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Extramural Research

2006 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: 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, 2005 through October 31, 2006
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 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 is to test this hypothesis by addressing four specific questions: (1) Does exposure to neurotoxic metals alter the expression of adhesion and repulsion molecules during 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 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 minimized.

Progress Summary:

During Year 5 of the project, significant progress has been made on all four research questions. Emerging data for our laboratories and others (e.g., Belmonte, et al., 2004) have provided strong support of our hypothesis that abnormal targeting of neuronal projections results in miswiring of the brain in autistic patients. Using both in vivo and in vitro models of neural development, we have confirmed the critical importance of morphoregulatory molecules in establishing and maintaining neural architecture. Moreover, we have established that exposure to the toxic metals methylmercury, lead, or trimethyltin can cause functional and structural abnormalities that directly are attributable to disruption of these molecules. A critical target of metals during early brain development appears to be the Eph/ephrin system of repulsion molecules, which guides axons during fasciculation and help establish permanent synaptic networks. Metals inhibit the expression of certain classes of these molecules preferentially in the hippocampus and cerebellum, sites shown to be abnormal in autistic brains. Simultaneously, these metals also disrupt the expression of the adhesion molecule, neural cell adhesion molecule (NCAM), at the forming synapse. As a consequence of these effects, the balance between adhesion and repulsion is disturbed and brain development is subtly, but significantly, altered. Animals treated with low levels of these toxic metals show behavioral alterations resembling some clinical features of autism. Pretreatment or concurrent treatment of the animals with antioxidants prevents or significantly ameliorates the expression of these toxic signs, supporting the cautious use of antioxidants in high-risk pregnancies.

Together with Dr. Lioy (Exposure Assessment and Intervention Project), we are collaborating with Mr. George Braddock of Creative Design Solutions of Eugene, Oregon. Mr. Braddock is a pioneer in the design and construction of innovative housing for children with disabilities, including autism. This housing frequently uses nontraditional building material to meet the special needs of these children: this material often is a composite plastic and glues, many of which outgas over time. Using the analytical tools of the Exposure Assessment and Intervention group, we are developing a profile of the air and surface environment in this novel housing.

Significance

This work has confirmed and characterized adhesion and repulsion molecules as important targets of heavy metals during development. The consequences of selective disruption of both the repulsion Eph/ephrin and adhesion NCAM molecules have been defined using molecular (knockout and transgenic) and pharmacological approaches, and molecular models by which metals affect them have been developed. Demonstration of a protective effect provided by antioxidants suggests that at least some of the adverse effects leading to autism-like symptoms can be prevented or minimized by timely administration of these drugs.

Future Activities:

During the next funding year, work will focus on three specific projects. First, we will continue the mechanistic work on metal disruption of morphoregulatory molecules at the posttranslational level by examining the specific function of the molecules at the growth cone and synaptic levels. Second, we will examine further the regulation of NCAM and Eph/ephrin at the synapse of developing and adult animal to determine whether adverse effects of metals can be reversed pharmacologically. Finally, we will continue to evaluate the potential neurotoxicity of novel chemicals detected in the homes of autistic children (with Dr. Lambert) and in homes being custom-designed for use by autistic children (with Dr. Lioy and Mr. Braddock).


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 T-F, Zhang Y-L, Xu W-L, Li Z-Q, Hou B, Wang C-L, Fan M, Qian L-J, Zhou R-P, Zhang C-G. Prokaryotic expression, polyclonal antibody preparation, and sub-cellular localization analysis of Na+, K+-ATPase β2 subunit. Protein Expression and Purification 2004;37(1):47-52. R829391 (2004)
R829391 (2005)
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R829391C002 (2006)
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  • Journal Article Hu Z, Cooper M, Crockett DP, Zhou R. Differentiation of the midbrain dopaminergic pathways during mouse development. Journal of Comparative Neurology 2004;476(3):301-311. R829391 (2004)
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    R829391 (2006)
    R829391C002 (2006)
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  • Journal Article Wagner GC, Reuhl KR, Cheh M, McRae P, Halladay AK. A new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate. Journal of Autism and Developmental Disorders 2006;36(6):779-793. R829391 (2004)
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    R829391 (2006)
    R829391C002 (2006)
    R829391C003 (2004)
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  • Journal Article Zhang C, Meng F, Wang C, Guo H, Fan M, Liu S, Zhou R, He F. Identification of a novel alternative splicing form of human netrin-4 and analyzing the expression patterns in adult rat brain. Molecular Brain Research 2004;130(1-2):68-80. R829391 (2004)
    R829391 (2005)
    R829391 (2006)
    R829391C002 (2006)
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  • Full-text: ScienceDirect-Full-Text
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  • Abstract: ScienceDirect-Abstract
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  • Other: ScienceDirect-Full Text PDF
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  • 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
    2005 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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