Autism Risk, Prenatal Environmental Exposures, and Pathophysiologic Markers

自闭症风险、产前环境暴露和病理生理标志物

• 批准号: 8323912
• 负责人: Irva Hertz-Picciotto
• 金额: $ 181.54万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-24 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323912
• 关键词: Address; Age-Years; Attention; Autistic Disorder; Basic Science; Behavior; Behavioral; Biological Assay; Birth; Boxing; Brain; Chemical Exposure; Child; Citrate (si)-Synthase; Clinical; Clinical Sciences; Collection; Complex; Data; Development; Diagnosis; Disease; Dose; Early identification; Education; Enrollment; Ensure; Environment; Environmental Exposure; Environmental Health; Environmental Risk Factor; Epidemiology; Etiology; Exposure to; Flame Retardants; Foundations; Funding; Household; Household Products; Human Milk; Immune; Immune response; Impairment; Incidence; Individual; Infant; Intervention; Intervention Studies; Investigation; Lead; Learning; Life; Link; Lymphocyte; Maternal antibody; Measurable; Measurement; Measures; Medical; Mitochondria; Mitochondrial DNA; Molecular; Mothers; Mutation; National Institute of Environmental Health Sciences; Neurocognitive; Neurologic; Neurons; Newborn Infant; Outcome; Participant; Pathway interactions; Patient Self-Report; Pesticides; Plasma; Play; Population Study; Pregnancy; Pregnant Women; Prevention; Product Labeling; Proteins; Psychometrics; Public Health; Pyruvate; Recruitment Activity; Relative (related person); Research; Research Infrastructure; Risk; Risk Factors; Role; Signal Transduction; Specimen; Structure-Activity Relationship; Testing; Toxic effect; Variant; Xenobiotics; autism spectrum disorder; base; cohort; design; disorder risk; environmental chemical; excitotoxicity; fetal; high risk; in utero; innovation; interest; mitochondrial dysfunction; modifiable risk; neurobehavioral; neurodevelopment; neurotoxicity; non-genetic; phenyl ether; population based; postnatal; pregnant; prenatal; prenatal environmental exposure; prenatal exposure; prevent; prospective; pyrethroid; receptor; trend

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.

描述（由申请人提供）：尽管事实上对自闭症谱系障碍的非基因原因（ASD）知之甚少，但目前，对这种病因的病因中的环境因素的严格研究很少正在进行中。该提案扩展了在NIEHS资助的戴维斯分校儿童环境健康中心（CCEH）的流行病学项目（婴儿自闭症风险标记 - 学习早期迹象）。大理石已经招募了近200名孕妇，这些孕妇已经有了ASD的孩子，因此有很高的风险，即提供也将发展为ASD的婴儿。在此R01中，我们将招募另外250位怀孕的母亲，并遵循他们的怀孕和孩子。通过纵向收集1）广泛的行为，医学和暴露数据，2）来自母亲和儿童的生物学标本，以及3）从出生到三岁的详细心理测定评估，大理石创建了一个基础设施，以解决病因学问题并寻找早期的病理生理标志物。感兴趣的暴露是在家用产品中常见的两类化合物，并且具有神经发育或神经发育毒性：拟除虫菊酯农药和多溴二苯基醚（火焰阻燃剂）。首先，我们将评估自我报告的暴露，内部剂量的测量以及毒理学上衍生的生物学有效剂量的估计值，一方面，另一方面有ASD或其他损害的风险。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有关，以及这些标记物是否预测三岁临床确认的儿童发育状况。因此，该项目始于典型的黑盒流行病学的宏观关联，完善了剂量的估计值，然后更深入地探讨了环境暴露可能改变神经发育并导致临床结果的机制。跨学科的团队使这种综合方法成为可能，该团队将分子和基础研究，基于流行病语的方法和临床科学汇集在一起​​。如果支持我们的假设，这将是基于对常用家用产品中化合物的前瞻性测量的较高自闭症风险的第一个证据，也是第一个确定可修改风险因素的化合物。结果将在个人行为和社会层面打开预防大门，例如，有可能通过教育，产品标签和/或监管行动。结果还可能导致有针对性的干预措施改变儿童的发育轨迹。总体而言，我们预计这项研究将刺激该领域的范式转变，向更多学位和机械驱动的研究议程迈进，并更加关注环境暴露和跨学科方法的发展。