessment of current U.S. air quality standards, and yield insight into the relatively gradual decline of sudden cardiac death rates among U.S. women over the last decade.
Crisp Terms/Key Words: cardiovascular disorder risk, clinical research, gene environment interaction, women's health, human data, socioeconomics, female, human morbidity, longitudinal human study, human population study, mathematical model, electrocardiography, sudden cardiac death, arrhythmia, geographic site, postmenopause, cardiovascular function, cardiovascular disorder epidemiology, air pollution, human old age (65+), human middle age (35-64)
DESCRIPTION (provided by applicant): Binding and activation of the Ah receptor (AhR) is required for the environmental toxin 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD, dioxin) to produce its toxic effects. TCDD toxicity includes a lethal wasting syndrome and cardiovascular dysfunction, but it is not known how TCDD activation of the AhR produces those effects. This research seeks to understand how TCDD activation of the AhR leads to suppression of gluconeogenesis, energy failure and death and to identify contributions of cytochrome P450 (CYP) 1A enzymes, the major transcriptional products of AhR activation, to the toxicity. The following hypothesis will be tested: (1) Transcriptional and posttranslational effects of TCDD on signaling pathways converging on PGC1?, i.e. Akt, AMPK, PKA and Sirt1, contribute to suppression of gluconeogensis by TCDD. PGC1? governs transcription of PEPCK and glucose 6-phosphatase, regulators of flux through the gluconeogenic pathway; (2) Suppression of gluconeogenesis forces reliance on lipids for energy but also limits availability of lipids as a fuel source; (3) Effects of TCDD on CYP-dependent metabolism of the membrane lipid arachidonic acid (aa) contribute to energy failure in liver and heart. The research will follow up on discoveries under prior funding periods of the grant that TCDD causes cardiac contractile dysfunction and increases hepatic formation of CYP-dependent aa epoxides, EETs, and decreases formation of 20-HETE, aa products with major physiologic cardiovascular regulatory effects, to examine their involvement in nutrient metabolism. TCDD will be used as a tool to learn how AhR activation and changes in CYP-dependent aa metabolism can lead to physiologic disturbances in glucose and lipid metabolism involved in the wasting syndrome (specific aim (SA) 1) and in ion channel and cardiac muscle function (SA2). Studies in SA2 will also determine whether increased production of EETs in liver affect the heart and are cardioprotective or cardiotoxic. The chick embryo close to hatching will continue to be used as the major model based on its track record in studying TCDD toxicity, its similarity to humans with respect to aa metabolism and its special utility for this research in permitting hepatic metabolic effects to be studied independently of confounding effects of food intake. Findings will be confirmed in mammalian cells. Definitive evidence for or against a role of CYP1A in AhR effects will be sought by silencing or overexpressing CYP1A4 and CYP1A5 in chick embryo hepatocytes and by a novel molecular approach in which sense and antisense CYP1A gene constructs in retroviral vectors will be targeted to liver or heart in chick embryos at early stages of development and the effects examined at a later stages. This research is expected to show that CYP1A enzymes contribute to metabolic and cardiovascular regulatory pathways, to improve understanding about relationships between glucose and lipid metabolism and the role of the AhR in regulating physiologic and pathologic responses to changes in nutrient availability, and to have implications for common related diseases, cardiovascular disease and diabetes. Relevance: Responses to changes in nutrient supply and metabolism contribute to aging and common human diseases including diabetes, cardiovascular disease and cancer. The environmental toxin, TCDD, by the single action of binding to the aryl hydrocarbon receptor (AhR), which is present in all our cells, initiates a lethal wasting syndrome characterized by a failure to synthesize glucose and leading to energy failure and death. By learning how TCDD activation of the AhR produces massive dysregulation of nutrient responses we expect to learn more about how the body normally orchestrates responses to changing levels of nutrients and how normal regulatory processes can spin out of control, with implications for common human diseases as well as normal physiology.
DESCRIPTION (provided by applicant): The overall objective of this application is to better understand the molecular mechanism of cardiovascular disease that are modified by environmental pollutants. The investigator's models of environmental toxicity will be diesel and gasoline emissions. The underlying hypothesis of this work is that transcriptional regulation in response to these emissions will identify genes that are important in the development of pollution-related cardiovascular disease. Their primary goal is to determine the transcriptional response to complex emissions and the secondary goal is to evaluate any synergistic effect of hypercholesterolemia on this process. Thus, this project will have two specific aims: Specific Aim 1: To define the transcriptional response to whole-exhaust emissions in monocytes and endothelial cells in vivo. Our hypothesis is that the different chemical make-up of diesel exhaust and coal emissions will elicit varied transcriptional responses in endothelial cells and monocytes. We will conduct exposures at two concentrations and with both acute (3 day) and chronic (6 week) duration. Specific Aim 2: To determine the interaction of hypercholesterolemia with inhaled pollutants on gene regulation in these cells. Our hypothesis is that whole exhaust will elicit transcriptional pathways relevant to the formation of atherosclerotic vascular disease, and that these effects will be more substantial in a susceptible model. We will therefore expose control and ApoE -/- mice, on a atherosclerotic diet, to low levels of whole exhaust for 6 weeks. We will use thorough transcriptional analysis to identify genes that are regulated in response to emission, in a novel mouse model that permits assessment of in vivo endothelial responses. They expect that these studies will generate an understanding of the mechanism of exhaust-related cardiovascular morbidity and identify the most important components of whole exhaust that cause such morbidity. They further anticipate that these insights will enhance our understanding of vascular pathology and potentially direct efforts at reducing the toxicity of combustion exhaust.
DESCRIPTION (provided by applicant): Chronic exposure to trivalent arsenic (As III) is well known to cause cardiovascular diseases. In the human liver, As (III) promotes vascular remodeling, portal fibrosis, and hypertension, but the molecular pathophysiology of these As III-induced vascular changes is unknown. In general, the pathogenesis of As III induced vascular diseases has been understudied, in part, due to a lack of relevant animal models sensitive to chronic low dose As III effects. Our preliminary results show that exposure of intact adult mice to as low as 10 ppb of As III in their drinking water caused defenestration and capillarization of liver sinusoidal endothelium (LSEC). Furthermore, we also show that primary, short term cultures of murine or human LSEC are useful in revealing functional roles for As (III)-stimulated NADPH oxidase (NOX) generation of reactive oxygen species in the early signaling events affecting phenotype (e.g. fenestration) of this important target cell. The objective of the proposed studies is to use these in vivo and ex vivo models to investigate the mechanisms through which As (III) initiates LSEC remodeling and the molecular pathology of As (III)-induced vascular diseases. The global hypothesis for these studies states that As (III) acts at the level of g-protein coupled cell signaling to promote NOX oxidant generation that disrupts maintenance of LSEC fenestrations and suppression of capillarization. Accordingly, the specific aims of this proposal are to determine: I. the molecular mechanism by which As (III) causes liver sinusoidal capillarization and remodeling in intact mice. Wildtype and NOX deficient (p47phox -/-) mice will be exposed to As (III) (10-50 ppb) for 2 weeks and morphometric (light and electron microscopic level) determinants of SEC defenestration and capillarization will be quantified. Pharmacologically (antibodies to vascular endothelial cell growth factor receptor or Pertussis toxin) modified mice will be used to assess the contribution VEGF receptor and Gi-protein linked signaling to As III-induced vascular changes. II. the role of NOX generated superoxide in mediating As III-induced phenotypic conversion of primary murine and human LSEC. LSEC isolated from human liver or wildtype and p47phox -/- mice will be exposed to As (III) ex vivo to demonstrate mechanisms through which an imbalance of reactive oxygen and nitrogen species generation mediates AsIII-dysregulation of VEGF receptor maintained LSEC fenestration. III. if an imbalance in LSEC GT Pase activity mediates As (III) stimulated remodeling of the LSEC. Targeted delivery of RhoA or Rac1-GTPase siRNA and selective GT Pase activity assays will be used to dissect the roles of Rho family members in As (III)-stimulated LSEC capillarization.
