The long range goal 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.
The specific aims are to expose mouse strains with low (C57BL/6J) or high (SJL mice) susceptibility to autoimmunity perinatally to either methylmercury (MeHg), polychlorinated biphenyl 95 (PCB 95) or polybrominated diphenyl ether 47 (BDE 47). We will then compare the effects of toxicant exposure between these mouse strains on brain development, complex social behaviors, and immune system function. The 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES011269-10
Application #
8118294
Study Section
Special Emphasis Panel (ZES1)
Project Start
Project End
2013-05-31
Budget Start
2010-08-01
Budget End
2013-07-31
Support Year
10
Fiscal Year
2010
Total Cost
$135,235
Indirect Cost
Name
University of California Davis
Department
Type
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Keil, Kimberly P; Miller, Galen W; Chen, Hao et al. (2018) PCB 95 promotes dendritic growth in primary rat hippocampal neurons via mTOR-dependent mechanisms. Arch Toxicol 92:3163-3173
Zheng, Jing; McKinnie, Shaun M K; El Gamal, Abrahim et al. (2018) Organohalogens Naturally Biosynthesized in Marine Environments and Produced as Disinfection Byproducts Alter Sarco/Endoplasmic Reticulum Ca2+ Dynamics. Environ Sci Technol 52:5469-5478

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