Grantee Research Project Results

Manganese Toxicokinetics at the Blood-Brain Barrier

EPA Grant Number: R828112C119
Subproject: this is subproject number 119 , established and managed by the Center Director under grant R828112
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Health Effects Institute (Prior to 2000)
Center Director: Greenbaum, Daniel S.
Title: Manganese Toxicokinetics at the Blood-Brain Barrier
Investigators: Yokel, Robert A.
Institution: University of Kentucky Medical Center , Health Effects Institute
EPA Project Officer: Chung, Serena
Project Period: April 1, 2000 through March 31, 2005
RFA: Health Effects Institute (1996) RFA Text |  Recipients Lists
Research Category: Human Health , Air Quality and Air Toxics , Air

Objective:

Metals comprise a large group of elements. Many of these metals are essential to living systems because they participate in a variety of biological functions, but they can be toxic at concentrations above those needed in the body. Exposure to some metals has been found to cause neurologic damage—for instance, in children exposed to low levels of lead via ingestion and in workers exposed to moderate to high levels of manganese via inhalation. Metals are present as particles or particle components in emissions from vehicles and other sources and have been implicated as one possible reason for the adverse health effects associated with airborne particulate matter exposure.

Dr. Robert Yokel’s objective is to study the mechanisms by which manganese enters and leaves the brain across the blood–brain barrier and, in particular, whether transporter molecules are involved. The blood–brain barrier is a function of the walls of small blood vessels that shield the brain from possibly harmful molecules. Certain molecules may cross the blood–brain barrier via diffusion or via carrier-mediated transport, which includes active transport (a process that uses energy to move molecules against a concentration gradient). The investigators proposed study will be the first direct investigation of whether specific transporter molecules remove manganese from the brain. Evidence for carrier-mediated transport of manganese out of the brain would be particularly interesting in that it would indicate a possible mechanism for preventing manganese accumulation, thereby affecting the likelihood of neurologic damage from chronic low-level exposure.

Approach:

In this study the investigators will use in vivo brain perfusion in rats as well as in vitro tests in several cell lines to assess specific characteristics of manganese transport, such as pH and energy dependence. Manganese transport rates will be compared with those of sucrose and dextran, which do not easily cross the blood–brain barrier. Experiments to identify putative transporters will focus on known transport molecules, such as a divalent metal transporter, a monocarboxylate transporter, and calcium channels. The investigators will use both a genetic approach (comparing results in rats with and without a functional divalent metal transporter) and a pharmacologic approach (evaluating manganese transport function in the presence of several selective inhibitors).

Expected Results:

Investigators expect to study the mechanisms by which manganese enters and leaves the brain across the blood–brain barrier and, in particular, whether transporter molecules are involved. The investigators plan to use in vivo brain perfusion in rats as well as in vitro tests in several cell lines to assess specific characteristics of manganese transport, such as pH and energy dependence. Manganese transport rates will be compared with those of sucrose and dextran, which do not easily cross the blood–brain barrier. Experiments to identify putative transporters will focus on known transporter molecules, such as a divalent metal transporter, a monocarboxylate transporter, and calcium channels.

Supplemental Keywords:

Health Effects, Air Toxics, biomarkers, epidemiology, manganese, fuel additives

Relevant Websites:

http://pubs.healtheffects.org/getfile.php?u=60 Exit

Progress and Final Reports:

2000

2001

2002

2003

Final

Main Center Abstract and Reports:

R828112    Health Effects Institute (Prior to 2000)

