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Extramural Research

2005 Progress Report: Adhesion and Repulsion Molecules in Developmental Neurotoxic Injury

EPA Grant Number: R829391C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R829391
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: CECEHDPR - University of Medicine and Dentistry of New Jersey Center for Childhood Neurotoxicology and Assessment
Center Director: Lambert, George H.
Title: Adhesion and Repulsion Molecules in Developmental Neurotoxic Injury
Investigators: Reuhl, Kenneth R.
Institution: Rutgers, The State University of New Jersey , University of Medicine and Dentistry of New Jersey
Current Institution: University of Medicine and Dentistry of New Jersey
EPA Project Officer: Fields, Nigel
Project Period: November 1, 2001 through October 31, 2006
Project Period Covered by this Report: November 1, 2004 through October 31, 2005
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2001)
Research Category: Health Effects , Children's Health

Description:

Objective:

Development of the central nervous system (CNS) involves the coordinated expression of several families of adhesion and repulsion molecules, which serve to guide and regulate the movement of neural elements. Failure of these molecules to function normally would result in defects in brain formation and psychomotor deficits. The hypothesis of this project is that neurotoxic metals perturb brain development/morphogenesis by disrupting the coregulated expression and functions of critical morphoregulatory adhesion and repulsion molecules.

The objective of this research project is to test this hypothesis by addressing four specific questions: (1) Does exposure to neurotoxic metals alter the expression of adhesion and repulsion molecules curing critical stages of brain development, and thereby compromise morphogenesis? (2) Do selective transcriptional, translational, or posttranslational processes mediate metal-induced changes in adhesion and repulsion molecules? (3) What are the behavioral consequences of toxicant-disturbed adhesion and repulsion molecules? (4) Can the deleterious effects of toxic metals on morphoregulatory molecules be modified or ameliorated by intervention strategies?

The results of this project will be evaluated in the context of several animal models of autism and of neurotoxic injury to determine the mechanisms by which developmental toxicity contributes to the spectrum of clinical signs present and their underlying neurobiological basis. The long-term objective of this research project is to elucidate the mechanisms by which toxic metals and other xenobiotics alter neural pathway formation and synaptic regulation and how consequences of such exposures might be minimalized.

Progress Summary:

Significant progress has been made on Research Questions 1, 2, and 3. Using mouse models in which specific morphoregulatory molecules are mutated, we have demonstrated the central involvement of neural adhesion and repulsion molecules in the formation of specific neural pathways in the CNS. The pathways involved, the corpus collosum (Hu, et al., 2003) and the hippocampus (Chen, et al., 2004), are involved in interhemispheric communication and memory processing, respectively. Previous studies by members of this Center have shown that these mutant animals have behavioral abnormalities as well.

Three prototype neurotoxic metals, methylmercury (MeHg), trimethyltin, and inorganic lead, have been investigated. All three metals disrupt the expression of several adhesion molecules, most notably the neural cell adhesion molecule (NCAM) and L1, but only lead has a major effect on the calcium-dependent adhesion molecule, N-cadherin. Further, the changes in adhesion molecules are effected by both transcriptional and posttranslational processes. For example, trimethyltin alters the polysialyated isoform of NCAM (a posttranslational changes) and the pattern of RNA species produced (a transcriptional event). The resultant proteins are thus altered in both form and amount. Animals in which NCAM is perturbed by trimethyltin show altered behavioral profiles, supporting a role of the NCAM molecule in synaptic function (Halladay, et al., 2003, 2004, submitted).

The Eph family of repulsion molecules also are affected by metals. Using a cell model of neuronal development (Wilson, et al., 2003, 2004, 2005) showed changes in both Ephs and their ephrin ligands with MeHg. At low concentrations, MeHg induced expression of mRNA for the ephrins B1, B2, B3, and A5, and high concentrations induced the Eph receptors -A2, -A3, -A8, -B3, and -B6. Because both Ephs and ephrins show a unique combinatorial pattern of expression in the brain, we have begun in vivo assessments of regional mRNA expression in the brain. Preliminary results confirm induction by MeHg of Eph-A5 and Eph-A3 in hippocampus and cerebellum of wild-type mice.

Significance

The temporally and spatially regulated expression of adhesion and repulsion molecules represents one of the central control mechanisms for brain morphogenesis. This work is the first to demonstrate and characterize the roles of both families of these molecules in toxicant-induced brain dysgenesis. This will result in a greater mechanistic understanding of how metals disrupt development at the molecular level. Moreover, because each of the molecules shows a relatively unique expression pattern during development, they may serve as biomarkers for determining when in development an insult may have occurred.

