Project 2: Persisting Neurobehavioral Dysfunction Caused by Interacting Toxicant Exposures During Development: Mechanistic and Treatment Studies with Zebrafish and Rats

摘要 持续的神经行为毒性已被证明是由于发育早期接触了许多 不同类型的毒物，包括多环芳烃(PAHs)和重金属。而当 个别化学物质的发育神经行为毒性已经得到了很好的研究，它们之间的相互作用已经 事实并非如此，尽管人们最常接触的是有毒化合物。项目1的重点是 了解发育中多环芳烃暴露如何影响重金属的神经毒性效应。我们将使用 效应驱动的机制研究，从持续性神经行为功能障碍入手 发育性毒物暴露以确定导致神经行为的关键机制 毒性。两种典型的多环芳烃(苯并[a]芘和荧菲)与两种重金属(铅和铅)的相互作用 镉)导致运动活动、情绪障碍和认知障碍的持续性改变 将会被确定。机制研究的范围将从分子(DNA甲基化)到细胞内 (氧化应激与线粒体功能障碍有关)到细胞间(多巴胺、5-羟色胺和乙酰胆碱) IL-1β、6、10和IL-1介导的神经递质损伤和小胶质细胞介导的炎症过程改变 相关细胞因子)。在生物体层面上，行为应激反应增强的重要性 将测定对多环芳烃和重金属的神经行为毒性。斑马鱼将被用作前端 评估多环芳烃和重金属神经毒性与同功图的详细量效交互作用的模型 表征，绘制相互作用的剂量-效应函数。老鼠将被用来确定角色和 与人类更直接相关的持续性神经行为损害的机制，包括性别选择性 效果。从这种对神经行为毒性的机械理解出发，这个项目将 对复杂环境混合物的研究进展。项目2将决定潜在救援的效果 在毒物暴露期间使用抗氧化剂、甲基供体和抗炎细胞因子进行治疗。 这些将在斑马鱼身上进行开发，并在老鼠模型中得到验证。另一种重要的毒物相互作用 就是连续曝光。在一个探索性的目标中，我们将确定早期接触一种神经毒物可能会有多大程度的影响 导致适应不良发展，这将削弱对后来暴露于另一种神经毒物的反应。这 毒物暴露的顺序变化对于了解通过 一辈子。项目2将与其他项目合作，特别是关于表观遗传学(项目3)、氧化 压力(项目3和项目4)、行为障碍(项目1和项目4)、复杂环境混合物(项目 1、4和5)、神经递质分析(分析化学核心)、混合物统计评估(数据 管理和分析核心)，并与更广泛的社区共享信息(社区参与 核心)加强对现实世界对有毒混合物的神经毒性风险的了解，并开发治疗方法 减少不良神经行为毒性。

Abstract Persisting neurobehavioral toxicity has been shown to result from early developmental exposure to many different types of toxicants, including polyaromatic hydrocarbons (PAHs) and heavy metals. While the developmental neurobehavioral toxicity of individual chemicals have been well-studied, their interactions have not, despite the fact that people are most often exposed to toxicant combinations. Project 1 focuses on understanding how developmental PAH exposure impacts neurotoxic effects of heavy metals. We will use an effects-driven mechanistic investigation, working from the persisting neurobehavioral dysfunction caused by developmental toxicant exposures back to determine the critical mechanisms that caused the neurobehavioral toxicity. Interactions of two prototypic PAHs (benzo[a]pyrene and fluoranthene) and two heavy metals (lead and cadmium) producing persisting alterations in locomotor activity, emotional dysfunction and cognitive impairment will be determined. The mechanistic investigations will range from molecular (DNA methylation) to intracellular (oxidative stress related to mitochondrial dysfunction) to intercellular (dopamine, serotonin and acetylcholine neurotransmitter impairments and microglial-mediated changes in inflammatory processes via IL-1β, 6, 10 and related cytokines). At an organismal level, the importance of behavioral stress response potentiating neurobehavioral toxicity to PAHs and heavy metals will be determined. Zebrafish will be used as a front-end model to assess detailed dose-effect interactions of PAH and heavy metal neurotoxicity with isobolographic characterization, charting interacting dose-effect functions. Rats will be used to determine the character and mechanisms of persisting neurobehavioral impairment more directly relevant to humans, including sex-selective effects. Working from this improved mechanistic understanding of the neurobehavioral toxicity, this project will advance to the study of complex environmental mixtures. Project 2 will determine the efficacy of potential rescue treatments using antioxidants, methyl donors and anti-inflammatory cytokines during the toxicant exposure. These will be developed in zebrafish and verified with the rat model. Another important type of toxicant interaction is sequential exposures. In an exploratory aim we will determine how early exposure to one neurotoxicant could cause maladaptive development that would impair response to later exposure to another neurotoxicant. This sequential change in toxicant exposure is important for understanding risks of changing exposures through a lifetime. Project 2 will collaborate with the other projects, particularly regarding epigenetics (Project 3), oxidative stress (Projects 3 and 4), behavioral impairments (Projects 1 and 4), complex environmental mixtures (Projects 1, 4, and 5), neurotransmitter analysis (Analytic Chemistry Core), mixture statistical evaluation (Data Management and Analysis Core), and sharing information with the broader community (Community Engagement Core) to enhance understanding of real world neurotoxic risks to toxicant mixtures and develop treatments to reduce adverse neurobehavioral toxicity.