The Roles of Environmental Risks and GEX in Increasing ASD Prevalence

环境风险和 GEX 在增加 ASD 患病率中的作用

• 批准号: 8919056
• 负责人: Young Shin Kim
• 金额: $ 53.77万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2018-12-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8919056
• 关键词: Adult; Age; Animal Model; Animals; Antibodies; Antibody-Producing Cells; Antinuclear Antibodies; Archives; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biological Assay; Blood; Brain; CD4 Positive T Lymphocytes; Characteristics; Child; Chronic; Clinical; Complex; Data; Development; Diagnosis; Diet; Disease; Dose; Environment; Environmental Risk Factor; Epidemiologic Studies; Equation; European; Exhibits; Experimental Animal Model; Exposure to; Family; Frequencies; Functional disorder; Genetic; Genetic Predisposition to Disease; Geographic Locations; Grant; Health Services Accessibility; Human; Immune response; Immune system; Immunologics; Infection; Intervention; Koreans; Lead; Maternal Exposure; Measures; Mediating; Mercury; Modeling; Mothers; Parents; Pathogenesis; Patients; Pattern; Phenotype; Play; Population; Prevalence; Public Health; Relative (related person); Reporting; Research; Research Design; Risk; Risk Factors; Role; Route; Sample Size; Sampling; Scoring Method; Selection Bias; Severities; Structure; Structure of nail of toe; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic Agents; Woman; Work; autism spectrum disorder; biobank; comorbidity; cytokine; design; developmental disease; disorder risk; early onset; fetal; high risk; immune function; in utero; memory CD4 T lymphocyte; neuropathology; neuropsychiatry; novel therapeutics; offspring; peripheral blood; population based; proband; residence; risk variant; sex

ASD, an early onset neuropsychiatric developmental disorder with prevalence estimates of 1.1-2.6%, is etiologically complex and highly heterogeneous. Identifying ASD pathophysiology has been challenging due to the combination of insufficient sample sizes, difficulty collecting clinical samples without biased selection, and the complexity of etiological mechanisms, including the roles of genetics, environmental risks and gene-environmental interactions (GEX). The proposed research designed will overcome these obstacles by using a biorepository and archived data collected from a population-based, representative Korean sample of ASD families and their matched controls from our ongoing epidemiologic study in the PI's parent R01 grant. A growing body of evidence supports the role of maternal immune responses in the development of ASD, including higher levels of Anti-Brain Antibodies (ABAs) and autoimmune diseases in mothers of probands with ASD, relative to controls. CD4+ T-cells play a critical role in transforming B-cells into antibody producing cells by providing cytokines and co-stimulation. While findings from several studies examining the association between mercury (Hg) exposure in children and ASD risk largely weigh toward negative associations, no studies have examined whether maternal Hg exposure increases ASD risk in offspring. This is particularly relevant to ASD risk since Hg has been shown to alter immune function in humans and animals, resulting in autoantibody formation and altered T-lymphocyte activity. Taken together, one plausible mechanism for increased ASD risk is autoimmunity mediated by T-cell activation in mothers exposed to Hg. This is a plausible and important hypothesis because: (1) Environmental Hg exposure is virtually ubiquitous for adults~ (2) Increased ASD risk has been associated with maternal immune system changes similar to those seen in animal models with Hg exposure~ and, (3) Public health interventions can be developed to reduce the environmental Hg exposure. Consistent with the ViCTER RFA, we propose to explore this high risk and potentially high yield hypothesis. Specific Aim 1: Establish the Relationship between ABAs in Maternal Blood and Offspring ASD Risk Specific Aim 2: Investigate the Mechanisms for Maternal Autoimmunity in Children with ASD Sub-aim 2.1: Determine Whether Mothers with ABAs Exhibit Evidence for CD4+ T-cell Activation Sub-Aim 2.2: Determine Whether Maternal Exposure to Chronic, Low Dose Hg is a Risk Factor for the Presence of ABAs and/or CD4+ T-cell Activation Specific Aim 3: Examine Whether Chronic Low Dose Maternal Mercury Exposure Increases Risk for ASD in Their Offspring via Alterations in Maternal Immune Function When completed, this study will add to understanding of the pathogenesis of ASD and lead to public health interventions for decreasing ASD risk.

ASD是一种早期发病的神经精神发育障碍，患病率估计为1.1-2.6%， 病因复杂且高度异质性。由于以下原因，识别ASD的病理生理学一直具有挑战性 样本量不足，在没有偏向选择的情况下难以收集临床样本，以及 病因机制的复杂性，包括遗传、环境风险和 基因-环境相互作用(GEX)。拟议的研究将通过以下方式克服这些障碍 使用从以人口为基础的、具有代表性的韩国人样本中收集的生物仓库和存档数据 ASD家庭和他们的匹配对照，来自我们正在进行的流行病学研究，在PI的父母R01赠款中。 越来越多的证据支持母体免疫反应在ASD发展中的作用， 包括先证者的母亲更高水平的抗脑抗体(ABAs)和自身免疫性疾病 ASD，相对于控件。在将B细胞转化为抗体产生细胞的过程中，CD4+T细胞起着关键作用 提供细胞因子和共刺激。虽然几项研究的结果考察了 儿童汞暴露与自闭症风险在很大程度上是负相关的，没有研究表明 检查母亲接触汞是否会增加子代患自闭症的风险。这与ASD尤其相关 风险，因为汞已被证明会改变人类和动物的免疫功能，导致自身抗体 形成和改变T淋巴细胞的活性。总而言之，ASD风险增加的一个看似合理的机制是 汞暴露母亲T细胞活化介导的自身免疫。这是一个看似合理而又重要的 假设是因为：(1)环境汞暴露对成年人来说几乎无处不在~(2)自闭症风险增加 与母亲免疫系统的变化有关，类似于在患汞的动物模型中看到的 (3)可以制定公共卫生干预措施，减少环境汞暴露。 与Victer RFA一致，我们建议探索这一高风险和潜在的高收益假说。 具体目标1：建立母血中ABAs与子代ASD风险的关系 特定目标2：探讨自闭症儿童母亲自身免疫的机制 次级目标2.1：确定患有ABAS的母亲是否表现出CD4+T细胞激活的证据 次级目标2.2：确定母亲长期接触低剂量汞是否为 ABAs的存在和/或CD4+T细胞的激活 具体目标3：检查母亲长期低剂量汞暴露是否会增加罹患 母体免疫功能改变对子代ASD的影响 这项研究完成后，将增加对ASD发病机制的了解，并有助于公众健康 降低自闭症风险的干预措施。