Future Activities:

Experiments during the current funding year have provided confirmation of several aspects of our global hypothesis. Studies during the next year will determine the specific mechanisms by which the toxicants affect RNA transcription and translation of the morphoregulatory molecules. Simultaneously, we will use molecular biology techniques to probe the effects of these effects on synaptic plasticity during neonatal learning. Finally, novel chemicals identified by the Exposure Assessment and Clinical Intervention Projects in the homes of children with autism will be tested for their ability to disrupt development via effects on morphoregulatory molecules.


Journal Articles on this Report : 4 Displayed | Download in RIS Format

Other subproject views: All 23 publications 9 publications in selected types All 9 journal articles
Other center views: All 86 publications 50 publications in selected types All 49 journal articles

Type Citation Sub Project Document Sources
Journal Article Chen Z-Y, Sun C, Reuhl K, Bergemann A, Henkemeyer M, Zhou R. Abnormal hippocampal axon bundling in EphB receptor mutant mice. Journal of Neuroscience 2004;24(10):2366-2374. R829391 (2004)
R829391 (2005)
R829391 (2006)
R829391C002 (2005)
  • Abstract from PubMed
  • Full-text: Journal of Neuroscience-Full Text HTML
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  • Abstract: Journal of Neuroscience-Abstract
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  • Other: Journal of Neuroscience-Full Text PDF
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  • Journal Article Halladay AK, Wilson DT, Wagner GC, Reuhl KR. Trimethyltin-induced alterations in behavior are linked to changes in PSA-NCAM expression. NeuroToxicology 2006;27(2):137-146. R829391 (2004)
    R829391 (2005)
    R829391 (2006)
    R829391C002 (2005)
  • Abstract from PubMed
  • Full-text: ScienceDirect-Full Text HTML
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  • Abstract: ScienceDirect-Abstract
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  • Other: ScienceDirect-Full Text PDF
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  • Journal Article Hu Z, Yue X, Shi G, Yue Y, Crockett DP, Blair-Flynn J, Reuhl K, Tessarollo L, Zhou R. Corpus callosum deficiency in transgenic mice expressing a truncated ephrin-A receptor. Journal of Neuroscience 2003;23(34):10963-10970. R829391 (2004)
    R829391 (2005)
    R829391 (2006)
    R829391C002 (2005)
  • Abstract from PubMed
  • Full-text: Journal of Neuroscience-Full Text HTML
    Exit
  • Abstract: Journal of Neuroscience-Abstract
    Exit
  • Other: Journal of Neuroscience-Full Text PDF
    Exit
  • Journal Article Wilson DT, Polunas MA, Zhou R, Halladay AK, Lowndes HE, Reuhl KR. Methylmercury alters Eph and ephrin expression during neuronal differentiation of P19 embryonal carcinoma cells. NeuroToxicology 2005;26(4):661-674. R829391 (2004)
    R829391 (2005)
    R829391 (2006)
    R829391C002 (2005)
  • Abstract from PubMed
  • Full-text: ScienceDirect-Full Text HTML
    Exit
  • Abstract: ScienceDirect-Abstract
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  • Other: ScienceDirect-Full Text PDF
    Exit
  • Supplemental Keywords:

    children’s health, disease and cumulative effects, ecological risk assessment, environmental chemistry, health risk assessment, risk assessments, susceptibility/sensitive population/genetic susceptibility, toxicology, genetic susceptibility, assessment of exposure, assessment technology, autism, behavioral assessment, behavioral deficits, childhood learning, children, developmental disorders, developmental effects, environmental health hazard, environmental toxicant, exposure assessment, gene-environment interaction, neurodevelopmental, neurological development, neuropathological damage, neurotoxic, neurotoxicity, outreach and education, public health,, RFA, Health, Scientific Discipline, Health Risk Assessment, Biochemistry, Children's Health, developmental neurotoxicity, biological response, neurodevelopmental toxicity, autism, environmental toxicant, brain development, environmental health hazard, children's environmental health, growth & development

    Progress and Final Reports:
    Original Abstract
    2004 Progress Report
    2006 Progress Report


    Main Center Abstract and Reports:
    R829391    CECEHDPR - University of Medicine and Dentistry of New Jersey Center for Childhood Neurotoxicology and Assessment

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R829391C001 Neurotoxicant Effects on Cell Cycle Regulation of Neurogenesis
    R829391C002 Adhesion and Repulsion Molecules in Developmental Neurotoxic Injury
    R829391C003 Disruption of Ontogenic Development of Cognitive and Sensory Motor Skills
    R829391C004 Exposure Assessment and Intervention Project (EAIP)
    R829391C005 Clinical Sciences Project

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    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.

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