The Roles of Environmental Risks and GEX in Increasing ASD Prevalence

ASD是一种早发性神经精神发育障碍，患病率估计为1.1 - 2.6%， 病因复杂且高度异质。确定ASD病理生理学一直具有挑战性， 样本量不足，难以在无偏倚选择的情况下收集临床样本，以及 病因机制的复杂性，包括遗传学的作用，环境风险和 基因-环境相互作用（格克斯）。拟议的研究将通过以下方式克服这些障碍： 使用生物储存库和从基于人口的，具有代表性的韩国样本中收集的存档数据， ASD家庭及其匹配的对照组来自我们正在进行的流行病学研究，在PI的父母R01补助金。 越来越多的证据支持母体免疫反应在ASD发展中的作用， 包括先证者母亲的抗脑抗体（ABA）和自身免疫性疾病水平较高， ASD，相对于对照。CD4 + T细胞在将B细胞转化为抗体产生细胞中起关键作用， 提供细胞因子和共刺激。虽然几项研究的结果表明， 儿童汞（Hg）暴露和ASD风险在很大程度上倾向于负面关联，没有研究表明 研究了母体汞暴露是否会增加后代患自闭症的风险。这与ASD特别相关 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 形成和改变的T淋巴细胞活性。综上所述，ASD风险增加的一个合理机制是 接触汞的母亲体内T细胞活化介导的自身免疫。这是一个似是而非的重要 这一假设是因为：（1）环境汞暴露对成年人来说几乎无处不在~（2）ASD风险增加 与母体免疫系统的变化有关，类似于在汞动物模型中观察到的变化 （3）可以制定公共卫生干预措施，以减少环境汞暴露。 与ViCTER RFA一致，我们建议探索这种高风险和潜在高收益假设。 具体目标1：确定母体血液中的ABA与后代ASD风险之间的关系 具体目标2：研究ASD儿童中母体自身免疫的机制 子目标2.1：确定患有ABA的母亲是否表现出CD4 + T细胞活化的证据 子目标2.2：确定母亲长期接触低剂量汞是否是 存在ABA和/或CD4 + T细胞活化 具体目标3：检查母亲长期低剂量汞接触是否会增加 通过母体免疫功能的改变在其后代中的ASD 这项研究完成后，将增加对ASD发病机制的了解，并导致公共卫生 降低ASD风险的干预措施。

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.