Developmental Origins of Neurotoxicity of the PFAS GenX

项目概要/摘要 全氟烷基和多氟烷基物质（PFAS）是合成的含氟化合物， 由于其不粘和耐污的特性，可用于许多应用。较长碳链化合物[C8; 例如，在一个实施例中，全氟辛酸（PFOA）和全氟辛烷磺酸（PFOS）]，根据 健康风险。生产较短碳链（<C8）的PFAS以最大限度地减少环境持久性， 生物累积PFAS是一类新兴的环境化学污染物及其替代品 PFAS不受联邦机构监管。发育中的中枢神经系统对 毒物暴露和越来越多的证据表明，发育神经毒性（DNT）可能导致 PFAS暴露包括注意力缺陷/多动障碍风险增加和运动功能降低 和执行功能。与其他PFAS毒性研究相似，有限的DNT实验室研究 主要集中在PFOS或PFOA。其中一些DNT研究表明对多巴胺能（DA） 系统现在估计有超过4000种PFAS，其中大多数的毒性信息有限或没有。 然而，一些研究，包括我们的初步数据表明，类似的毒性结果，一些甚至 比C8化合物更有效。此外，大多数PFAS以混合物的形式存在于环境中， 这可能导致各种混合物相互作用。因此，在我们的基本理解方面仍然存在重大差距， PFAS和PFAS混合物的DNT，对发育中的CNS的机制和功能影响，以及 在健康和疾病的发展起源范例（DOHaD）中的持续性神经毒性。PFAS的 特别值得关注的是GenX（C6，PFOA的替代品）和PFBS（全氟丁烷磺酸，C4， 全氟辛烷磺酸替代品）。这些PFAS替代品在环境样品和处理过的 饮用水关于DNT和短期发育暴露的持续神经毒性仍然存在问题 (e.g., DOHaD范式）。考虑到据报道GenX比 PFOA和可能会发生GenX和PFOA的共同暴露。我们的中心假设是， 在早期发育阶段暴露于GenX将导致DNT靶向DA系统， GenX和PFOA的联合作用导致了一种相加的毒性反应。 我们将首先使用斑马鱼通过评估大体和精细形态学变化来定义GenX的DNT， 行为和与DA系统相关的目标。结果将与PFOA、PFBS和 GenX/PFOA混合物和β-肾上腺素能系统的改变（目的1）。第二，我们将持续评估 在DOHaD范例中发育PFAS暴露的神经毒性（目的2）。斑马鱼，一种- 建立了研究DNT和神经行为的模型，将作为一个综合的脊椎动物模型， 评估短期和长期的神经学结果。将评估几个终点以确定机制 研究单一和二元PFAS暴露的神经毒性，为未来的监管决策提供信息和指导。

PROJECT SUMMARY / ABSTRACT Per- and polyfluoroalkyl substances (PFAS) are synthetic fluorine-containing compounds that are present in many applications due to their non-stick and stain-resistant properties. Longer carbon chain compounds [C8; e.g., perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS)], were phased out based on health risks. Shorter carbon chain (<C8) PFAS were produced to minimize environmental persistence and bioaccumulation. PFAS are an emerging class of environmental chemical contaminants and the replacement PFAS are not regulated by federal agencies. The developing central nervous system is particularly sensitive to toxicant exposure and a growing body of evidence suggests developmental neurotoxicity (DNT) may result from PFAS exposures including increased risk for attention deficit/hyperactivity disorder and reduced motor and executive functioning. Similar to other PFAS toxicity studies, the limited DNT laboratory studies have mainly focused on PFOS or PFOA. Some of these DNT studies suggest impacts to the dopaminergic (DA) system. It is now estimated there are >4000 PFAS with most having limited to no toxicity information available. Futhermore, some studies including our preliminary data indicate similar toxicity outcomes with some even being more potent than the C8 compounds. Moreover, most PFAS are present in the environment in a mixture, which can result in various mixture interactions. As such, a significant gap remains in our basic understanding of DNT of PFAS and PFAS mixtures, mechanisms and functional impacts to the developing CNS, and the risk of persistent neurotoxicity in the developmental origins of health and disease paradigm (DOHaD). PFAS of particular concern are GenX (C6, replacement for PFOA) and PFBS (perfluorobutanesulfonic acid, C4, replacement for PFOS). These PFAS alternatives are detected in environmental samples and in treated drinking water. Questions remain on DNT and persistent neurotoxicity of a short-term developmental exposure (e.g., the DOHaD paradigm). This question is significant considering GenX is reported to be more potent than PFOA and is likely that co-exposure to GenX and PFOA will occur. Our CENTRAL HYPOTHESIS is that exposure to GenX at early developmental stages will result in DNT targeting the DA system and persistent neurotoxicity in adults with the combined effects of GenX and PFOA resulting in an additive toxicity response. We will first define DNT of GenX using the zebrafish by assessing gross and fine morphological changes, behavior, and targets associated with the DA system. Results will be compared to PFOA, PFBS, and GenX/PFOA mixtures and alterations in the serotonergic system (aim 1). Second, we will assess persistent neurotoxicity of the developmental PFAS exposure in the DOHaD paradigm (aim 2). The zebrafish, a well- established model to study DNT and neurobehavior, will be used as an integrative vertebrate animal model to assess short and long-term neurological outcomes. Several endpoints will be assessed to define mechanisms of neurotoxicity from single and binary PFAS exposures to inform and guide future regulatory decisions.