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R828112C042 Does Inhalation of Methanol Vapor Affect Human Neurobehavior?
R828112C043 Human Responses to Nitrogen Dioxide
R828112C044 The Role of Inflammation in Ozone-Induced Lung Injury
R828112C045 How Does Exercise Affect the Dose of Inhaled Air Pollutants?
R828112C046 How Do Chemicals in Diesel Engine Exhaust Damage DNA?
R828112C047 Effect of Nitrogen Dioxide on Bacterial Respiratory infectionin Mice
R828112C048 Effects of Ozone Exposure on Airway Epithelium
R828112C049 Inhalation of Aldehydes and Effects on Breathing
R828112C050 Does Ozone Cause Precancerous Changes in Cells?
R828112C051 Effects of Formaldehyde on Human Airway Epithelial Cells Exposed in a Novel Culture System
R828112C052 Carbon Monoxide and Cardiac Arrhythmias
R828112C053 Effects of Formaldehyde and Particle-Bound Formaldehyde on Lung Macrophage Functions
R828112C054 Mechanisms for Protecting Lung Epithelial Cells Against Oxidant Injury
R828112C055 Relationship of Nitropyrene-Derived DNA Adducts to Carcinogenesis
R828112C056 Particle Trap Effects on Heavy-Duty Diesel Engine Emissions
R828112C057 Carbon Monoxide and Atherosclerosis
R828112C058 Nitrogen Dioxide and Respiratory Illness in Children
R828112C059 Noninvasive Methods for Measuring Ventilation in Mobile Subjects
R828112C060 Oxidant Air Pollutants and Lung Cancer: An Animal Model
R828112C061 Detection of Carcinogen-DNA Adducts: Development of New Methods
R828112C062 Effects of Carbon Monoxide on Heart Muscle Cells
R828112C063 Development of Personal Ozone Samplers: Three Approaches
R828112C064 Development of Biomarkers to Monitor Carcinogen Exposure
R828112C065 Effects of Prolonged Ozone Inhalation on Collagen Structure and Content in Rat Lungs
R828112C065II Prolonged Ozone Exposure and the Contractile Properties of Isolated Rat Airways
R828112C065III Changes in Complex Carbohydrate Content and Structure in Rat Lungs Caused by Prolonged Ozone Inhalation
R828112C065IV Genetic Control of Connective Tissue Protein Synthesis After Prolonged Ozone Inhalation
R828112C065V Pulmonary Function Alterations in Rats After Chronic Ozone Inhalation
R828112C065VII Prolonged Ozone Exposure Leads to Functional and Structural Changes in the Rat Nose
R828112C065VIII - IX Studies of Changes in Lung Structure and Enzyme Activitiesin Rats After Prolonged Exposure to Ozone
R828112C065X An Innovative Approach to Analyzing Multiple Experimental Outcomes: A Case Study of Rats Exposed to Ozone
R828112C065XI The Consequences of Prolonged Inhalation of Ozone on Rats: An Integrative Summary of the Results of Eight Collaborative Studies
R828112C066 Interactive Effects of Nitropyrenes in Diesel Exhaust
R828112C067 Detection of Formaldehyde–DNA Adducts: Development of New Methods
R828112C068I Comparison of the Carcinogenicity of Diesel Exhaust and Carbon Black in Rat Lungs
R828112C068II An Investigation of DNA Damage in the Lungs of Rats Exposed to Diesel Exhaust
R828112C068III No Evidence For Genetic Mutations Found In Lung Tumors From Rats Exposed To Diesel Exhaust or Carbon Black
R828112C069 Noninvasive Determination of Respiratory Ozone Absorption: The Bolus-Response Method
R828112C070 The Effects of Inhaled Oxidants and Acid Aerosols on Pulmonary Function
R828112C071 Biochemical Consequences of Ozone Reacting with Membrane Fatty Acids
R828112C072 DNA Mutations in Rats Treated with a Carcinogen Present in Diesel Exhaust
R828112C073 Developmental Neurotoxicity of Inhaled Methanol in Rats
R828112C074 Methanol Distribution in Non Pregnant and Pregnant Rodents
R828112C075 Is Increased Mortality Associated with Ozone Exposure in Mexico City?
R828112C076 Effects of Fuel Modification and Emission Control Devices on Heavy-Duty Diesel Engine Emissions
R828112C077 Metabolic Studies in Monkeys Exposed to Methanol Vapors
R828112C078 Effects of Ozone on Pulmonary Function and Airway Inflammation in Normal and Potentially Sensitive Human Subjects
R828112C079 Improvement of a Respiratory Ozone Analyzer
R828112C080 Mechanism of Oxidative Stress from Low Levels of Carbon Monoxide
R828112C081 Long-Term Exposure to Ozone: Development of Methods to Estimate Past Exposures and Health Outcomes
