Developmental Origins of Neurotoxicity of the PFAS GenX

项目摘要/摘要 全氟和多氟烷基物质(PFA)是合成的含氟化合物，存在于 由于其不粘和防污渍的特性，许多应用。长碳链化合物[C8； 例如全氟辛酸(全氟辛酸)和全氟辛酸(全氟辛烷磺酸)]，根据 健康风险。生产了较短的碳链(&lt；C8)全氟辛烷磺酸，以最大限度地减少环境持久性和 生物积累。全氟辛烷磺酸是一种新兴的环境化学污染物及其替代品 PFAS不受联邦机构的监管。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，可能会导致发育神经毒性(DNT) 来自PFAS暴露，包括注意力缺陷/多动障碍风险增加和运动减少 和行政职能。与其他全氟辛烷磺酸毒性研究类似，有限的DNT实验室研究具有 主要集中在全氟辛烷磺酸或全氟辛烷磺酸。其中一些DNT研究表明对多巴胺能(DA)的影响 系统。据估计，目前有4000种全氟辛烷磺酸，其中大多数仅限于无毒性信息可用。 此外，包括我们的初步数据在内的一些研究表明，类似的毒性结果甚至 比C8化合物更有效。此外，大多数全氟辛烷磺酸以混合物的形式存在于环境中， 这可能会导致各种混合物的相互作用。因此，我们的基本认识仍然存在很大差距 全氟辛烷磺酸和全氟辛烷磺酸混合物的DNT、机理和对发展中的中枢神经系统的功能影响及其风险 持续神经毒性在健康和疾病发育起源范式(DOHAD)中的作用。全氟辛烷磺酸 特别令人关注的是GenX(C6，全氟辛烷磺酸的替代品)和PFBS(全氟丁烷磺酸，C4， 取代全氟辛烷磺酸)。这些全氟辛烷磺酸替代品在环境样本中被检测到，并在经过处理的 喝水。关于DNT和短期发育性暴露的持续性神经毒性的问题仍然存在 (例如，DOHAD范例)。这个问题很重要，因为据报道，GenX比 全氟辛酸，很可能会同时接触GenX和全氟辛酸。我们的中心假设是 在发育的早期阶段接触GenX将导致DNT靶向DA系统并持续 成人的神经毒性，GenX和全氟辛酸的联合作用导致相加毒性反应。 我们将首先使用斑马鱼通过评估粗略和精细的形态变化来定义GenX的DNT， 行为和与DA系统相关联的目标。结果将与全氟辛酸、全氟辛烷磺酸和全氟辛烷磺酸进行比较 GEnx/PFOA混合物和5-羟色胺能系统的改变(目标1)。第二，我们将评估持之以恒 DOHaD范例中发育性全氟辛烷磺酸暴露的神经毒性(目标2)。斑马鱼，一口井- 建立了研究DNT和神经行为的模型，将作为综合脊椎动物模型用于 评估短期和长期的神经学结果。将对几个端点进行评估以定义机制 评估单一和二元全氟辛烷磺酸暴露的神经毒性，以便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.