Environmental-use chemicals that target pathways linked to autism and other neurodevelopmental disorders

针对与自闭症和其他神经发育障碍相关途径的环境使用化学品

• 批准号: 10618242
• 负责人: Mark J. Zylka
• 金额: $ 85.2万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618242
• 关键词: Affect; Attention; Attention deficit hyperactivity disorder; Biological Monitoring; Brain; CRISPR/Cas technology; Chemical Exposure; Chemicals; Data; Development; Developmental Delay Disorders; Disease; End Point Assay; Engineering; Environment; Environmental Health; Environmental Risk Factor; Exposure to; Future Generations; Gene Mutation; Genetic; Goals; Heritability; Home environment; Human; Impairment; Individual; Joints; Knowledge; Link; Longevity; Maternal Exposure; Mitochondria; Molecular Target; Mutation; Neurodevelopmental Disorder; Neurons; Pathology; Pathway interactions; Persons; Pesticides; Placenta; Plastics; Predisposition; Pregnancy; Prevalence; Process; Public Health; Research; Research Personnel; Risk; Sampling; Time; Valproic Acid; Work; autism spectrum disorder; behavioral phenotyping; building materials; critical period; fungicide; high throughput screening; human model; in vivo; mouse model; mucidin; nerve stem cell; prenatal exposure; programs; pyrethroid

PROJECT SUMMARY While significant progress has been made in identifying de novo gene mutations linked to autism risk, much less attention has been paid to environmental risks and the extent to which these risks cause autism pathology in susceptible individuals. Environmental factors, including gestational exposure to pyrethroid pesticides and valproic acid, are implicated in risk for autism. Prenatal exposure to pyrethroids is also linked to risk for developmental delay and attention deficit hyperactivity disorder (ADHD)—one of the most common neurodevelopmental disorders. However, these environmental risks were identified retrospectively, after a large number of people were exposed. Thousands of chemicals are registered for use in the environment, and humans are potentially exposed to many of these chemicals to varying degrees, including chemicals in plastics and building materials. We currently lack a way to systematically evaluate which environmental-use chemicals have the greatest potential to harm the developing brain. The inability to identify environmental threats to the brain early—before they cause disease—represents one of the major public health challenges of our time. This challenge is particularly relevant to autism, which now affects 1 in 59 individuals in America, and where heritability studies indicate that genetic and environmental factors contribute to autism risk. Our research program is guided by the hypothesis that “candidate” environmental risks for autism and other neurodevelopmental disorders can be identified rationally, by identifying chemicals and mixtures that target molecular pathways implicated in these disorders. Our long term goals are to 1) identify environmental-use chemicals and mixtures that target molecular pathways implicated in neurodevelopmental disorders. These studies will utilize primary human neural progenitor cells (phNPCs), primary neurons, and endpoints that are compatible with high-throughput screening. 2) Assess real world exposure to these chemicals/mixtures. If environmental sampling and biomonitoring data are not available for these chemicals/mixtures, we will work with a network of Environmental Health Science (EHS) researchers to collect these data. 3) Evaluate exposure risk in vivo using wild-type and CRISPR/Cas9-engineered mice that model human de novo autism-linked mutations. We will prioritize chemicals/mixtures that a) impact one or more phNPC/neuron assay endpoints, b) are verified exposure risks to humans, and c) enter the placenta and/or developing brain following maternal exposure. While the specific projects will evolve over time, we plan to initially focus on individual and joint exposures to pyrethroids and strobilurins—a new class of fungicides that inhibits mitochondria. Both chemical classes impair neuronal functions and co-occur in the home environment. We will evaluate the extent to which prenatal exposure to these and other prioritized chemicals and mixtures exacerbate brain and behavioral phenotypes associated with autism and other neurodevelopmental disorders across the lifespan.

项目摘要 尽管在确定与自闭症风险有关的从头基因突变方面取得了重大进展，但很多 对环境风险和这些风险引起自闭症病理的程度的关注较少 在易感人士中。环境因素，包括妊娠暴露于拟除虫菊酯农药和 丙戊酸与自闭症的风险有关。产前暴露于拟除虫菊酯也与风险有关 发育延迟和注意力缺陷多动障碍（ADHD） - 最常见的之一 神经发育障碍。但是，这些环境风险是回顾性发现的 大量的人暴露了。数千种化学品已注册在环境中，并且 人类有可能在不同程度上接触到许多这些化学物质，包括塑料中的化学物质 和建筑材料。我们目前缺乏系统地评估哪些环境使用化学物质的方法 具有损害发展中大脑的最大潜力。无法确定对环境的威胁 早期大脑（在引起疾病）之前，会员是我们这个时代的主要公共卫生挑战之一。 这一挑战与自闭症特别相关，自闭症现在影响美国59个人，以及哪里 遗传力研究表明，遗传和环境因素会导致自闭症风险。我们的研究 计划以这样的假设为指导，即自闭症和其他“候选”环境风险 可以通过识别化学物质和混合物来理性地识别神经发育障碍 在这些疾病中实施的目标分子途径。我们的长期目标是1）确定 针对神经发育中实施的分子途径的环境使用化学物质和混合物 疾病。这些研究将利用原发性人神经元细胞（PHNPC），原发性神经元和 与高通量筛选兼容的端点。 2）评估现实世界的暴露 化学/混合物。如果环境采样和生物监测数据不可用 化学/混合物，我们将与环境健康科学网络（EHS）研究人员合作收集 这些数据。 3）使用野生型和CRISPR/CAS9工程小鼠在体内评估暴露风险 人类自闭症与自闭症相关的突变。我们将优先考虑a）影响一个或多个的化学药品/混合物 PHNPC/神经元测定端点，b）对人类有验证的暴露风险，c）输入plapeta和/或 在母子暴露后发展大脑。尽管特定项目会随着时间的流逝而发展，但我们计划 最初，专注于拟除虫菊酯和霉菌素的个体和联合暴露，这是一种新的杀菌剂类别 抑制线粒体。两种化学类别都会损害家庭环境中的神经元功能和共发生。 我们将评估产前暴露于这些和其他优先化学物质和混合物的程度 加剧与自闭症和其他神经发育障碍相关的大脑和行为表型 整个生命周期。