DESCRIPTION (provided by applicant): Epidemiological studies show significant associations between exposure to particulate matter with particles of aerodynamic diameter of <_2.5 ¿m (PM2.5) and cardiovascular-related morbidity including ventricular arrhythmias and sudden cardiac death. While there appears to be little doubt that PM2.5 exposure poses a significant cardiovascular health risk, the underlying causes are poorly understood. The decreased heart rate variability (HRV) associated with PM2.5 exposure is particularly important since decreased HRV has been shown to be an index of cardiac vagal regulation and is associated with increased susceptibility to ventricular arrhythmias and risk for cardiovascular-related sudden death. Even less understood is the mechanism(s) mediating the reduced HRV and hence the cardiovascular-related morbidity. Using the mouse we propose to use state-of-the-art inhalation facilities to deliver environmentally relevant particulate pollutants (iron/soot) from a true combustion source that captures the carbon-based particles and a transition metal ubiquitous in the environment to test the Hypothesis that short-term (3-day) exposure to PM2.5 results in a reduced HRV due to decreases in the intrinsic membrane properties and/or synaptic excitability of anatomically- and functionally-identified CNS cardiac vagal neurons in the nucleus ambiguous (NA) that regulate HRV. We will test the hypothesis in mice exposed to two concentrations of iron/soot particles and filtered air (FA) as a control by the following Specific Aims. 1. To determine whether short-term (3-day) exposure to PM2.5 in the form of iron/soot particles produces the phenotype of a reduced cardiac vagal regulation of heart rate, by quantifying overall 24-h HRV, diurnal changes in HRV, and heart rate recovery following an acute stressor (exercise). 2. To determine whether the PM2.5 exposure-induced decrease in HRV is mediated by decreased intrinsic excitability of the NA cardiac vagal neurons by measuring resting membrane potential, membrane conductance and spiking responses to depolarizing current injections. 3. To determine whether the PM2.5 exposure-induced decreased intrinsic excitability of NA cardiac vagal neurons is mediated by increased potassium currents, left shift in activation kinetics, and/or right shift in inactivation kinetics of three major potassium channels present in NA neurons. 4. To determine whether the PM2.5 exposure-induced decrease in HRV is mediated by decreased synaptic excitability by enhanced inhibitory ;?-aminobutyric acid (GABA) mechanisms at the NA cardiac vagal neurons, by measuring the frequency and amplitude of tonic GABA-mediated inhibitory postsynaptic currents (GABA IPSCs). 5. To determine whether the PM2.5 exposure-induced decrease in HRV is mediated by decreased synaptic excitability by depressed glutamatergic (GLU) excitatory mechanisms at the NA cardiac vagal neurons, by measuring the frequency and amplitude of tonic excitatory postsynaptic currents (GLU EPSCs) and the amplitude of evoked GLU EPSCs.
DESCRIPTION (provided by applicant): Although consistent associations between ambient PM pollution and cardiovascular disease have been identified, the exact mechanisms, the time course by which PM causes the toxic effects, and effects of different PM species are not adequately understood. This study investigates clinically relevant arrhythmogenic, cardiac autonomic control, repolarization, myocardial ischemia, blood pressure (BP), inflammatory, coagulation, and fibrinolytic mechanisms and time course of PM2.5 effects (both concentration and species). Specifically, is personal short-term exposure to elevated ambient PM2.5 directly related to: (I) the onset of arrhythmic episodes (2) higher frequency of arrhythmias (3) lower heart rate variability (HRV) indices? (4) prolonged repolarization measured by QT index? (5) ST-segment level? Can this association be totally or partially attributed to the change of HRV and QT? (6) elevated ambulatory BP (SBP, DBP, and PP)? What are the time-courses (from minutes to hours) of the effects listed from 1-6 above? (7) Is personal short-term exposure to elevated ambient PM2.s (24-hour cumulative exposure) directly related to elevated markers of inflammation, blood coagulation, and fibrinolytic activity? (8) Are 24-hour cumulative concentrations of the ambient PM2.5 species, mostly emitted/formed from coal-fire power plant and vehicle combustion, associated with the above endpoints (Hypotheses 1-7)? (9) Are the associations between ambient PM2.5 concentration and cardiac endpoints (Hypotheses 1-7) modified by the types of PM2.5 spec/es? (10) Is there a synergistic interaction between PM2.5and long-term cardiac risk in the above relationships? (II) Are persons with older age, diabetes, and hypertension more susceptible to the above PM2.5 effects? We will (1) Recruit 100 patients with only arrhythmias of moderate frequency; (2) Perform a battery of cardiac tests to determine cardiac structural and functional status; (3) Measure concurrently 24-hour Holter ECG, ambulatory BP, and personal PM2.5 exposure, and derive real-time PM2.5 concentration, EGG, and BP data on each participant; (4) Analyze filters to assess major PM2.5 species; (5) Collect pre- and post- monitoring blood samples to assess inflammation and fibrinolytic activities; (6) Assess long-term risks of cardiac events; and (7) use time-series and cross-sectional analyses (both multivariable linear regression, transition models) to test the above research hypotheses. This study requires multidisciplinary collaborations of environmental, cardiovascular, and biostatistics researchers. The results will allow us to better understand the mechanisms and time course by which PM2.5 affects the cardiac system, and identify factors that lead to differential susceptibility to PM, and guide regulatory agencies in designing air pollution control standards.
DESCRIPTION (provided by the applicant):
Ambient participate matter (PM) air pollution contributes significantly to cardiopulmonary morbidity and mortality. There are strong epidemiologic data that link daily levels of ambient PM to hospitalizations for cardiopulmonary disease and daily rates of cardiovascular mortality. Acute exposure to increased levels of PM is also associated with increased risk of acute myocardial infarction, and ischemic stroke. However, the mechanisms by which PM elicits these pathologic events and increases cardiovascular mortality are largely unknown. Exposure of animals and humans to PM alters hemostasis; increasing the levels of fibrinogen, and von Willebrand factor and inducing peripheral arterial thrombosis. In support of a PM-induced prothrombotic state, we have recently observed that exposure of mice to well-characterized PM collected from ambient air in Dusseldorf, Germany caused shortening of the bleeding, prothrombin and partial thromboplastin times, and increased the platelet count and the levels of factor VIII. Moreover, exposure of mice to PM increased bronchoalveolar lavage fluid levels of IL-6, which promotes coagulation and enhances platelet production and thrombin formation. Accordingly, we found that generation of intravascular thrombin was increased 24 hours after exposure to PM. The effect of PM-exposure on thrombin formation was abrogated in mice with targeted deletion of IL-6. Similarly, inhibition of beta-adrenergic receptors, an important regulator of IL-6, attenuated PM-induced thrombin generation. PM-induced stimulation of inflammation and cytokine release has been suggested to be due to the generation of reactive oxygen species (ROS) by epithelial cells and macrophages. These new findings led us to hypothesize that PM causes IL-6 release, which causes a hyper-coagulable state via a ROS-dependent mechanism. To test our hypothesis, we propose to (1) determine whether PM-induced IL-6 production and the resultant hyper-coagulable state are mediated by alveolar macrophages, alveolar epithelial cells, or both, (2) determine whether the PM-induced generation of ROS is required for IL-6 production and the resultant hyper-coagulable state, and (3) determine the role of beta-adrenergic receptors in modulation of the PM-induced IL-6 production and hyper-coagulable state. The studies we are proposing address an important human health problem and could lead to the development of novel therapies to diminish PM-induced cardiovascular events and mortality.
