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.

项目摘要 /摘要每种和多氟烷基物质（PFA）是存在于合成氟的化合物中许多应用程序由于其不粘和耐染色的特性而引起的应用。较长的碳链化合物[C8; 例如，全氟辛酸（PFOA）和全氟辛磺酸（PFOS）]根据基于健康风险。生产较短的碳链（<c8）PFA，以最大程度地减少环境持久性和生物蓄积。 PFA是一类新兴的环境化学污染物和替代品 PFA不受联邦机构的监管。发展中心神经系统对毒性暴露和越来越多的证据表明可能导致发育神经毒性（DNT）来自PFA的暴露，包括增加注意力缺陷/多动症的风险和减少电机和执行功能。与其他PFAS毒性研究类似，有限的DNT实验室研究具有主要专注于PFO或PFOA。其中一些DNT研究表明对多巴胺能（DA）的影响系统。现在估计有> 4000个PFA，大多数有限于无毒性信息。 futhermore，一些研究在内包括我们的初步数据表明与某些数据相似的毒性结果比C8化合物更有效。此外，大多数PFA都存在于混合物中的环境中，这会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的差距 PFA和PFA混合物的DNT，机制和对发展中心的功能影响以及风险健康和疾病范式（DOHAD）的发育起源中持续的神经毒性。 PFA的特别关注的是Genx（C6，替代PFOA）和PFBS（Pertluorobutanesulfonic Acid，C4，C4，替代PFO）。这些PFA替代方案在环境样本中检测到饮用水。关于短期发育暴露的DNT和持续性神经毒性的问题（例如，Dohad范式）。考虑到GENX据报道，这个问题是重要的 PFOA，可能会发生对GenX和PFOA的共同暴露。我们的中心假设是在早期发育阶段接触GENX将导致DNT针对DA系统并持续具有GenX和PFOA综合作用的成年人的神经毒性导致添加毒性反应。我们将首先使用斑马鱼通过评估斑马鱼来定义Genx的DNT 行为以及与DA系统相关的目标。结果将与PFOA，PFB和 GenX/PFOA混合物和血清素能系统的改变（AIM 1）。其次，我们将评估持久性 DOHAD范式中发育PFAS暴露的神经毒性（AIM 2）。斑马鱼，一个很好的研究DNT和Neurobehavior的已建立模型将被用作脊椎动物的综合动物模型评估短期和长期神经系统结果。将评估几个终点以定义机制来自单个和二元PFA的神经毒性暴露，以告知和指导未来的监管决策。