Piloting a Novel Approach for Examining Intersecting Environmental Exposures and Social Behavior

试验一种检查交叉环境暴露和社会行为的新方法

• 批准号: 10518668
• 负责人: Heather B Patisaul
• 金额: $ 7.6万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10518668
• 关键词: Address; Adverse event; Air Pollution; Animal Model; Animals; Anxiety; Anxiety Disorders; Behavior; Behavioral; Brain; Breeding; Caring; Chemical Exposure; Chemicals; Child; Child Health; Childhood; Chronic stress; Communities; Complement; Complex; Data; Development; Developmental Disabilities; Diagnosis; Disease; Dose; Electronics; Environmental Exposure; Environmental Pollution; Experimental Designs; Exposure to; Face; Fathers; Feasibility Studies; Female; Flame Retardants; Funding; Furniture; Future; Generations; Genetic; Goals; Human; Impaired cognition; Impairment; Individual; Infant; Knowledge; Life; Link; Mental disorders; Microtus; Modeling; Motivation; Mus; Nature; Neurobiology; Neurodevelopmental Disorder; Neurosecretory Systems; Oral; Outcome; Pair Bond; Perinatal; Pilot Projects; Plasticizers; Poverty; Prevalence; Rattus; Reproducibility; Research Project Grants; Risk; Rodent Model; Scheme; Sex Bias; Sex Differences; Social Behavior; Social Interaction; Social isolation; Stress; Testing; Tissues; Toxicology; United States National Institutes of Health; Weight; Work; aged; anxiety-related behavior; autism spectrum disorder; behavior test; behavioral impairment; boys; brain behavior; disorder risk; early life adversity; early life exposure; environmental stressor; experimental study; exposed human population; generalized anxiety; girls; innovation; interest; male; novel; novel strategies; nutrition; offspring; personal care products; pollutant; postnatal; prairie vole; prenatal exposure; preservation; programs; psychosocial; relating to nervous system; sex; social; social anxiety; social deficits; social stress; stressor; tool; trait; virtual

Project Summary/Abstract Rates of neurodevelopmental disorders (NDDs) are rapidly and inexplicably rising with one in six US children aged 3-17 diagnosed with a developmental disability between 2009 and 2017, and nearly 33% of US children aged 13-18 suffering from an anxiety disorder. Mental health disorders such as anxiety and autism spectrum disorder (ASD) manifest in each sex differently and can persist for a lifetime, thus understanding their origins is highly significant. Prenatal exposure to chemical pollutants such as air pollution, plasticizers, and flame retardants (FRs), are hypothesized to be one causal factor elevating NDD risk in both sexes. The available experimental data, however, testing this hypothesis is surprisingly minimal and discordant. Moreover, chemical exposures frequently occur in combination with other stressors known to heighten risk of psychosocial disorders including chronic stress and social isolation. Thus, understanding how multiple adverse environmental “hits” act in combination to exacerbate risk of socioemotional deficits is a critically important but unmet need. This project addresses the pressing need for rigorous, reproducible, human-relevant studies examining potential links between environmental exposures and social deficits common to many NDDs. We will use the prairie vole (Microtus ochrogaster), a well-established, pro-social animal model for exploring the neurobiology of ASD and other social disorders, but generally unfamiliar to toxicologists, to test the hypothesis that father absence during rearing will exacerbate known behavioral deficits induced by developmental exposure to the chemical flame retardant (FR) mixture FireMaster 550, (FM 550) particularly in male offspring. Unlike rats and mice, this species is monogamous and biparental and thus a uniquely suitable model for examining the impact of adverse events on social behavior. Our preliminary data in FM 550 exposed prairie voles reveal heightened anxiety in females and loss of pair bonding in males. The focus on FRs is significant because exposure to this chemical class has long been associated with behavioral and cognitive impairments in humans, including heightened risk of ASD, and human exposure is global and increasing. The proposed self-contained study builds on our prior work by using oral exposure to a human relevant dose, more refined testing strategies to better capture pair bonding behaviors, and the inclusion of father absence as a second adverse childhood exposure; a situation all too common in heavily polluted communities. This innovative, feasibility study is highly responsive to NIH interest in the “exposome” (chemical and experiential) as a driver of children's health. Through this small, defined project we hope to elucidate the impact of combined early life stressors on social traits of relevance to human NDDs in both sexes. Critically, the behavioral results gained from piloting the prairie vole as a powerful tool for toxicology paves the way for future work seeking to identify the mechanisms by which chemical exposures may contribute to the growing prevalence of NDDs in the context of the full exposome.

项目总结/摘要 神经发育障碍（NDD）的发病率正在迅速而令人费解地上升，六分之一的美国儿童 2009年至2017年间，3-17岁儿童被诊断出患有发育障碍，近33%的美国儿童 13-18岁患有焦虑症。精神健康障碍，如焦虑症和自闭症谱系 自闭症（ASD）在每个性别中表现不同，并且可以持续一生，因此了解它们的起源是 非常重要。产前暴露于化学污染物，如空气污染、增塑剂和火焰 阻滞剂（FR），被假设为一个因果因素，提高NDD的风险在两个性别。可用 然而，验证这一假设的实验数据令人惊讶地少得可怜，而且不一致。此外，化学 暴露经常与其他已知会增加心理社会障碍风险的应激源结合发生 包括长期压力和社会孤立。因此，了解多重不利环境“打击”如何起作用， 这是一个极其重要但尚未得到满足的需求。这个项目 解决了对严格的，可重复的，与人类相关的研究的迫切需要，研究潜在的联系 环境暴露和许多NDD常见的社会缺陷之间的关系。 我们将使用草原田鼠（Microtus ochrogaster），一种成熟的亲社会动物模型， 探索ASD和其他社会障碍的神经生物学，但毒理学家通常不熟悉， 为了验证父亲在抚养过程中的缺席会加剧已知的行为缺陷的假设， 由于暴露在化学阻燃剂（FR）混合物FireMaster 550（FM）中， 550)特别是在雄性后代中。与大鼠和小鼠不同，该物种是一夫一妻制和双亲制，因此 这是一个独特的适合研究不良事件对社会行为影响的模型。我们的初步数据 在FM 550暴露的草原田鼠中，雌性表现出高度的焦虑，雄性表现出配对关系的丧失。的 关注FR是重要的，因为长期以来，暴露于这类化学物质与行为有关。 和人类认知障碍，包括ASD的风险增加，人类暴露是全球性的， 增加。这项独立的研究建立在我们之前的工作基础上，通过对人类进行口腔暴露， 相关的剂量，更精细的测试策略，以更好地捕捉对结合行为，并包括父亲 缺席是童年时期的第二次不良接触;这种情况在污染严重的社区非常普遍。 这项创新的可行性研究高度响应了NIH对“麻烦组”（化学和生物学）的兴趣。 作为儿童健康的驱动力。通过这个小而明确的项目，我们希望阐明 结合早期生活压力对社会特征的相关性，人类NDD在两性。关键是， 将草原田鼠作为毒理学研究的有力工具， 努力查明化学品接触可能导致流行率上升的机制 在全面困难的背景下，