DESCRIPTION (provided by applicant): Ambient air pollution correlates with cardiovascular mortality and morbidity and is a cause of systemic inflammation. Inflammation is the hallmark of atherosclerosis, which is the primary underlying pathophysiology of cardiovascular diseases (CVD). Significant associations between air pollution and subclinical atherosclerosis have been reported in adults, using sonographically measured thickness of the carotid artery wall. Carotid intima-media thickness (CIMT) is an established marker of subclinical atherosclerosis. CIMT gradually increases from birth, is associated with subclinical inflammation in early life, and is a strong determinant of CVD. This project pursues the hypothesis that long-term exposure to local and regional air pollutants from outdoor origin promotes atherogenesis in early life, leading to differences in CIMT in 10-12yr old children. CIMT and covariates will be assessed among 650 children followed up from 13 Southern California communities. Lifetime residents from non-smoking households will be selected from an ongoing cohort study on air pollution and health. On average, children spend more than 80% of their time indoors at home and in school. Thus, exposure assessment will be based on fine particulate matter (PM2.5) from outdoor origin measured indoors in the home and school of each child and in selected outdoor locations. A Harvard long-term sampler will collect PM2.s in each location over a period of nine months. Light reflectance of PM2.s serves as a marker of local mobile source emissions and sulfur mass indicates regional PM2.s. Time spent indoors at home and school, in commuting, and in outdoor activities will be assessed by questionnaire. The microenvironmental concentrations and time-activity information will provide the input to derive exposure to local and regional pollution for each child. Associations between CIMT and personal lifetime exposure to local and regional outdoor pollution will be analyzed in multilevel spatial regression models. Relevance: The American Heart Association recommends focusing on prevention of atherosclerosis in children. Inflammatory air pollutants represent ubiquitous exposures, and millions of American children live in areas that exceed current government standards. It is biologically plausible that exposure to local and regional ambient pollutants effects CIMT in children. Small differences in CIMT at a young age translate into clinically relevant CVD later in life - the leading cause of morbidity and mortality in the U.S.
DESCRIPTION (provided by applicant): Background: The cardiovascular consequences of long-term exposure to low concentrations of mercury or arsenic are insufficiently understood. Mercury has been linked to cardiovascular risk in some, but not all, studies, and its association with the progression of atherosclerosis is uncertain. High arsenic exposure is an established cause of vascular disease, but the effect of low concentrations, more typical of the exposure of the US population, is essentially unknown. Since fish intake is the main source of methylmercury exposure in the general population, and a major source of organic arsenic compounds, the effects of these compounds may be confounded by the cardioprotective n-3 fatty acids in fish. Objective: To investigate the association of mercury and arsenic exposure with carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis, in a cohort of individuals followed during 1989-99. Hypothesis: Exposure to mercury or arsenic, as determined in toenails, are associated with baseline carotid IMT and with its progression over 10 years follow-up. These associations are independent of established coronary risk factors and of plasma phospholipid long-chain n-3 fatty acids, a biomarker of fish oil intake. Setting: Cohort of 2,085 men and women, aged 45 years and older and residents in Washington County, MD, who participated simultaneously in the CLUE II cohort (that collected toenail clippings) and either in ARIC or in the CHS cohorts (that measured IMT and cardiovascular risk factors). Design and measurements: Prospective longitudinal study of the association of baseline mercury and arsenic levels with carotid IMT progression over 10 years. Toenail mercury and arsenic will be measured by instrumental neutron activation analysis, and plasma n-3 fatty acids by capillary gas chromatography. Carotid IMT has already been measured by B-mode ultrasound. Statistical analysis plan: Longitudinal data analysis methods will be used to model IMT progression. Important statistical issues will be the control of measurement error in repeated IMT measurements, the control of the effect of cardiovascular risk factors on IMT progression, and the evaluation of the joint effect of mercury or arsenic and n-3 fatty acids. Relevance: Confirmation of the role of mercury or arsenic on atherogenesis could impact current environmental and dietary public health recommendations.
Crisp Terms/Key Words: cardiovascular disorder risk, environmental exposure, clinical research, longitudinal human study, ultrasonography, nutrition related tag, diet, mercury poisoning, arsenic, human subject, cardiotoxin, omega 3 fatty acid, activation analysis, carotid artery, cardiovascular disorder epidemiology, atherosclerosis, fish
DESCRIPTION (provided by applicant):
Lipid Peroxidation and Antioxidant Mechanisms is a competitive renewal proposal for an NIEHS Program- Project that was funded in September of 2005. Environmental stress and lifestyle play an important role in diseases that contribute significantly to mortality in the U.S. Cigarette smoking, alcohol consumption and poor diet combine with other environmental factors to affect the incidence of several diseases. The formation of oxidants is a hallmark of many of these diseases and lipid peroxidation is a common result of diverse environmental insults. Indeed, oxidative stress has been closely associated with the onset of pathologies as diverse as cancer and cardiovascular disease. The underlying mechanisms linking environmental stresses with disease pathogenesis remain obscure. The studies proposed here will test the hypothesis that the balance of competing oxidation pathways for different lipid substrates governs adaptation to oxidative stress and oxidative injury. The Program Project also directly addresses the hypothesis that protein adduction by lipid peroxidation products alters cellular signaling and modulates diseases linked to oxidative stress. This Program Project includes four research projects and one scientific core facility in a tightly-knit group that will provide important insights into the role that oxidation and antioxidants play in human pathophysiology. Project 1 provides a mechanistic framework for understanding peroxidation profiles and leads the chemistry that provides novel lipid affinity-tags for studying protein-electrophile adducts. Project 2 explores the chemistry and biology of eicosapentaenoic acid (EPA), a fatty acid prominent in fish oil, and explores the hypothesis that EPA oxidation products may contribute significantly to the biological properties of this fatty acid. Project 3 evaluates electrophiles that play critical roles in cell signaling and provides the biological platform for studying lipid affinity tags in whole cells. Project 4 suggests that secondary electrophilic products of lipid peroxidation play critical roles in oxidant-associated molecular pathologies and explores methodologies for identification and analysis of protein adducts of these electrophiles. All of the projects are highly collaborative and are highly dependent on the Lipidomics Analysis scientific core.
BACKGROUND
This is a renewal application of a Program Project Grant by a highly integrated team of investigators, led by Dr. Porter, which was initially funded in 2005. The PPG seeks to continue studies towards the mechanisms of lipid oxidation and the role of lipid-derived electrophiles in biological responses to oxidative stress, using innovative strategies and advanced analytical tools to identify biological targets for lipid-derived electrophiles. Although the original proposal was requested for a 5-year period, and the previous review team unanimously recommended reduction to 3 years, in order to focus on development of tools and analytical strategies and for subsequent use in biological studies. The current application consists of 4 Projects, led by the same investigators as in the original application, and includes 2 Cores, an Administrative Core and a newly added Lipidomics Analytical Core, which replaces the original Mass Spectrometry and Proteomics Core.
