Autism Risk, Prenatal Environmental Exposures, and Pathophysiologic Markers

描述(由申请人提供)：尽管对自闭症谱系障碍(ASD)的非遗传原因知之甚少，但目前对这种疾病的病因学中的环境因素进行的严格调查很少。这项提案扩展了由NIEHS资助的加州大学戴维斯分校儿童环境健康中心(CCEH)发起的流行病学项目，该中心被称为“弹珠”(婴儿自闭症风险的标记物-学习早期迹象)。Marble已经招募了近200名孕妇，她们已经有一个患有自闭症的孩子，因此生下也会患自闭症的婴儿的风险很高。在本次R01中，我们将额外招募250名孕妇，并跟踪她们的怀孕和孩子。通过纵向收集1)广泛的行为、医学和暴露数据，2)母亲和孩子的生物样本，以及3)从出生到3岁的详细心理测量评估，大理石创造了一个解决病因问题和寻找早期病理生理标记的基础设施。感兴趣的暴露是两类在家用产品中常见的化合物，它们具有已知的神经或神经发育毒性：拟除虫菊酯杀虫剂和多溴二苯醚(阻燃剂)。首先，我们将一方面评估自我报告的暴露、内部剂量的测量和生物有效剂量的毒理学估计与ASD或其他神经行为发育障碍的风险的相关性。其次，我们将检查暴露或剂量估计是否与异常免疫反应或线粒体功能障碍的标记物有关，以及这些标记物是否预测三岁时临床确认的儿童发育状况。因此，该项目从典型的黑盒流行病学的宏观层面的关联开始，改进剂量的估计，然后更深入地探索环境暴露可能改变神经发育并导致临床结果的机制。这种综合方法是由一个跨学科团队使之成为可能的，该团队将分子和基础研究、流行病学人口方法和临床科学结合在一起。如果我们的假设得到支持，这将是根据对常用家用产品中化合物的前瞻性测量得出的第一个自闭症风险较高的证据，也是第一个确定可改变的风险因素的证据之一。因此，结果将打开在个人行为和社会层面上预防的大门，例如，可能通过教育、产品标签和/或监管行动。结果还可能导致有针对性的干预，以改变儿童的发展轨迹。总体而言，我们预计这项研究将促进该领域的范式转变，转向更多因素和机制驱动的研究议程，更多地关注环境暴露和跨学科方法的发展。 公共卫生相关性：自闭症谱系障碍(ASD)对公共卫生具有相当重要的意义，目前的估计表明，近1%的儿童将发展为这种疾病。人们不仅对其原因知之甚少，而且对其机制也知之甚少。这项研究被称为大理石(婴儿自闭症风险的标记-学习早期迹象)，解决了这两个差距，并可能阐明防止这种疾病发生的潜在方法。我们建议使用一种最大限度地提高研究效率的创新设计，确定两类常见的家用化学物质暴露的作用，即拟除虫菊酯杀虫剂和溴化阻燃剂。此外，弹珠将探索母体免疫失调和新生儿线粒体功能障碍的作用，作为导致神经发育异常的潜在机制的标志。通过解决在妊娠期开始了解自闭症风险因素的需要和阐明潜在机制的需要，大理石有能力推动自闭症领域向前发展，走向更多因素和机制驱动的研究议程。从这项研究中，可以建议在个人行为或社会层面上进行干预。

DESCRIPTION (provided by applicant): Despite the fact that little is known about non-genetic causes of autism spectrum disorders (ASD), currently, few rigorous investigations of environmental factors in the etiology of this condition are underway. This proposal extends the epidemiology project initiated under the NIEHS-funded UC Davis Center for Children's Environmental Health (CCEH) known as "MARBLES" (Markers of Autism Risk in Babies - Learning Early Signs). MARBLES has enrolled close to 200 pregnant women who already have a child with ASD and therefore are at high risk for delivering an infant who will also develop ASD. In this R01, we will recruit an additional 250 pregnant mothers and follow their pregnancy and their child. Through longitudinal collection of 1) extensive behavioral, medical, and exposure data, 2) biologic specimens from the mother and child, and 3) detailed psychometric assessments from birth to three years of age, MARBLES has created an infrastructure for addressing etiologic questions and searching for early pathophysiologic markers. The exposures of interest are two classes of compounds common in household products, and having known neuro- or neurodevelopmental toxicity: pyrethroid pesticides and polybrominated diphenyl ethers (flame retardants). First, we will assess associations of self-reported exposure, measurements of internal dose, and toxicologically-derived estimates of biologically effective dose, on the one hand, with risk for ASD or other impairments in neurobehavioral development on the other. Secondly, we will examine whether the exposure or dose estimates are associated with markers of aberrant immune responses or mitochondrial dysfunction and whether these markers predict clinically confirmed child developmental status at three years of age. Thus, this project begins with the macro-level associations typical of black-box epidemiology, refines the estimates of dose, and then explores more deeply into the mechanisms by which environmental exposures might alter neurodevelopment and lead to clinical outcomes. This integrated approach is made possible by an interdisciplinary team that brings together molecular and basic research, epidemiologic population-based approaches, and clinical sciences. If our hypotheses are supported, this will be the first evidence of higher autism risk based on prospective measurements of compounds in commonly used household products, and one of the first to identify modifiable risk factors. The results will thereby open the door to prevention at the individual behavioral and societal level, e.g., potentially through education, product labeling, and/or regulatory action. Results may also lead to targeted interventions to alter children's developmental trajectory. Overall, we expect this study to stimulate a paradigm shift in the field, towards a more multifactorial and mechanistically driven research agenda, with significantly more attention to environmental exposures and the development of inter-disciplinary approaches. PUBLIC HEALTH RELEVANCE: Autism spectrum disorders (ASDs) are of considerable public health importance, with current estimates suggesting that close to 1% of children will develop the condition. Not only is little known about their causes, but also the mechanisms are poorly understood. This study, known as MARBLES (Markers of Autism Risk in Babies - Learning Early Signs), addresses both gaps and may illuminate potential ways to prevent this disorder from occurring. We propose to determine the role for two classes of common household chemical exposures, namely pyrethroid pesticides and brominated flame retardants, using an innovative design that maximizes the efficiency of the study. Additionally, MARBLES will explore the role of maternal immune dysregulation and of mitochondrial dysfunction in the newborn as markers of potential mechanisms leading to aberrant neurodevelopment. By addressing both the need to understand risk factors for ASDs beginning during gestation and the need to elucidate underlying mechanisms, MARBLES has the ability to move the field of autism forward to towards a more multifactorial and mechanistically driven research agenda. From this study, interventions at the individual behavioral or societal level may be suggested.