Core 5 - Michael Aschner

Core 5 - Michael Aschner

Manganese Health Research Program: Phase 1, Core 5

Research Core Project Number: W81XWH-05-1-0239O
Research Core Project: Magnetic Resonance Imaging (MRI) of Manganese Accumulation in the Rat Brain Associated with Iron-Deficiency and Supplementation
Core Principal Investigator (CPI): Michael Aschner
  Department of Pediatrics
  B-3307 MCN, Campus Zip 2495
  Vanderbilt University Medical Center
  1162 21st Avenue South
  Nashville , TN 37232
   
  Tel: 615-322-8024
  Fax: 615-322-6541
www.vandymolecneuro.org
   
Key Collaborators: Vanessa A. Fitsanakis, Co-PI
  Department of Pediatrics
  B-3307 MCN, Campus Zip 2495
  Vanderbilt University Medical Center
  1162 21st Avenue South
  Nashville , TN 37232

Project Objectives:

  • To determine the deposition pattern of Mn in rats receiving a control diet compared to rats receiving weekly injections of Mn
  • To determine the role of Fe deficiency and Fe supplementation in modulating the temporal deposition pattern of brain Mn

Project Description:

Practical limitations in methodology have obscured our insights into brain Mn deposition and neurotoxicity. One such constraint in studies examining either Mn brain deposition, or the interaction between Fe and Mn, has been the technical inability to follow Mn deposition in the same animals over time, as conventional techniques require that animals be sacrificed at various time points. Now, however, MR technology facilitates the monitoring of Mn deposition in the same animal over time, providing a powerful tool to further address the function of both Fe deficiency and Fe supplementation in the exacerbation or amelioration, respectively, of Mn brain levels in vivo . To date, no studies have incorporated MR technology to address this question. We will test the working hypothesis that brain Mn deposition in rats is dependent on the Fe status of the animal . It follows that rats maintained on an Fe deficient diet should have increased brain Mn levels compared with rats maintained on a diet replete with Fe (normal diet), and Fe supplemented rats should have decreased levels of Mn compared to those on a normal diet.

Project Status:

Project started: March 1, 2005
Scheduled completion date: February 28, 2008
Completed:  

Key research accomplishments:

  • Rats were fed normal diets, with treated animals receiving weekly injections of MnCl 2 for 14 weeks, with no significant toxicity.

s 1, 3, 5, 7, 9, 11, 13 and 14. This allowed for successful comparison of images between groups as well as within groups at various time points.

  • Blood samples were taken at weeks 8 and 14 for determination of both Mn and Fe levels.
  • At the conclusion of the study, animals were humanely euthanized and brains were removed and dissected into the following regions: cerebellum, brain stem (pons and medulla), midbrain, hippocampus, striatum and cortex.
  • Metal analysis, as determined by atomic absorption spectroscopy (AAS), has been completed for each brain region.
  • Initial analysis of specific regions of interest (ROIs) from the MR images suggests that brain Mn accumulation is saturated by week 5.
  • Comparison of metal content (AAS) to specific regions of interest (ROI) R 1 values (a rate constant associated with T 1 -weighted images) suggests a regionally specific relationship between brain Mn accumulation and MR parameters.
  • Current data suggest that it is indeed feasible to move into the next phase of the proposed research to determine the effects of dietary Fe manipulation of brain Mn accumulation.

Project URL Project w eb address (if available)

Publications/Presentations

arising from project:

 Abstracts arising from project:

  • Fitsanakis VA, Zhang N, Anderson JG, Erikson KM, Gore JC, Avison MJ, Aschner M. Determination of brain manganese accumulation using magnetic resonance imaging (MRI) and atomic absorption spectroscopy. Toxicol Sci 59, 2006.
  • Aschner M, Fitsanakis VA, Milatovic D, Aschner. Dietary iron modulates manganese neurotoxicity. American Society of Neurochemistry, Portland, OR, March 11-14, 2006, J. Neurochem. 2006.
  • Zhang N, Fitsanakis VA, Aschner M, Avison MJ, Gore JC. Non-uniform manganese relaxivity in rat brain tissues. The International Society for Magnetic Resonance in Medicine, Seattle, WA, May 6-12, 2006.
  • Gunter TE, Aschner M, Salter J, Gunter KK. Where does Mn2+ inhibit oxidative phosphorylation? In: Environment and Neurodevelopmental Disorders, Twenty-Third International Neurotoxicology Conference, Little Rock, AR, September 19-20, 2006.
  • Aschner JL, Furlong H, Daily D, Aschner M.  Neuroimaging and neurodevelopmental correlates of intravenous manganese exposure In parenterally-fed infants: A clinical trial in the neonatal intensive care unit (NICU).  In: Environment and Neurodevelopmental Disorders, Twenty-Third International Neurotoxicology Conference, Little Rock, AR, September 19-20, 2006.
  • Fitsanakis VA, Zhang N, Anderson JG, Erikson KM, Gore JC, Avison MJ, Aschner M. Changes in dietary iron levels affect brain manganese accumulation and distribution. In: Environment and Neurodevelopmental Disorders, Twenty-Third International Neurotoxicology Conference, Little Rock, AR, September 19-20, 2006.
  • Aschner M. Transport and mechanisms of neurotoxicity. The 40th Annual Winter Conference on Brain Research (WCBR). Snowmass, Colorado, January 27-Feb 2, 2007. 
  • Aschner M, Fitsanakis VA, Milatovic D, Nass R, Erikson KM, dos Santos APM. Manganese: transport and mechanisms of neurotoxicity. In: Determinants of environmentally-borne manganese neurotoxicity: From worms to men. The Society of Environmental Toxicology and Chemistry (SETAC) Europe Annual Meeting, Porto, Portugal, May 20-24, 2007.
  • Zhang N, Fitsanakis VA, Aschner M, Avison MJ, Gore JC. A model of competition between Manganese and Iron and their combined influence on R1 in Rat Brain Tissues. The International Society for Magnetic Resonance in Medicine, Berlin, Germany, May 19-25, 2007.
  • Finkelstein Y, Milatovic D, Aschner M. Dynamics of cholinergic synaptic mechanisms affected by manganese. 11th meeting of the International Neurotoxicology Association (INA), Asilomar Conference Grounds, Pacific Grove, CA, June 10-15, 2007.