PROGRAM AS AN INTEGRATED EFFORT
DESCRIPTION (provided by applicant): The main objective of this project is to test the hypothesis that exposure to metals in children will affect their cardiovascular risk and may predispose them to cardiovascular disease. It is based upon a growing epidemiological literature, by us and others, indicating that exposure to lead, cadmium, or arsenic increases cardiovascular risk. However, most studies of the impact of metals on cardiovascular risk have been carried out in adults, and the susceptibility of children to the cardiovascular effects of metals is largely unknown. Primary hypotheses: 1) Exposures to lead, cadmium, or arsenic are positively associated with blood pressure levels in children; 2) Exposures to lead, cadmium, or arsenic, are positively associated with serological markers of inflammation and endothelial dysfunction (C-reactive protein [CRP], interleukin-6 [IL-6], intercellular adhesion molecule-1 [ICAM-1], and tumor necrosis factor alpha [TNF-alpha]) in children; and 3) Exposures, cadmium, or arsenic are inversely associated with heart rate variability in children. Design and setting: We propose to conduct a cross sectional epidemiological study of the association between exposure to lead, cadmium, or arsenic and markers of cardiovascular risk in children residing in the Torresn metropolitan area, Mexico. We will contact the children who participated in the Torresn Study of Lead and Neurocognitive Function in 2001, when they were 6 - 7 years old. We expect to recruit 512 (85%) of the original study participants, who will be 14 - 15 years old at the time of field work for the present study in 2009. This population offers a unique opportunity to evaluate the cardiovascular effects of metals in a large and well characterized group of children whose lead exposure has been previously studied. In the present study, we will obtain two measurements of metal exposure two months apart (lead in whole blood and cadmium and arsenic in urine) and evaluate their association with cardiovascular risk markers. The primary outcomes will be blood pressure, serological markers of inflammation and endothelial dysfunction (CRP, IL-6, ICAM-1, and TNF- alpha), and heart rate variability. Other endpoints will also be assessed, including markers of renal proximal tubular injury, cardiometabolic abnormalities (insulin resistance and lipid levels), and neurotoxic endpoints. Significance: Children in Torresn are exposed to lead, cadmium, and arsenic from dusts generated by the Met-Mex Peqoles smelter, the largest lead smelter operating in the Americas. While the average exposure to metals in this population is high, the range of exposure overlaps with that of children in US and in other Western countries. The current population thus represents an efficient way to obtain information on the impact of a wide range of metal exposure at the population level. The information obtained from children in Torresn will be relevant not only to local area residents, but to many children in the US and abroad. PUBLIC HEALTH RELEVANCE: The main objective of this project is to test the hypothesis that exposure to metals in children will affect their cardiovascular risk and may predispose them to later cardiovascular disease. We propose to conduct a cross- sectional epidemiological study of the association between exposure to lead, cadmium, or arsenic and markers of cardiovascular risk in children residing in the Torresn metropolitan area, Mexico. Almost all studies of the impact of metals on cardiovascular risk have been carried out in adults, and the susceptibility of children to the cardiovascular effects of metals is largely unknown. The information obtained in this study will be relevant to millions of children in the US and abroad who are chronically exposed to lead, cadmium, and arsenic in the environment.
DESCRIPTION (provided by applicant):
Exposure to ambient air particulate matter is associated with increased risk for cardiovascular disease. UItrafine particles (UFP) may be important in this regard because of their high surface area, oxidant capacity, and ability to enter the lung interstitium and vascular space. These studies will test the hypothesis that exposure to ambient UFP causes endothelial dysfunction in both the pulmonary and systemic vascular beds, via oxidant mechanisms. The investigators will determine whether people with type 2 diabetes, who have underlying vascular dysfunction related to oxidative stress, will be more susceptible than healthy subjects to the acute vascular effects of UFP exposure. These studies will consist of three human exposure protocols, using the Harvard Ultrafine Ambient Particle Concentrator. The first protocol will examine effects in healthy subjects, the second protocol will examine effects in age-matched subjects with type 2 diabetes, and the third protocol will assess the role of supplementation with antioxidant vitamins C and E in preventing the vascular effects of UFP exposure. Pulmonary vascular effects will be assessed by changes in the diffusing capacity for carbon monoxide, and the pulmonary capillary blood volume. Systemic vascular effects will be measured using forearm flow-mediated dilatation, with and without nitroglycerin. In addition, the investigators will measure the oxidant capacity of the concentrated ultrafine aerosol, and the level of systemic oxidative stress using glutathione redox balance and plasma lipid peroxides. Confirmation of the hypothesis that UFP oxidant capacity mediates vascular effects will have important implications for air pollution regulatory efforts, and will provide new approaches for the prevention of cardiovascular health effects.
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): Since the late 1980s, studies of acute and chronic exposure to particulate air pollution have shown it to be associated with early death. It was quickly apparent that most of these early deaths were from cardiovascular disease. Definition of the underlying mechanisms that may explain the epidemiological findings of cardiac mortality/morbidity associated with exposure to ambient particles, definition of subpopulation at increased risk of adverse health outcomes from particulate matter, and understanding the differential toxicity of different types of particles are among the research priorities defined by the U. S. National Research Council. We propose to examine the association of different types and sources of particle exposure with cardiovascular and pulmonary responses along a mechanistic pathway, using data from the Normative Aging Study, a prospective cohort study conducted by the Veterans Administration in the greater Boston area. Specifically, we will examine whether short term changes in automatic function, as indexed by heart rate variability, are associated with particle exposure, and determine whether that effect is mediated by part by oxidative stress and metal toxicity by examining effect modification by genotypes that modify defenses against oxidative stress and metal handling. We will similarly examine associations, and effect modification, for vascular function, as indexed by a non-invasive pulse Doppler measures of arterial compliance and blood pressure, and examine a direct association with systemic markers of inflammation and oxidative stress (c reactive protein, Sicam, Svcam, homocysteine, and 8-hydroxyguanosine.
