Project 3: Neurodevelopmental Toxicology of Autism

项目3：自闭症神经发育毒理学

• 批准号: 7476540
• 负责人: Isaac N Pessah
• 金额: $ 15.3万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7476540
• 关键词: Age; Animal Testing; Antibodies; Anxiety; Autistic Disorder; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Behavior; Behavioral; Biological Assay; Birth; Brain; CCL2 gene; CCL3 gene; CCL4 gene; CSF2 gene; Cerebellum; Chemokine (C-C Motif) Ligand 4; Child; Complex; Development; Disease; Environmental Pollution; Enzyme-Linked Immunosorbent Assay; Etiology; Exposure to; Fibroblast Growth Factor; Flurothyl; Fright; Glutamate Receptor; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Hippocampus (Brain); Histologic; Homer 1; IL8 gene; Immune System and Related Disorders; Immune response; Immune system; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunohistochemistry; Immunophilins; In Vitro; Infection; Interferon Type II; Interleukin-10; Interleukin-17; Interleukin-4; Interleukin-5; Interleukin-6; Kindling (Neurology); Laboratories; Learning; Leptin; Localized; Long-Term Potentiation; Measures; Memory; Metabotropic Glutamate Receptors; Methods; Methylmercury Compounds; Mitogens; Modeling; Mothers; Mouse Strains; Mus; N-Methylaspartate; Neurodevelopmental Disorder; Neurologic; Neuronal Injury; Neurons; Numbers; Patient currently pregnant; Pentylenetetrazole; Peptidylprolyl Isomerase; Perinatal; Perinatal Exposure; Plasma; Poison; Polychlorinated Biphenyls; Predisposition; Preparation; Principal Investigator; Procedures; Proteins; RANTES; Range; Research Design; Research Personnel; Risk; Role; Ryanodine Receptor Calcium Release Channel; SJL Mouse; SJL/J Mouse; Seizures; Sensory Motor Performances; Serological; Serum; Signal Pathway; Signal Transduction; Slice; Small Inducible Cytokine A3; Social Behavior; Social Interaction; Source; Splenocyte; Structure; Synapses; System; T-Cell Proliferation; Testing; Tetanus; Tetanus Toxoid; Tetanus Vaccine; Thinking; Toxic Environmental Substances; Toxicant exposure; Toxicology; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factors; Week; Western Blotting; Work; Xenobiotics; autistic children; behavior test; chemokine; cytokine; density; developmental disease; developmental neurotoxicity; fetal; human TNF protein; immunotoxicity; in vivo; link protein; mouse model; neurobehavioral disorder; neurodevelopment; neurotoxicity; phenyl ether; postnatal; prenatal; prenatal exposure; programs; receptor; receptor function; repaired; research study; response; sensory gating; social; social communication; synaptotagmin; toxicant

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.

远距离目标是确定开发早期对环境有毒物质的暴露是否有助于 神经发育障碍（例如自闭症）的病因。一个相关目标是确定是否 自身免疫性疾病的敏感性增加了环境污染物和 增加患有自闭症等疾病的风险。了解如何接触环境 毒物可能有助于神经发育障碍的病因很重要，因此暴露 可以识别和最小化风险。如果发现免疫系统功能障碍会增加 接触环境有毒物质，然后可以降低对有毒物质的暴露限制，儿童 通过免疫系统功能障碍可能会增加风险，可以识别和保护。具体 目的是暴露低（C57BL/6J）或高（SJL小鼠）自身免疫性的小鼠菌株 围绕甲基汞（MEHG），多氯化双苯基95（PCB 95）或多溴 二苯基乙醚47（BDE 47）。然后，我们将比较这些小鼠之间的毒性暴露的影响 大脑发育，复杂的社会行为和免疫系统功能的压力。该假设是 围产期暴露于每种有毒物质会损害大脑发育和行为，以及 对自身免疫性疾病的可疑性将增加这些药物的神经和免疫毒性。我们 还将探索一种潜在的自闭症的新模型，以独特的自身抗体注入产前注射的小鼠 与另外两个自闭症儿童分娩的母亲的血清隔离。脑 开发将使用立体学程序和免疫组织化学对组织学检查。 将使用我们实验室中建立的行为测试程序研究复杂的社会行为 这种衡量小鼠的社会认可，社会互动和社会交流。免疫系统状态 将通过测量细胞因子，趋化因子，免疫球蛋白和量化免疫系统来建立 对抗原刺激的反应。另外，将在毒物暴露中测量癫痫发作的易感性 小鼠以及海马脑切片中突触兴奋性和可塑性的度量。这些研究会 提供有关免疫系统作用及其与环境的互动的关键新信息 自闭症和其他神经发育障碍中的污染物。