Neurotoxicology

Director: Merle G. Paule, Ph.D.

Introduction      Current Research Projects

Introduction

Fifty-million Americans have a permanent, neurological disability that limits their daily activities. One in three will experience some form of mental disorder during their lifetime. Annual health care, lost productivity, and other economic costs associated with brain-related diseases are estimated to exceed $500 billion. Disability from depression alone exceeds that of diabetes, hypertension, gastrointestinal, and lung diseases and costs over $43 billion annually. The number of persons with Alzheimer’s and other age-related neurological disorders will increase dramatically as our population ages. Known and suspected causes of brain-related disorders include exposures to chemicals, such as therapeutic drugs, food additives, food products, cosmetic ingredients, pesticides, and naturally occurring substances. Recent advances in technology are currently providing our scientists with a variety of new tools with which to better study and understand the etiology of brain-related disorders and the mechanisms associated with chemically induced neurotoxicity and to further reduce the risks associated with neurotoxic events.

The number of neuroactive chemicals that require FDA regulation is estimated to be in the thousands. Thus, identifying methods and approaches for assessing neurotoxicity is critical for the development of guidelines applicable for the assessment of neurotoxic risk. It is clear that chemicals that are known or suspected causes of brain-related disorders are vital to the national economy and our quality of life. Therefore, the challenge is to determine at what doses, or exposure levels, and under what conditions these compounds can be used effectively while minimizing the likelihood that they will cause adverse effects on the nervous system.

The overall goals of the Division of Neurotoxicology are to develop and validate quantitative biomarkers and identify biological pathways associated with the expression of neurotoxicity. Towards this end, specific research efforts address several focal areas of fundamental research designed to broadly examine the involvement of: 

1. monoamine-neurotransmitter systems as targets for neurotoxicity
2. mitochondrial dysfunction and oxidative stress as mechanisms of neurotoxicity
3. NMDA (N-methyl-D-aspartic acid) receptor complex as a mediator of adult and developmental neurotoxicity
4. role of amyloid ß-peptide (Aß) aggregation in the expression of neurotoxicity.

An increased understanding of the processes associated with neurotoxic outcomes will provide opportunities for improved assessments of risk and identification of potential therapeutic approaches. The strategy employed for achieving these goals has been to use multidisciplinary approaches that capitalize on the neurochemistry, molecular neurobiology, neuropathology, neurophysiology, and behavioral expertise of Division personnel. The Division is expanding capabilities in the area of imaging by adding both microPET and magnetic resonance imaging (MRI) instruments and personnel. In addition, efforts to develop sensitive, high-throughput systems for screening potential neurotoxicants are underway. 

Other unique features of the Division’s research capabilities include the ability to: 

1. determine chemical concentrations and cellular-level interactions in target tissue
2. determine changes in gene and protein expression associated with chemical exposures
3. effect high-throughput, comprehensive cognitive or behavioral assessments
4. employ multiple species including nonhuman primates, rodents, and, in some cases, humans, in the risk-assessment process to reduce the uncertainty associated with extrapolating findings across species
5. develop novel histochemical tracers to aid in the evaluation of chemical-induced pathologies

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Current Research Projects 

• Analyses of the Rat Hippocampus via DNA Microarrays and a Novel Antibody Array, Coupled with Laser Capture Microdissection (LCM) - Evaluation of the Effect of Aging on Gene and Protein Expression Associated with Learning (E0713901)
• Assessment of Gaseous Anesthetics in the Developing Nonhuman Primate (E0728501)
• Assessment of Ketamine in the Developing Nonhuman Primate (E0718901)
• Assessment of Specific Cognitive Domains in Girls with a History of Sexual Abuse (E0724701)
• Brain Sexual Dimorphic Structures and Sex Hormone-like Compounds: Animal Request for Methods Development and Training (P00710)
• Characterizing the Amphetamine-Induced Changes in Vascular Tone, Vasotrauma and Alterations in Angiogenesis in Rodent Brain (E0729501)
• Complex Brain Function in Children as Measured by Performance in the NCTR Operant Test Battery (E0703301)
• Complex Brain Function Study in Children With and Without Major Depression (E0717701)
• Development of Novel Histochemical Markers of Brain Vascular Elements and Their Application for Localizing Neurotoxicant Induced Pathologies (E0731201)
• Developmental and Standardization of a Microdialysis Technique in Mice (P00697)
• Developmental Neurotoxicity Assessment of Acrylamide in Rats (E0215101)
• Effects of Anxiety on Complex Brain Function in Children (E0721701)
• Evaluation of Novel Genetic Changes and Post-Translational Modification in the Protein Products of Specific Genes in Parkinson's Disease and in Substituted Amphetamine Neurotoxicity Using Quantitative Proteome Analysis in Mice Models and Human Subjects (E0712101)
• Further Studies on the Effects of Afmid/TK Deficiencies and Brain, Liver, and Kidney Function (E0726101)
• Gender-Specific Gene Expression Analysis and Cross-Mapping Differentially Expressed Genes to Specific Chromosomal Locations in the Male and Female Rat (E0730901)
• Histochemical Test Battery for Evaluating the Efficacy and Toxicity of Putative Alzheimer's Disease Therapeutics of FDA Relevance (E0727301)
• Long-Term Effects of Morphine Treatment in Preterm Infants Exposed to Repetitive Neonatal Pain (E0724301)
• Methods Development for High-Resolution Dedicated Positron Emission Tomography (microPET) to Rodent Neuroplasticity and Toxicity During Development (E0726401)
• Neuroprotective Effects of Pramipexole Against Methamphetamine- and MPTP-Induced Cytotoxicity in In Vitro and In Vivo Models (E0732001)
• Neurotoxicity Assessment of Manganese (Mn) Nanoparticles in PC-12 Cells and in Mice (E0725701)
• Neurotoxicity Assessment of Silver (Ag) Nanoparticles in PC-12 Cells and in Rats (E0728201)
• NMDA Antagonist/GABA Agonist-Induced Cell Death in the Developing Rat Brain (E0215501)
• Novel Studies on Sites-of-Action and Mechanisms in Chronic Balance Dysfunction (E0722301)
• Pramipexole: Thirty-Week Toxicity Study in Juvenile Rhesus Monkeys Followed by a Twelve-Week Recovery Period: Use of a Nonhuman Primate Model for Studying the Consequences of Long-Term Dopaminergic Receptor Stimulation on Complex Brain Functions Using the NCTR Operant Test Battery (OTB) (E0725201)
• Sex Differences in Drug Abuse Susceptibility in Methylphenidate (MPH)-Treated Rats (E0727201)
• The Effects of Acrylamide and PhIP on Normal Human Brain Cortical Neuronal (HCN-1), PC12, and HepG2 Cells in vitro: Activation or Inactivation of Phase I and II Enzymes (E0726301)
• The Role of Mitochondrial Energy Disruption in the Mechanism of Neurotoxicity: Neurophysiological, Neurochemical, and cDNA Microarray Approaches (E0711001)
• Training for Bisphenol A Studies (P00706)
• Training to Dissect and Isolate Different Brain Regions and the Use of Microdialysis Techniques in Rats and Mice (P00712)
• Wireless Deep Brain Stimulation in Nonhuman Primates with MPTP-Induced Parkinson's Disease (E0723801)

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The NCTR Annual Report provides information on the latest accomplishments and plans for the Division of Neurotoxicology as well as project and publication listings for NCTR.