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): Particulate air pollution is an important public health problem with respect to cardiovascular morbidity and mortality. Important strides have been made in understanding the neural and cardiac mechanisms involved. Heart rate variability analysis revealed important disturbances in autonomic tone during exposure to concentrated air particles (CAPs). We have obtained evidence in our canine models that CAPs may increase the severity of ischemia during acute coronary artery occlusion. These findings provide the direction for our studies, which are intended to expand our understanding of the mechanisms of air particulate exposure on the cardiovascular system. The specific aims are: 1) To determine the effect of ambient air particles on coronary hemodynamic function and arterial blood pressure in conscious dogs using CAPs exposures. 2) To determine whether the influence of ambient air particles on coronary artery blood flow and resistance is exacerbated by coronary artery stenosis in conscious dogs using CAPs exposures. Our studies will continue to employ the Harvard Ambient Particulate Concentrator (HAPC), a device that can increase ambient particle concentrations up to 30x without changing the physical or chemical characteristics of the particles; 2) a typical urban aerosol; 3) animal models of disease including myocardial ischemia in dogs to simulate the condition of compromised humans with ischemic heart disease, the primary substrate for adult cardiac mortality. The animals will be chronically instrumented with flow probes and telemetry devices to monitor arterial blood pressure and EKG. Coronary blood flow and pressure will be monitored in normal dogs and in dogs with partial coronary artery stenosis and compared during sympathetic or parasympathetic nerve blockade. The vasoactive balance controlled by endothelins and nitric oxide will be assessed during regulation of the coronary vascular response. The effects of components of pollutants will be systematically studied. Thus, the present application will entail unique application of comprehensive techniques to improve understanding of the mechanisms whereby CAPs can exert its deleterious influences on the heart and circulation
DESCRIPTION (provided by applicant): The goal of this application is to engage a multidisciplinary team of leading environmental, cardiovascular and proteomics researchers in the study of the pro-oxidative and pro-inflammatory pathways by which ambient pariculate matter (PM) enhance atherogenesis in apolipoprotein (apoE) and LDL receptor (LDL-R) deficient mice. The principal hypothesis is that PM-induced oxidative stress synergizes with oxidized lipid components to enhance inflammation and apoptosis in atherosclerotic lesions. There are three specific aims. Aim 1 will determine whether ambient PM exposures exacerbate atherosclerosis in these genetically susceptible strains. Animals will be exposed to ambient ultrafine (aerodynamic diameter < 0.1 mu m) and fine (< 2.5 mu m) particulates collected by particle concentrators in the Los Angeles basin. The endpoints will be a quantitative assessment of early and late atherosclerotic lesion development. These studies will be supplemented by in vivo and in vitro studies looking at the pro-oxidative, pro-inflammatory, and pro-apoptotic effects of concentrated ambient particulates (CAPs) on vascular endothelial, smooth muscle and phagocytic cells. Aim 2 will determine the role of PM-induced oxidative stress in inflammation and apoptosis. Aortic vascular tissue from CAPs exposed animals will be examined for lipid peroxidation and for heme oxygenase 1 (HO-1) expression, MAP kinase activation, and apoptosis. Blood will be used to study CAPs effects on acute phase proteins, fibrinogen and oxidative modification of protective HDL activity. Transgenic HO-1 promoter-luciferase mice will be used for in vivo imaging of the kinetics and vascular sites of oxidative stress generation. In vitro studies will include proteome analysis of the oxidative stress response in endothelial cells. All oxidative stress effects will be correlated with the PAH and quinone content of the CAPs, as well as their in vitro redox cycle capacity, determined by the DTT assay. Aim 3 will determine whether modified antioxidant defense mechanisms affect the induction of atherosclerotic lesions by CAPs in apoE deficient mice, which have been crossed with HO-1 transgenic as well as paraoxonase knockout animals. The investigators will also determine whether a deficiency of the Nrf-2 transcription factor, which regulates antioxidant enzyme expression, will affect lesion development in apoE t/- animals. These mice will be exposed to CAPs as discussed in Aims 1 and 2, and select endpoints used to demonstrate the effect on atherosclerotic inflammation and apoptosis.
Crisp Terms/Key Words: proteomics, environmental exposure, terminal nick end labeling, heme oxygenase, disease /disorder etiology, apolipoprotein E, mitogen activated protein kinase, low density lipoprotein receptor, oxidative stress, enzyme activity, apoptosis, high performance liquid chromatography, particle, pollutant interaction, oxidized lipid, enzyme linked immunosorbent assay, transcription factor, inflammation, pathologic process, gas chromatography mass spectrometry, polymerase chain reaction, atherosclerosis, genetically modified animal, laboratory mouse, air pollution
DESCRIPTION (provided by applicant): Large population studies of fine particulate air pollution have shown a link with heart disease, but for practical reasons they have not included direct assessment of biochemical risk factors or personal exposures. In this Exploratory/Developmental Research application we develop the methodology to collect blood samples and recruit study participants from a national cohort of unionized trucking company workers who have regular occupational exposures to fine particulate matter (PM) from motor vehicle exhaust. With the cooperation of the Teamsters we propose to assess the rate that unionized trucking company workers agree to provide a blood sample and complete a health questionnaire for a health study. Phlebotomy and study recruitment sites will be located in Teamster union halls near large trucking terminals in Chicago, IL and Carlisle, PA that employ 3,481 workers. The demographics and exposure distribution of subjects who provide a blood sample will be compared to workers who do not provide a blood sample. This strategy of locating phlebotomy centers in Union halls will be compared to the results from a companion study where another group of Teamsters are recruited by mail and requested to provide a blood sample by overnight mail using a blood collection kit. Preliminary information regarding the relationship between combustion particle exposures (based on job title and terminal location) and blood markers of inflammation that include C-reactive protein (CRP, measured using a high sensitivity assay), fibrinogen, interleukin-6 (IL-6), and markers of vascular endothelial activation and inflammation (soluble intercellular adhesion molecule-1 (slCAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1)) will be obtained. Cross-sectional relationships between combustion particle exposures, blood markers of inflammation, and concentrations of 1,2-naphthoquinone and 1,4- naphthoquinone albumin adducts, specific biomarkers of polycyclic aromatic hydrocarbons (PAHs) will be assessed. This approach will offer the possibility of prospective personal monitoring for a large population, greatly increasing the power to detect health effects and link them to personal risk factors and exposure to motor vehicle exhaust. The results from the proposed exploratory and developmental study will aid us in designing a prospective study to determine the relationship between PM exposures from motor vehicles and cardiovascular disease. This is of public health importance because large segments of the general US population have exposures to fine particles similar to trucking company worker exposures.
Crisp Terms/Key Words: air pollution, engine exhaust, biomarker, blood toxicology, vascular endothelium, blood chemistry, carbopolycyclic compound, inflammation, medical outreach /case finding, human subject, data collection methodology /evaluation, naphthoquinone, occupational hazard, particle counter, particle, human population study, environmental toxicology, method development, clinical research, sample collection, environmental exposure, cardiovascular disorder risk
DESCRIPTION (provided by applicant): It is now recognized that lipid oxidation produces an array of compounds capable of initiating redox cell signaling. Some of the pathways induce apoptosis while others induce the synthesis of proteins which increase the threshold at which oxidative stress and cytotoxicity occurs. Understanding how these responses are distinguished is critical in determining the molecular events that protect the cell against oxidative damage mediated by xenobiotics or during the pathophysiology of disease. In the previous funding period the central focus of this proposal was to define the mechanisms through which oxidized lipids adapt the endothelial cell to oxidative stress using the induction of the intracellular antioxidant glutathione (GSH) as a model. Preliminary data and published observations developed through the previous funding period identified mechanisms through which a specific sub-class of oxidized lipids, those with electrophilic reactive carbon centers, mediate signal transduction. We found that cytoprotection was dependent on the activation of the electrophile response element (also known as the antioxidant response element) which induces the synthesis of cytoprotective proteins such as heme oxygenase and glutamyl cysteine ligase. In the course of these studies we have used a proteomics approach to define the subset of proteins reactive to electrophilic lipids in the cell which we have designated as the electrophile responsive proteome. These data have led to the hypothesis that electrophilic lipids generated during lipid peroxidation control cell function through modification of the proteins that compose the electrophilic responsive proteome. This hypothesis will be tested by pursuit of the following Specific Aims: 1) Determine whether distinct classes of lipid derived electrophilic cyclopentenones react with different members of the electrophile responsive proteome 2) Determine the effect of the activation of endogenous enzymatic sources of lipid oxidation products on the electrophile responsive proteome. 3) Determine the functional impact of the interaction of electrophilic lipids with endothelial cell mitochondria. The information gained from the accomplishment of these specific aims will give insight into the mechanisms of adaptation and cytotoxicity of the endothelium under toxicological and pathological stress.
