Developmental Origins of Neurotoxicity of the PFAS GenX

X 代 PFAS 神经毒性的发育起源

基本信息

批准号：
10392474
负责人：
Jennifer L Freeman
金额：
$ 18.77万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-14 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10392474
关键词：
Acids Adult Age-Months Animal Model Attention deficit hyperactivity disorder Automobile Driving Behavior Biological Models Blood Brain Carbon Carpet Chemical Exposure Chemicals Clothing Data Development Disease Electronics Embryo Endocrine disruption Environment Epigenetic Process Exposure to Fishes Fluorine Food Packaging Fright Furniture Future Health Hepatotoxicity Knowledge Laboratory Study Larva Link Manufacturer Name Modeling Morphology Motor Names Neuraxis Neurological outcome Organ Organism Outcome Participant Pathway interactions Pattern Phase Poly-fluoroalkyl substances Population Product Packaging Property Propionic Acids Regulation Reporting Resistance Risk Rivers Safety Sampling Serotonergic System Specificity Stains System Testing Tissues Toxic effect Toxicant exposure Toxicology Vertebrates Water Zebrafish base bioaccumulation carcinogenicity developmental neurotoxicity developmental toxicity dimer drinking water environmental chemical epidemiology study executive function immunotoxicity mathematical model mortality neurobehavior neurotoxicity perfluorooctane sulfonate perfluorooctanoic acid response substance use

项目摘要

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.

项目概要/摘要全氟烷基物质和多氟烷基物质 (PFAS) 是合成的含氟化合物，存在于由于其不粘和防污特性，其应用广泛。较长碳链化合物[C8；例如，全氟辛酸（PFOA）和全氟辛烷磺酸（PFOS）]，已根据健康风险。生产较短碳链（<C8）的 PFAS 是为了最大限度地减少环境持久性和生物累积。 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。正在发育的中枢神经系统对以下因素特别敏感有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） PFAS 暴露导致注意力缺陷/多动症风险增加和运动能力下降和执行功能。与其他 PFAS 毒性研究类似，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) 的影响系统。目前估计有超过 4000 种 PFAS，其中大多数仅有有限的毒性信息甚至没有可用的毒性信息。此外，一些研究，包括我们的初步数据，表明了类似的毒性结果，有些甚至比 C8 化合物更有效。此外，大多数 PFAS 以混合物形式存在于环境中，这可能导致各种混合物相互作用。因此，我们的基本理解仍然存在很大差距 PFAS 和 PFAS 混合物的 DNT、机制和对中枢神经系统发育的功能影响以及风险健康和疾病范式（DOHaD）发育起源中的持续神经毒性。 PFAS 的特别值得关注的是 GenX（C6，PFOA 的替代品）和 PFBS（全氟丁磺酸，C4，替代全氟辛烷磺酸）。这些 PFAS 替代品在环境样品和经过处理的样品中被检测到饮用水。关于 DNT 和短期发育暴露的持续神经毒性的问题仍然存在（例如，DOHaD 范式）。这个问题很重要，因为据报道 GenX 比 PFOA 很可能会同时暴露于 GenX 和 PFOA。我们的中心假设是在早期发育阶段接触 GenX 将导致针对 DA 系统的 DNT 并持续存在 GenX 和 PFOA 的综合作用导致成人神经毒性，导致附加毒性反应。我们将首先使用斑马鱼通过评估总体和精细形态变化来定义 GenX 的 DNT，与 DA 系统相关的行为和目标。结果将与 PFOA、PFBS 和 GenX/PFOA 混合物和血清素系统的改变（目标 1）。其次，我们将评估持久性 DOHaD 范例中发育期 PFAS 暴露的神经毒性（目标 2）。斑马鱼，一种很好的建立的模型用于研究 DNT 和神经行为，将用作综合脊椎动物模型评估短期和长期神经系统结果。将评估几个端点来定义机制单一和二元 PFAS 暴露的神经毒性，为未来的监管决策提供信息和指导。