R828112C082 Effects of Ambient Ozone on Healthy, Wheezy, and Asthmatic Children
R828112C083 Daily Changes in Oxygen Saturation and Pulse Rate Associated with Particulate Air Pollution and Barometric Pressure
R828112C084 Evaluation of The Potential Health Effects of the Atmospheric Reaction Products of Polycyclic Aromatic Hydrocarbons
R828112C085 Mechanisms of Response to Ozone Exposure: The Role of Mast Cells in Mice
R828112C086 Statistical Methods for Epidemiologic Studies of the Health Effects of Air Pollution
R828112C087 Development of New Methods to Measure Benzene Biomarkers
R828112C088 Alveolar Changes in Rat Lungs After Long-Term Exposure to Nitric Oxide
R828112C089 Effects of Prenatal Exposure to Inhaled Methanol on Nonhuman Primates and Their Infant Offspring
R828112C090 A Pilot Study of Potential Biomarkers of Ozone Exposure
R828112C091 Effects of Concentrated Ambient Particles on the Cardiac and Pulmonary Systems of Dogs
R828112C092 Cancer, Mutations, and Adducts in Rats and Mice Exposed to Butadiene and Its Metabolites
R828112C093 Effects of Concentrated Ambient Particles in Rats and Hamsters: An Exploratory Study
R828112C094I The National Morbidity, Mortality, and Air Pollution Study: Methods and Methodologic Issues
R828112C094II The National Morbidity, Mortality, and Air Pollution Study: Morbidity and Mortality from Air Pollution in the United States
R828112C095 Association of Particulate Matter Components with Daily Mortality and Morbidity in Urban Populations
R828112C096 Acute Pulmonary Effects of Ultrafine Particles in Rats and Mice
R828112C097 Identifying Subgroups of the General Population That May Be Susceptible to Short-Term Increases in Particulate Air Pollution
R828112C098 Daily Mortality and Fine and Ultrafine Particles in Erfurt, Germany
R828112C099 A Case-Crossover Analysis of Fine Particulate Matter Air Pollution and Out-of-Hospital Sudden Cardiac Arrest
R828112C100 Effects of Mexico City Air on Rat Nose
R828112C101 Penetration of Lung Lining and Clearance of Particles Containing Benzo[a]pyrene
R828112C102 Metabolism of Ether Oxygenates Added to Gasoline
R828112C103 Characterization and Mechanisms of Chromosomal Alterations Induced by Benzene in Mice and Humans
R828112C104 Acute Cardiovascular Effects in Rats from Exposure to Urban Ambient Particles
R828112C105 Genetic Differences in Induction of Acute Lung Injury and Inflammation in Mice
R828112C106 Effects on Mice of Exposure to Ozone and Ambient Particle Pollution
R828112C107 Emissions from Diesel and Gasoline Engines Measured in Highway Tunnels
R828112C108 Case-Cohort Study of Styrene Exposure and Ischemic Heart Disease Investigators
R828112C110 Effects of Metals Bound to Particulate Matter on Human Lung Epithelial Cells
R828112C111 Effect of Concentrated Ambient Particulate Matter on Blood Coagulation Parameters in Rats
R828112C112 Health Effects of Acute Exposure to Air Pollution
R828112C113 Benzene Metabolism in Rodents at Doses Relevant to Human Exposure from Urban Air
R828112C114 A Personal Particle Speciation Sampler
R828112C115 Validation and Evaluation of Biomarkers in Workers Exposed to Benzene in China
R828112C116 Biomarkers in Czech Workers Exposed to 1,3-Butadiene: A Transitional Epidemiologic Study
R828112C117 Peroxides and Macrophages in the Toxicity of Fine Particulate Matter in Rats
R828112C118 Controlled Exposures of Healthy and Asthmatic Volunteers to Concentrated Ambient Particles in Metropolitan Los Angeles
R828112C119 Manganese Toxicokinetics at the Blood-Brain Barrier
R828112C120 Effects of Exposure to Concentrated Ambient Particles from Detroit Air on Healthy Rats and Rats with Features of Asthma or Mild Bronchitis
R828112C121 Field Evaluation of Nanofilm Detectors for Measuring Acidic Particles in Indoor and Outdoor Air
R828112C123 Time-Series Analysis of Air Pollution and Mortality: A Statistical Review
R828112C126 Effects of Exposure to Ultrafine Carbon Particles in Healthy Subjects and Subjects with Asthma
R828112C128 Neurogenic Responses of Rat Lung to Diesel Exhaust
R828112C130-I Relationships of Indoor, Outdoor, and Personal Air (RIOPA). Part I. Collection Methods and Descriptive Analyses
R828112C132 An Updated Study of Mortality Among North American Synthetic Rubber Industry Workers