DESCRIPTION (provided by applicant): Gump, B. B. (PI) A number of studies have found that increasing lead (Pb) exposure is associated with increases in cardiovascular disease (CVD; e.g., hypertension) in humans. A mechanism to explain this association remains unclear. A number of studies have considered increased cardiovascular reactivity (CVR) to acute stress as a potential mechanism for the development of atherosclerosis. Heightened CVR has been shown to prospectively predict higher baseline blood pressure and increased left ventricular mass in children as well as predict future hypertension and carotid atherosclerosis in adults. We have considered whether lead might affect blood pressure and CVD through changes in CVR. For example, studies with animals have shown lead-induced increases in vascular resistance. We recently demonstrated that 9 1/2 year old children with higher early childhood lead levels were associated with greater total peripheral (vascular) resistance (TPR) responses to acute stress (Gump et al., 2005). These effects were significant for lead levels considered low, notably, below the 10 ¿g/dL threshold currently adopted by the CDC for deleterious effects. We replicated this effect in a small pilot study (N = 40) and at blood lead levels below 3.76 ¿g/dL. The mechanism explaining the association between lead and vascular reactivity is not clear, however, it is presumed to involve a number of systems that regulate vasoconstriction and vasodilation, including the kallikrein-kinin system (KKS), oxidative stress, the renin-angiotensin system (RAS), the sympathoadrenal-medullary (SAM) system, and the hypothalamic-pituitary-adrenal (HPA) system. These potential mediators have not been studied in the context of the association in children between blood lead levels and heightened vascular responses to acute stress. In addition to this question of mechanism, some effect modifiers for the association between lead and vascular reactivity may operate. For example, we recently observed a significant interaction between socioeconomic status and blood lead in the prediction of vascular reactivity in children [19]. We observed that blood lead levels were most strongly associated with blood pressure and vascular reactivity for those children with relatively high SES. The goals in the current research application are therefore to: (a) confirm the lead-TPR reactivity association in children, (b) consider potential mechanisms for this important association, using both a targeted assay approach and a more exploratory proteomics approach, and (c) consider SES as an effect modifier for this association. - Gump, B. B. (PI) Cardiovascular disease (CVD) remains the leading cause of death in the United States and disables 10 million Americans each year. Blood lead (Pb) may increase cardiovascular risk factors in children and thereby contribute to the development CVD. These effects of lead on cardiovascular risk factors may occur at very low levels, levels well below the thresholds currently adopted by the CDC for deleterious effects of lead.
DESCRIPTION (provided by applicant):
Epidemiological evidence indicates that acute pulmonary exposure to airborne pollutants such as particulate matter (PM) increases the risk of pulmonary and cardiovascular morbidity and mortality. This implies that PM affects extra-pulmonary tissues, as evidenced by the occurrence of cardiovascular dysfunction on high pollution days. Furthermore, Federal Criteria Documents for PM have provided a wealth of evidence demonstrating PM dependent effects on the cardiovascular system. However, despite its obvious importance in regulating the delivery of cells and molecules to all tissues, and in the etiology of most cardiovascular diseases, the Principal Investigator's laboratory conducts the lone investigations that explore how systemic microvascular function is affected by pulmonary PM exposure. The overall aim of this project is to determine if there is a true causal link between the inflammatory events that follow PM exposure and the disruption of endothelium-dependent dilation. The central hypothesis is: Inflammatory mechanisms govern the systemic microvascular dysfunction that follows ultrafine PM exposure, and the severity of this dysfunction is augmented in clinically relevant populations. Intravital microscopy and isolated vessels will be used to test this hypothesis in the spinotrapezius muscle, bone marrow, and subendocardial circulations of rats and mice exposed to diesel exhaust particles (DEPs) or ultrafine titanium dioxide. The role of gender and age in determining the severity of these effects will also be studied. Various in vivo and in vitro techniques will be used to measure microvascular reactivity after PM exposure, and to characterize pathological changes at this crucial level of the circulation. DEPs are mobile source emission air pollutants representative of particles that humans are exposed to on a regular basis. Ultrafine titanium dioxide is a commonly used nanoparticle found in cosmetics, paints and various protective coatings. A better understanding of how these particles affect remote microvascular function will provide mechanistic insight into pathologic changes that contribute to cardiovascular morbidity and mortality. Moreover, these studies may provide a biological basis for the epidemiological associations between air pollution and cardiovascular dysfunction. A fundamental understanding of these mechanisms is vital to the prevention and treatment of life-threatening cardiovascular events, and will contribute to control strategy development.
DESCRIPTION (provided by applicant): Population-based epidemiologic studies of communities in the United States have revealed a consistent association between ambient particulate air pollution and increases in morbidity and mortality. The observed increases result from both respiratory and cardiovascular diseases. Similar associations have been observed for rates of hospital admissions for respiratory and cardiovascular diseases for subjects over age 65. Results from the first phase of this study (ES R01 09860) showed significant cardiac and airway changes after both environmental and occupational particulate exposures. The objective of this application is to investigate the role of both occupational and non-occupational exposure to particulates in the development of respiratory and cardiac responses in boilermakers. We will employ a detailed, continuous exposure assessment to PM2.5 with and PM1.0 with repeated measures of biologic and physiologic markers of response. In addition, we will employ novel techniques for the assessment of particulate-induced physiologic responses, including gene expression using mRNA microarrays. Hypotheses to be addressed in this established cohort of boilermakers include: (1) Short-term exposure to particulates from occupational, ambient, and indoor exposures results in airway inflammation and obstruction measured by serial expired NO and FEV1; (2) Chronic exposures to particulates result in long-term decreases in expired NO and FEV1; (3) Exposure to particulates results in acute changes in cardiovascular function measured as heart-rate variability, heart-rate, and blood pressure; (4) Exposure to particulates results in increased acute phase reactant (c-reactive protein, fibrinogen) concentration in the serum; (5) Exposure to particulates induces systemic responses resulting in alterations in white blood cell gene expression assessed by mRNA microarray analysis pre- and post-exposure; (6) Common chronic medical conditions such as hypertension, COPD, and asthma predispose particulate-exposed individuals to changes in cardiac function (heart rate, heart rate variability, and blood pressure). The results of this work will have important implications for preventive efforts aimed at reducing particle-associated morbidity and mortality.
DESCRIPTION (provided by applicant): Chronic exposure to mercury, a highly reactive heavy metal, may increase cardiovascular disease (CVD) risk. Because the major environmental exposure to mercury is from fish intake, which may otherwise have significant cardiovascular benefits, and because adequate data are critical to ongoing policy decisions regarding mercury contaminants, elucidating the relationship between mercury and CVD risk is of great scientific and public health importance. However, results of prior studies have been inconsistent, and prior studies excluded women and did not evaluate stroke, a major cause of CVD morbidity and mortality. Selenium, an essential dietary trace element, plays an important role in antioxidant defense systems and may protect against both CVD and toxic effects of mercury. Such a protective effect would have direct implications for recommendations regarding optimal selenium intake and for assessing the potential impact of mercury contamination from fish intake in selenium-replete populations. However, the possible interaction between mercury, selenium, and cardiovascular risk is not well-established. The objectives of this application are to assess the associations between mercury and selenium exposure and risk of coronary heart disease (CHD) and stroke in women and men. It is hypothesized that: 1. Chronic mercury exposure is associated with higher risk of CVD (CHD and stroke) in women and men. 2. Selenium intake is associated with lower risk of CVD. 3. The relation between mercury levels and CVD risk varies depending on intake of selenium. These aims will be investigated using a prospective nested case-control design among women and men participating in two large U.S. cohort studies, including 6,470 incident CVD cases. Exposures will be ascertained using stored toenail clippings, a reliable biomarker of chronic mercury and selenium intake. This study provides a unique and cost-efficient opportunity to evaluate the importance of mercury and selenium intake for cardiovascular risk in women and men. This research will greatly clarify the potential risks and benefits offish intake, mercury exposure, and selenium intake for cardiovascular disease prevention, fulfilling the NIH's mission to pursue fundamental knowledge about human health and illness and the application of that knowledge to extend healthy life and reduce burdens of death and disability.
