2007 Progress Report: Metals Neurotoxicity Research Project

EPA Grant Number: R831725C004
Subproject: this is subproject number 004 , established and managed by the Center Director under grant R831725
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Harvard Center for Children’s Environmental Health and Disease Prevention Research
Center Director: Hu, Howard
Title: Metals Neurotoxicity Research Project
Investigators: Maher, Tim , Weisskopf, Marc
Institution: Harvard T.H. Chan School of Public Health
EPA Project Officer: Callan, Richard
Project Period: June 1, 2004 through May 31, 2009 (Extended to May 31, 2011)
Project Period Covered by this Report: June 1, 2007 through May 31,2008
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2003) RFA Text |  Recipients Lists
Research Category: Health , Health Effects , Children's Health

Objective:

The Center for Children’s Environmental Health and Disease Prevention at the Harvard School of Public Health is now in its fourth year. Our fifth year of funding begins on April 1, 2008. More and more, this Center is emerging as a model of effective translational research. Our Center uses animal models to address fundamental mechanisms of metal pharmacokinetics and mechanisms of injury. It utilizes exposure measurements in humans, and is also measuring health outcomes in humans. Most importantly, we involve the community. Especially we have established communications with individuals in that community, as well as with government stake-holders. This year continued to see functioning partnerships with our community-based colleagues and with other collaborating institutions.

Year 04 was marked by substantial progress in all Projects and Cores.

Progress Summary:

Project 4 has utilized exposures to metals, especially by ingestion, and has focused on behavioral and neurochemical outcomes. Changes in body weight and other health and disease indicators have also been seen. This project utilizes exposures via drinking water. We have now measured changes in lead levels in blood, hippocampus, brain stem, and the remainder of the brain in response to different levels of lead exposure. We have examined these levels in both newborn pups as well as dams. At the highest levels of lead and manganese exposure, we have seen impaired learning.

Animals were tested in the Morris Water Maze (MWM) to determine the influence of metal exposure on learning and memory. Only animals exposed to the two highest doses of MnCl2 (5 and 10 mg/mL) displayed impaired learning in the MWM as evidenced by significantly increased latency to find the platform on the fourth consecutive day of training. Control male rats averaged 18±3 seconds on day 4, while manganese-exposed rats required 34±5 and 37±6 seconds to find the platform for MnCl2 5 and 10 mg/mL, respectively (Figure B4.1). However, the probe trial on the following day failed to demonstrate any significant impairment of memory, although the percentage of time swimming in the platform quadrant of MnCl2 5 mg/mL (27±5 %) and 10 mg/mL (30±3 %) appeared to be less than that of the control (34±3 %). The cue test was not altered by any metal exposures indicating that any differences observed in performance in these animals in the MWM were not due to any effect of the metals on the vision of the rats. Exposure to lead acetate did not significantly alter performance of rats in the MWM during the acquisition phase, the probe test, nor the cue test.

Microdialysis studies have shown that these metal exposures and behavioral changes are related to changes in dopamine release compared to controls. We have determined the effect of metal exposure on the potassium-evoked dopamine release in the prefrontal cortex and have demonstrated an effect of MnCl2, by increasing K+-evoked dopamine release compared to controls. However, only those exposure to MnCl2 5 mg/mL showed the statistically significant difference probably due to the still small sample sizes. In contrast to the effect of MnCl2 on the K+-evoked dopamine release, Pb acetate from any exposure tested did not show statistically significant differences from the control during the K+-evoked dopamine release experiments. More animals are being tested at this time and should add to the power of the analyses performed. Changes have also been seen in the potassium-invoked glutamate released in the hippocampus. This was seen in relation to both manganese and lead exposures.

A very successful third meeting of the External Advisory Committee was held. It was held in late May/ early June in Tar Creek, Oklahoma. This provided us an opportunity to hear from the community we are studying, as well as gave us a chance to communicate our preliminary findings and advice about reducing risk. We continue to maintain a monthly schedule of Project and Core meetings. The Center Scientists Program continues to identify and nurture young talent. The Chemistry Core is processing an increasing number of samples, especially for Project 2. A new apparatus is now being used to aerosolize chat samples, thus creating an opportunity to collect and characterize respirable particles, some of which will be neutron-activated by Project 3. The Biostatistics Core has been involved with multiple publications and continues to develop new analytic methods as needed. Increasingly, we are expanding our talent in regard to geographic information systems (GIS). Spatial analysis is emerging as an important tool. The Community Outreach and Translation Core is active. A comic book has been produced for use in Tar Creek. The meeting of the Advisory Committee and of all investigators in Tar Creek in May/June was a major opportunity for this Core to communicate with our colleagues in Oklahoma. We also participated in the annual Tar Creek Conference. The Administrative Core also continues to implement its quality management plan.


