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PROJECT 3: Models of NeurosusceptibilityEPA Grant Number: R833292C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R833292
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: UC Davis Center for Children’s Environmental Health
Center Director: Pessah, Isaac N.
Title: PROJECT 3: Models of Neurosusceptibility
Investigators: Pessah, Isaac N. , Berman, Robert F.
Institution: University of California - Davis
EPA Project Officer: Louie, Nica
Project Period: November 1, 2006 through October 31, 2011 (Extended to October 31, 2013)
RFA: Centers for Children’s Environmental Health and Disease Prevention Research (2005) RFA Text | Recipients Lists
Research Category: Health , Children's Health , Health Effects
The long range goal of Project 3 is to determine if exposure to environmental toxicants early in development contributes to the etiology of neurodevelopmental disorders such as autism. A related goal is to determine whether susceptibility to autoimmune disease increases the neurotoxicity of environmental contaminants and increases the risk for developing disorders such as autism. Understanding how exposure to environmental toxicants may contribute to the etiology of neurodevelopmental disorders is important so that the exposure risks can be identified and minimized. If immune system dysfunction is found to increase the risk of exposure to environmental toxicants, then exposure limits to toxic substances can be lowered, and children with immune system dysfunction who may be at increase risk can be identified and protected.
There are two major hypotheses in Project 3. Each will be tested in mice as models of the human condition. The first hypothesis is: Developmental neurotoxicity will be greater in mice susceptible to autoimmunity. The second hypothesis is: Developmental exposure of C57BL/6J and SJL/J mice to methylmercury (MeHg), a non-coplanar polychlorinated biphenyl (PCB) or a polybrominated diphenyl ether BDE will alter immune system function, with greater effects predicted in autoimmune-susceptible SJL/J mice. The objectives are to expose mouse strains with low (C57BL/6J) or high (SJL mice) susceptibility to autoimmunity perinatally to each of these environmental toxicants of concern to childrens health. We will compare the effects of toxicant exposure between these mouse strains on brain development, complex social behaviors, and immune system function. The overriding hypothesis is that perinatal exposure to each of these toxic substances will impair brain development and behavior, and that suscepbility to autoimmune disease will increase the neuro- and immunotoxicity of these agents. We will also explore a potentially new model of autism in mice injected prenatally with unique autoantibodies isolated from the serum of mothers who have given birth to two more more autistic children. Brain development will be examined histologically using stereological procedures and immunohistochemistry. Complex social behaviors will be studied using behavioral testing procedures established in our laboratory that measure social recognition, social interaction and social communication in mice. Immune system status will be established by measuring cytokines, chemokines, immunoglobulins, and quantifying immune system response to antigenic stimulation. In addition, seizure susceptibility will be measured in toxicant-exposed mice as well as measures of synaptic excitibility and plasticity in hippocampal brain slices. These studies will provide critical new information on the role of the immune system and its interaction with environmental contaminants in autism and other neurodevelopmental disorders.Approach:
Project 3 addresses the need to develop mouse models that can directly test specific hypotheses about how abnormal immune systems impact neurodevelopmental outcomes, especially those relevant to autism including social behaviors and susceptibility to seizure disorders. First and foremost, the mouse models we have chosen will permit direct analysis of measures of altered immune parameters in parallel with measures of neurobehavioral outcomes. Second, we will compare how exposures to known developmental toxicants influence the immune and nervous systems in mouse strains susceptible (SJL/J) and non-susceptible (C57BL/6J) to autoimmunity. Third, analysis of immunological and neurodevelopmental profiles measured in control mice and mice exposed perinatally to known immunological and neurodevelopmental toxicants will be compared to immunological profiles and cellular responses measured from peripheral blood samples obtained from children with and without autism who enroll in the CHARGE-BACK study. Fourth, we will test if prenatal exposure to purified IgG containing autoantibodies directed at fetal brain protein (AA-IgG) isolated from the serum of mothers of autistic children will alter brain development, behavior, and susceptibility to MeHg.Expected Results:
The experimental approach we propose in Project 3 addresses a major goal of CCEH investigators; to better understand how immune cells from autistic children respond differently to environmental triggers, to elucidate their underlying mechanisms, and to understand their impact on brain development and behavior through the use of relevant animal models.Supplemental Keywords:
autism, genes, environment, mercury, PCBs, PBDEs, immune, autoimmune, neurodevelopment, developmental neurotoxicity, persistent organic pollutants, CHARGE, MARBLES,, Health, Scientific Discipline, Genetics, Health Risk Assessment, Epidemiology, Risk Assessments, developmental neurotoxicology, children's health, ecotoxicogenomics, developmental effects, genetic analysis, susceptibility
Main Center Abstract and Reports:
R833292 UC Davis Center for Children’s Environmental Health
Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R833292C001 PROJECT 1: Environmental Epidemiology of Autism
R833292C002 PROJECT 2: Immunological Susceptibility in Autism
R833292C003 PROJECT 3: Models of Neurosusceptibility