DESCRIPTION (provided by applicant): It has been well documented that exposure to fine ambient air particulate matter (PM2.5) induces consistent increased risk for cardiovascular disorders (CVD) in humans at the levels currently encountered in the U.S. However, the mechanism(s) and component(s) responsible for PM2.5 associated cardiovascular effects are still unknown. In our recent subchronic inhalation study, we observed that dramatic increases in heart rate and decreases in heart rate variability occurred in the ApoE-/- mouse model on days when PM2.5 contained elevated concentrations of nickel (Ni) as compared to days with typically lower Ni exposure. We further found in humans that Ni and vanadium best explained the variation of the NMMAPS PM10 mortality risk coefficients across cities. Therefore, we hypothesize that Ni is a major component responsible for PM2.5 associated CVD. It has been difficult, however, to test this hypothesis due to lack of appropriate populations with adequate combination of exposures to both PM2.5 and Ni in the U.S. Recently, we identified two large cities in China, which have exposures to similar ambient PM2.5 mass concentrations but very different levels of Ni (~500ng Ni/m3 in Jinchang and ~10 ng Ni/m3 in Zhanye). Therefore, we propose to evaluate the feasibility of using these ideal and unique populations to examine the potential roles of Ni in PM2.5 associated CVD through population- based mortality and morbidity and panel-based biomarker studies. The specific aims of the study are: 1) to examine the feasibility of conducting time-series analyses of CVD mortality and morbidity in the overall populations of the two Chinese cites to identify the potential mechanistic roles of Ni in PM2.5 associated CVD; 2) to determine whether or not the commonly used CVD biomarkers can be employed to evaluate the role of Ni in PM2.5 related CVD in the identified populations. The candidate biomarkers of CVD include proinflammatory markers [IL-6, and C reactive protein (CRP)]; markers of leukocyte recruitment [monocyte chemoattractant protein 1 (MCP-1)]; and endothelial dysfunction biomarkers (ICAM and VCAM). This study will provide insights into the role of, and mechanism for action of a highly likely PM2.5 component in terms of inducing CVD. This study should have significant implications for both research and legislative regulation in controlling the health hazards associated with ambient PM exposure. PUBLIC HEALTH RELEVANCE: Particulate matter (PM) in ambient air is a mixture and a ubiquitous pollutant that induces consistent increase in hospital admission and death of cardiovascular disorders (CVD) in humans at the levels currently encountered in the U.S. However, why PM causes CVD is still unknown. This study was proposed to address the role that nickel may play in PM associated CVD. The study is relevant to the major environmental health issues and should have significant implications for both research and legislative regulation in controlling the health hazards associated with ambient PM exposure.
DESCRIPTION (provided by applicant): Air pollution is positively associated with an increased daily incidence of myocardial infarction and cardiovascular mortality. Recent findings strongly implicate a role for fresh vehicular exhaust, clearly showing elevated coronary events related acutely to traffic exposure. Clinical and experimental research suggests that air pollutants can acutely induce a vasoconstrictive mechanism, though a clear connection between such studies and the ultimate cardiac sequelae has not been confirmed. The proposed study will seek to validate our previous observations that specific gaseous components of engine exhaust, which are a significant contributor to ambient air pollution, may have pathological vasoactive properties by blunting coronary dilation and enhancing constriction. ECG and vascular abnormalities in ApoE-/- mice occurred when exposed by inhalation to fresh diesel or gasoline exhaust, but not aged, resuspended road dust, suggest that certain compounds in fresh emissions that drive cardiovascular responses may be lost in collected or concentrated particles. Many volatile and semivolatile compounds in fresh emissions can exist in both the gaseous and particulate phases of whole exhaust, and it may be that attempts to ascertain toxicity of filter-collected or concentrated PM may underestimate the adverse health effects by eliminating the gaseous co-pollutants. We have three primary hypotheses to test in this study: (1) We hypothesize that gaseous components of whole emissions can exert effects directly on vascular tissue as well as indirectly by oxidatively modifying endogenous circulating phospholipids, thereby altering the native function of those lipids. Our findings of oxidized low density lipoprotein in the circulation and lipid peroxidation by-products in the vasculature of engine emission-exposed mice, in the absence of overt pulmonary or systemic inflammation suggests that there may be a mild oxidative process in the lung that transfers systemically; (2) We hypothesize that the predominant mechanism driving impaired dilatory function is the formation of peroxynitrite and uncoupling of endothelial nitric oxide synthase. Nitrotyrosine is upregulated in the vasculature following chronic, low-level gasoline exhaust exposure, but it is unknown to what degree peroxynitrite impacts acutely on the vessels; and (3) We hypothesize that observed T-wave abnormalities reflect emission-induced impairment of endothelial cell function, leading to diminished coronary flow and myocardial ischemia in vulnerable subjects. Findings of air pollution-induced rat and mouse ECG abnormalities from several laboratories have not been validated in terms of absolute cardiovascular pathology; we predict diminished coronary flow and mild ischemia will occur in the susceptible mouse strain (ApoE-/-). PUBLIC HEALTH RELEVANCE Cardiovascular effects of air pollution are becoming recognized as a major public health concern. These studies will examine both biological and chemical mechanisms of air pollution-induced adverse coronary events. Results from these studies will assist in the assessment and management of personal risk of health effects from air pollution exposure.
This Program-Project Grant is to identify and define the cardiovascular effects of environmental aldehydes and pollutants that generate aldehydes. The project will integrate molecular and cellular aspects of aldehyde toxicity, delineate the contribution of individual pathways involved in the detoxification of the aldehydes, and elucidate how aldehydes affect atherosclerosis, platelet and endothelial activation, and myocardial function. Acrotein and trans-2-hexanal will be studied
as model aldehydes most prevalent in the environment. The Program consists of 4 Projects and 3 Cores. Project 1: Aldehyde Metabolism and Cardiovascular Disease focuses on the metabolism of these toxicants in mice. These studies are designed to identify the major metabolic products and the biochemical pathways that metabolize aldehydes, and how glutathione S-transferases regulate this metabolism and cardiovascular toxicity. Project 2: Atherogenic Effects of Environmental Aldehydes will test the hypothesis that exposure to unsaturated aldehydes exacerbates atherogenesis. Spontaneously atherosclerotic apoE-null mice will be exposed to these pollutants, and changes in lesion progression and markers of vascular inflammation will be measured, and resultant alterations in plasma lipoproteins will be determined. The central hypothesis of Project 3: Role of Platelet Activation and Vascular Pathology in Aldehyde Toxicity is that environmental aldehydes activate blood cells and induce proinflammatory responses in the vascular endothelium. To test this hypothesis, we will examine platelet activation by aldehyde, investigate the role of platelet microparticle formation in aldehyde-induced vascular changes, and assess the ability of these aldehydes to stimulate platelet-lesion interactions. In Project 4: Acute and Chronic Cardiotoxicity of Aldehydes will examine how aldehydes acutely depress contractibility, exacerbate ischemic injury, and chronically induce inflammatory states contributing to remodeling characteristic of heart failure. For this, we will delineate the mechanisms by which aldehyde inflict contractile dysfunction, abolish ischemic preconditioning and induce pathological myocardial remodeling. The Administrative Core (A) will serve as the organizational focus and will provide infrastructure support, including statistical analysis, data
management, coordinated sample handling and storage and sentinel monitoring for systemic toxicity. The Bioanalysis Core (B) will provide and integrated, centralized facility for biochemical determinations and mass spectrometry. The Inhalation Facility Core (C) will provide uniform acrolein exposures to mice via inhalation. Successful completion of this project will lead to a better understanding of the cardiovascular consequences of aldehyde exposure and will provide direction to future assessments of human risk and susceptibility.