Journal Articles on this Report : 12 Displayed | Download in RIS Format

Other subproject views: All 12 publications 12 publications in selected types All 12 journal articles
Other center views: All 35 publications 26 publications in selected types All 25 journal articles
Type Citation Sub Project Document Sources
Journal Article Arora M, Weuve J, Schwartz J, Wright RO. Association of environmental cadmium exposure with pediatric dental caries. Environmental Health Perspectives 2008;116(6):821-825. R831725 (2007)
R831725 (2009)
R831725C001 (2007)
R831725C001 (2008)
R831725C003 (2007)
R831725C004 (2007)
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  • Journal Article Brain JD, Heilig E, Donaghey TC, Knutson MD, Wessling-Resnick M, Molina RM. Effects of iron status on transpulmonary transport and tissue distribution of Mn and Fe. American Journal of Respiratory Cell and Molecular Biology 2006;34(3):330-337. R831725 (2005)
    R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2005)
    R831725C003 (2007)
    R831725C003 (2008)
    R831725C004 (2007)
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  • Journal Article Heilig EA, Thompson KJ, Molina RM, Ivanov AR, Brain JD, Wessling-Resnick M. Manganese and iron transport across pulmonary epithelium. American Journal of Physiology–Lung Cellular and Molecular Physiology 2006;290(6):L1247-L1259. R831725 (2005)
    R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2005)
    R831725C003 (2007)
    R831725C003 (2008)
    R831725C004 (2007)
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  • Journal Article Heilig E, Molina R, Donaghey T, Brain JD, Wessling-Resnick M. Pharmacokinetics of pulmonary manganese absorption: evidence for increased susceptibility to manganese loading in iron-deficient rats. American Journal of Physiology–Lung Cellular and Molecular Physiology 2005;288(5):L887-L893. R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2005)
    R831725C003 (2007)
    R831725C004 (2007)
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  • Journal Article Hu H, Shine J, Wright RO. The challenge posed to children’s health by mixtures of toxic waste: the Tar Creek Superfund Site as a case-study. Pediatric Clinics of North America 2007;54(1):155-175. R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2007)
    R831725C004 (2007)
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  • Journal Article Schaider LA, Senn DB, Brabander DJ, McCarthy KD, Shine JP. Characterization of zinc, lead, and cadmium in mine waste: implications for transport, exposure, and bioavailability. Environmental Science and Technology 2007;41(11):4164-4171. R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2007)
    R831725C004 (2007)
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  • Journal Article Surkan PJ, Schnaas L, Wright RJ, Tellez-Rojo MM, Lamadrid-Figueroa H, Hu H, Hernandez-Avila EM, Bellinger DC, Schwartz J, Perroni E, Wright RO. Maternal self-esteem, exposure to lead, and child neurodevelopment. NeuroToxicology 2008;29(2):278-285. R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C001 (2008)
    R831725C003 (2007)
    R831725C004 (2007)
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  • Journal Article Thompson K, Molina RM, Brain JD, Wessling-Resnick M. Belgrade rats display liver iron loading. Journal of Nutrition 2006;136(12):3010-3014. R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2007)
    R831725C003 (2008)
    R831725C004 (2007)
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  • Full-text: Journal of Nutrition-Full Text HTML
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  • Journal Article Thompson K, Molina R, Donaghey T, Brain JD, Wessling-Resnick M. The influence of high iron diet on rat lung manganese absorption. Toxicology and Applied Pharmacology 2006;210(1-2):17-23. R831725 (2005)
    R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2005)
    R831725C003 (2007)
    R831725C003 (2008)
    R831725C004 (2007)
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  • Journal Article Thompson K, Molina RM, Donaghey T, Schwob JE, Brain JD, Wessling-Resnick M. Olfactory uptake of manganese requires DMT1 and is enhanced by anemia. FASEB Journal 2007;21(1):223-230. R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2007)
    R831725C003 (2008)
    R831725C004 (2007)
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  • Journal Article Thompson K, Molina RM, Donaghey T, Brain JD, Wessling-Resnick M. Iron absorption by Belgrade rat pups during lactation. American Journal of Physiology-Gastrointestinal and Liver Physiology 2007;293(3):G640-G644. R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2007)
    R831725C003 (2008)
    R831725C004 (2007)
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  • Journal Article Wright RO, Baccarelli A. Metals and neurotoxicology. The Journal of Nutrition 2007;137(12):2809-2813. R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2007)
    R831725C004 (2007)
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  • Supplemental Keywords:

    RFA, Health, Scientific Discipline, ENVIRONMENTAL MANAGEMENT, INTERNATIONAL COOPERATION, Waste, Environmental Chemistry, Health Risk Assessment, Biochemistry, Hazardous Waste, Children's Health, Hazardous, Risk Assessment, community-based intervention, fate and transport , developmental toxicity, Human Health Risk Assessment, neurodevelopmental toxicity, children's environmental health, mining waste, metal wastes, metals, human health risk, metal contamination

    Progress and Final Reports:

    Original Abstract
  • 2004 Progress Report
  • 2005 Progress Report
  • 2006
  • 2008 Progress Report
  • 2009
  • Final

  • Main Center Abstract and Reports:

    R831725    Harvard Center for Children’s Environmental Health and Disease Prevention Research

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R831725C001 Metals, Nutrition, and Stress in Child Development
    R831725C002 Exposure Assessment of Children and Metals in Mining Waste: Composition, Environmental Transport, and Exposure Patterns
    R831725C003 Manganese, Iron, Cadmium, and Lead Transport from the Environment to Critical Organs During Gestation and Early Development in a Rat Model
    R831725C004 Metals Neurotoxicity Research Project