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: 10402265
• 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/10402265
• 关键词: Affect; Americas; 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; Industrial fungicide; Joints; Knowledge; Link; Longevity; Maternal Exposure; Mitochondria; Molecular Target; Mutation; Neurodevelopmental Disorder; Neurons; Pathology; Pathway interactions; Persons; Pesticides; Placenta; Plastics; Pregnancy; Prevalence; Process; Public Health; Research; Research Personnel; Risk; Sampling; Time; Valproic Acid; Work; autism spectrum disorder; behavioral phenotyping; building materials; critical period; 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.

项目概要 虽然在识别与自闭症风险相关的从头基因突变方面已经取得了重大进展，但 对环境风险以及这些风险导致自闭症病理的程度关注较少 在易感人群中。环境因素，包括妊娠期接触拟除虫菊酯农药和 丙戊酸与自闭症风险有关。产前接触拟除虫菊酯也与以下风险有关： 发育迟缓和注意力缺陷多动障碍（ADHD）——最常见的疾病之一 神经发育障碍。然而，这些环境风险是在经过一段时间的回顾后才被识别出来的。 大量人员被暴露。数千种化学品已注册用于环境中，并且 人类可能不同程度地接触其中许多化学物质，包括塑料中的化学物质 和建筑材料。我们目前缺乏一种方法来系统地评估哪些环境使用化学品 最有可能伤害正在发育的大脑。无法识别环境威胁 大脑早期——在它们引起疾病之前——代表了我们这个时代的主要公共卫生挑战之一。 这一挑战与自闭症尤其相关，目前美国每 59 个人中就有 1 人患有自闭症，并且 遗传性研究表明遗传和环境因素会增加自闭症风险。我们的研究 该计划以这样的假设为指导：自闭症和其他疾病的“候选”环境风险 通过识别化学物质和混合物，可以合理地识别神经发育障碍 与这些疾病有关的目标分子途径。我们的长期目标是 1) 确定 针对神经发育相关分子途径的环境使用化学品和混合物 失调。这些研究将利用原代人类神经祖细胞 (phNPC)、原代神经元和 与高通量筛选兼容的终点。 2）评估现实世界对这些的暴露程度 化学品/混合物。如果环境采样和生物监测数据无法用于这些 化学品/混合物，我们将与环境健康科学 (EHS) 研究人员网络合作，收集 这些数据。 3) 使用野生型和 CRISPR/Cas9 工程小鼠模型评估体内暴露风险 人类新发自闭症相关突变。我们将优先考虑 a) 影响一种或多种的化学品/混合物 phNPC/神经元测定终点，b) 已验证对人类的暴露风险，以及 c) 进入胎盘和/或 母亲暴露后大脑正在发育。虽然具体项目会随着时间的推移而发展，但我们计划 最初重点关注拟除虫菊酯和嗜球果伞素（一种新型杀菌剂）的个人和联合暴露 抑制线粒体。这两种化学物质都会损害神经元功能，并在家庭环境中同时出现。 我们将评估产前接触这些和其他优先化学品和混合物的程度 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 贯穿整个生命周期。