DESCRIPTION (provided by applicant)
Particle air pollution has been associated with cardiovascular hospitalization and mortality in population-based studies throughout the world. The program project goal is to understand the relation of particle pollution to clinical, physiologic and biochemical endpoints reflecting potential mechanisms underlying these associations. The investigators have focused on endpoints influenced by autonomic regulation, and have found pollution effects on heart rate variability and on ventricular and supraventricular tachyarrhythmias. The investigators also have published or preliminary evidence for associations of particle pollution with elevated pulmonary/systemic inflammatory markers (e.g. exhaled nitric oxide (NO), intercellular adhesion molecule (ICAM-1), oxygen desaturation, ST-segment repression, elevated blood pressure, and, most recently, reduced vascular reactivity. Building on these observations, the principal investigators propose to broaden their focus to evaluate not only autonomic mechanisms, but also potentially interrelated vascular and inflammatory mechanisms for air pollution cardiovascular effects in humans. This evaluation requires a multidisciplinary approach joining experts in epidemiology, air pollution measurement, cardiology and electrophysiology; diabetes and measurement of vascular and inflammatory outcomes, and environmental statistics.
Projects proposed would provide data on a spectrum of at-risk subjects including the elderly, and populations with Type 2 diabetes, coronary artery disease, implanted cardioverter defibrillators, and acute cerebrovascular events. Primary outcomes of interest will include brachial artery diameter and endothelium-dependent flow-mediated dilation, heart rate variability, tachyarrhythmias in patients with implanted defibrillators, and acute ischemic cerebrovascular events. Markers of pulmonary and systemic inflammation and endothelial dysfunction will be evaluated as intermediate outcomes. The investigators will also differentiate effects of particle components closely associated with traffic (e.g., black carbon) and long-range transport (e.g., sulfate), with improved assessment of spatial as well as temporal differences in exposure. To carry out the proposed projects, several core services will be required. These will include the following: an Administrative Core; a Data Coordination and Statistics Core to apply consistent methodology to gathering, processing, checking and analysis of data; the Particle Exposure Characterization Core to provide detailed characterization and quantification of ambient pollution; and the Health Outcomes Core to provide vascular, electrophysiologic, and endocrine assessment and measures of inflammation/endothelial dysfunction. These studies will provide additional insight into the relative sensitivity of different subgroups to air pollution, and potential mechanisms whereby ambient pollution is associated with excess morbidity and mortality. Moreover, the study may provide clues as to how to develop preventive strategies to reduce this excess.
DESCRIPTION (provided by applicant): The primary objective of the proposed studies is to study the effects of toxicant exposures during fetal development on the adult cardiovascular (CV) system. Little is known of the etiology and progression of cardiovascular disease (CVD) in adults resulting from toxicant exposures to the pregnant mother, and the proposed studies seek to uncover early markers of disease vital in the identification of signaling pathways involved in CVD. The effect of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) in CVD from fetal exposure will be examined. TCDD, the prototypical dioxin, is pervasive in the environment and causes a large number of seemingly unrelated biological effects in humans. TCDD is one of the most potent ligands for the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor responsible for the regulation of many detoxification genes. Because the AHR plays a role in CV development and cross talks with other signaling pathways, and because TCDD causes ischemic heart disease in the adult and induces changes in cell signaling; the intent of this proposal is to test the hypothesis that activation of the AHR by TCDD in the fetus causes a reprogramming of gene expression in the fetal CV system that results in the adult onset of CVD. To test this hypothesis, the following specific aims are proposed. (1) Determine the window of fetal TCDD sensitivity and the effect that the TCDD-activated AHR during gestation has on CVD and CV global transcription of adult progeny from mouse strains that differ at the Ahr locus. We hypothesize that the genomic and physiological effects of an acute TCDD exposure on the fetus are dependent on the activation of the AHR during particular time frames of gestation. (2) Determine the effect of the activated AHR on the CV system of adult progeny following treatment with biologically relevant doses of TCDD during gestation. We hypothesize that the genomic and physiological effects of biologically relevant doses of TCDD on the fetus play a large role in adult CVD. We expect to link gene profiles of acute- and chronic-based TCDD exposures to specific CVDs and to integrate our data sets with other gene profiling data sets. The results will lead to a clearer understanding of the mechanisms that are initiated from fetal exposures that lead to adult disease, and with such knowledge, preventative measures can begin to be implemented to protect mother and fetus.
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): Cardiovascular disease is the major cause of death in the U.S. Chronic arsenic ingestion causes atherosclerosis and is associated with increased mortality from myocardial infarction and stroke. Early life arsenic exposure may play a significant role in development of atherosclerosis in adult life, as suggested by reports of infant deaths from myocardial infarction caused by advanced arteriosclerosis in regions where mothers consumed water with high levels of arsenic. Transplacental arsenic exposure can disrupt liver DNA methylation patterns and thus alter liver gene expression. Underlying liver disease is an independent risk factor for atherosclerosis. Hence, arsenic exposure induced liver disease may predispose to atherogenesis, and widespread exposure to arsenic in drinking water in the U.S. likely contributes to atherogenesis and death from cardiovascular disease. Our working hypothesis is that arsenic exposure disrupts epigenetic control of hepatic gene expression predisposing the liver to inflammation that is an atherogenic trigger resulting in accelerated atherosclerosis in susceptible animals. Preliminary data indicate that atherosclerosis-prone apolipoprotein E knockout (ApoE -/-) mice transplacentally exposed to arsenic in drinking water develop overt vascular disease by 10 weeks of age without high lipid diet and that liver gene expression suggests a pro-inflammatory state. The aims of this exploratory grant application are 1) to refine and to optimize this newly developed model of transplacental arsenic induced atherogenesis by determining arsenic exposure response of arsenic blood levels in pregnant females and fetuses, determining exposure/time dependence of atherosclerotic lesion formation (rate and extent of lesion formation), assessing arsenic exposure-response of changes in vascular reactivity and characterizing the nature of arterial lesions (lesion cellularity, fibrosis and inflammation) in arsenic exposed mice; 2) explore transplacental arsenic-induced hepatic changes by characterizing liver pathology, determining circulating biomarkers of liver dysfunction and test the hypothesis that there is a temporal correlation between hepatic changes and vascular changes. Tissues will be examined at birth and at 10, 16 and 24 weeks of age to determine the course of disease and stability of molecular changes induced by in utero arsenic exposure. The goal of the proposed studies is to determine whether there is a threshold level of arsenic exposure necessary to accelerate atherogenesis using the ApoE model. The relevance of this model to human atherosclerosis is that people prenatally exposed to arsenic are likely more susceptible to dietary influences later in life. These studies will provide important information on the mechanisms of arsenic induced atherosclerosis and the role that fetal arsenic exposure plays in disease progression. This model also will be a rich resource for future research on the mechanism of arsenic induced atherosclerosis including determination of the critical stages of development for the arsenic effect, and molecular studies of arsenic exposure induced changes in DNA methylation, chromatin structure, gene expression and genetic imprinting. PUBLIC HEALTH RELEVANCE: Exposure to arsenic drinking water is a major concern in the United States. The effect of early life arsenic exposure on adult disease progression is unknown but potentially very important. This project uses a mouse model of fetal arsenic exposure induced vascular disease to investigate effects of fetal arsenic exposure on liver development that likely cause vascular disease by young adulthood.
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