Manuscripts originating from the project

  • Fitsanakis VA, Zhang N, Avison MJ, Gore JC, Aschner JL, Aschner M. The use of magnetic resonance imaging (MRI) in the study of manganese neurotoxicity. Neurotoxicology 2006; 27: 798-806.
  • Aschner M, Lukey B, Tremblay A. The Manganese Research Health Program (MHRP): Status report and future research needs and directions. Neurotoxicology 2006; 27:733-736.
  • Gunter KK, Aschner M, Gunter TE. Speciation of manganese in cells and mitochondria: A search for the proximal cause of manganese neurotoxicity. Neurotoxicology 2006; 27:765-776.
  • Gunter KK, Aschner M, Miller LM, Eliseev R, Salter J, Anderson K, Gunter TE. Determining the oxidation states of manganese in NT2 cells and primary cultures of astrocytes. Neurobiol Aging 2006; 27:1816-1826.
  • Aschner M, Guilarte TR, Schneider JS, Zheng W. Manganese: Recent advances in its transport and neurotoxicity. Toxicol Appl Pharmacol 2007; 221:131-47.
  • Milatovic D, Yin Z, Gupta RC, Sidoryk M, Albrecht J, Aschner JL, Aschner M. Manganese induces oxidative impairment in cultured rat astrocytes. Toxicol Sci 2007; 98:198-205.

Presentations arising from project (Aschner, M):

  • Manganese Transport, Toxicity and Speciation in the CNS. University of Porto Alegre , Brazil , August 22, 2005 .
  • Manganese Transport, Toxicity and Speciation in the CNS. University of Santa Maria , Brazil , August 24, 2005 .
  • Manganese Transport, Speciation and Toxicity in the Central Nervous System, In: Glutamate in metabolism and neurotransmission: complex interactions at the inter-and intracellular level, Wierzba , Poland , August 29, 2005 .
  • Manganese Transport in the Central Nervous System. In: Environment and Neurodevelopmental Disorders, Twenty-Second International Neurotoxicology Conference, Research Triangle Park , NC , September 14, 2005 .
  • Manganese Transport, Speciation and Toxicity in the Central Nervous System, MT-2005, Beijing , China , October 9, 2005 .
  • Manganese Transport, Neurotoxicity and Speciation in the Brain. In: Southeastern Chapter of the Society of Toxicology, Meharry Medical College , Nashville , TN , October 21, 2005 .
  • Use of magnetic resonance imaging (MRI) to determine brain manganese deposition in male Sprague Dawley rats. In: Annual meeting of the Israel Society for Neuroscience, Eilat , Israel , December 13, 2005 .
  • Manganese transport, speciation and neurotoxicity. Monthly Zlotowski Center, Invited Senior Investigator lecture, Faculty of Health Sciences, Ben-Gurion University of the Negev, December 15, 2005.
  • Manganese Transport, Toxicity and Speciation in the CNS. In: Winter Conference on Brain Research, Steamboat Springs , CO , January 21-27, 2006 .
  • Developmental Neurotoxicity of Manganese. In: Grand Rounds, the Kennedy Center , Vanderbilt University Medical Center , Nashville , TN , February 1, 2006 .
  • Dietary Iron Modulates Manganese Neurotoxicity . In: Society of Toxicology Annual Meeting, Symposium on Determinants of Manganese Neurotoxicity: From Worms to Man. San Diego , CA , March 5, 2006 .
  • Dietary Iron Modulates Manganese Neurotoxicity. In: Mn in CNS neurotoxicity and idiopathic Parkinson's disease, colloquium for the 37th annual meeting of the American Society for Neurochemistry (ASN), Portland, OR, March 11-15, 2006.

 

Last updated: March 2011


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