NIH Plunk The Effects of Gestational and Lactational Exposure to Perfluorohexanoic Acid on Cerebellum Development in the Mouse

美国国立卫生研究院 (NIH) 确定妊娠期和哺乳期接触全氟己酸对小鼠小脑发育的影响

• 批准号: 10747709
• 负责人: Elizabeth Cate Plunk
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747709
• 关键词: Acids; Affect; Animal Behavior; Autopsy; Behavior; Behavioral Assay; Biodistribution; Brain; Brain region; Breast Feeding; Cells; Central Nervous System; Cerebellum; Child; Data; Development; Developmental Toxicant; Environment; Epidemiology; Exposure to; Fetus; Film; Food; Furniture; Genes; Genetic; Health; Home; Human; Human Milk; Imaging Techniques; Immune; Immune response; Immunohistochemistry; Industrial Product; Infant; Ingestion; Injury; Lactation; Literature; Location; Microglia; Modeling; Morphology; Motor; Motor Activity; Mus; Myelin; Nervous System; Neuroanatomy; Neuroglia; Neurons; Neurotoxins; Pattern; Peripheral; Phase; Phenotype; Physiological; Placenta; Play; Poly-fluoroalkyl substances; Pregnancy; Production; Proteins; Reporting; Research; Research Personnel; Role; Route; Serum; Signal Pathway; Soil; Stains; Synapses; Testing; Time; Toxicant exposure; United States; United States National Institutes of Health; Vaccines; Water; Work; angiogenesis; aqueous; brain cell; cell behavior; chemical property; cognitive function; consumer product; contaminated water; developmental neurotoxicity; differential expression; epidemiology study; experimental study; exposed human population; immune function; immunosuppressed; in vivo two-photon imaging; maternal serum; mouse model; myelination; neural circuit; neurodevelopment; neurotoxic; offspring; protein expression; response; sex; substance use; transcriptome sequencing; transcriptomics; two photon microscopy

Project Summary Perfluorohexanoic acid (PFHxA) is a short-chain per- and polyfluoroalkyl substance (PFAS) used in industrial and consumer products, such as aqueous film forming foam (AFFF), food wrappers, stain repellants on furniture, and makeup. PFHxA use is not regulated in the United States. PFHxA is found ubiquitously in the environment significantly contaminating soil and water resulting in humans being exposed through ingestion. Epidemiology literature has reported PFHxA in maternal serum and breastmilk, and PFHxA crosses the placenta. Together, these data demonstrate that fetuses are exposed through the placenta and infants through breast feeding. In humans, PFHxA accumulates higher in the cerebellum than in most other brain regions. The cerebellum is critical to both motor and cognitive functions, is the home of 50% of the neurons, has a unique cytoarchitecture, and develops later than other regions making it an important region to study in the context of developmental toxicant exposures. While the health effects of PFHxA are still largely unstudied, it is well established that legacy PFAS alter immune function, including suppressing peripheral immune responses. However, the effects of PFHxA on the immune cells of the brain, microglia, have not been investigated. Microglia have the same mesodermal origins as peripheral immune cells, suggesting that developmental exposures may target microglial function. Interestingly, microglia in the cerebellum may be particularly sensitive to neurotoxicants compared to microglia in other brain regions as they have a unique transcriptomic profile. In addition to immune function, microglia play a critical role in brain development by aiding in angiogenesis, providing factors for myelin development, and pruning synapses thereby remodeling neural circuits. Thus developmental PFHxA exposure could affect their immune and neuroanatomical functions. Despite the importance of microglia in brain development and evidence that PFHxA enters the brain, PFHxA has not been investigated in the mammalian nervous system. Based on evidence from epidemiology studies on PFHxA as well as long-chain PFAS, I hypothesize that gestational and lactational exposure to PFHxA in a mouse model disrupts cerebellar development, affecting neuronal and glial phenotypes, as well as motor activity. Microglia may be uniquely affected by this exposure, becoming immunosuppressed. To test this hypothesis, I will pursue two aims using a mouse model representing human exposure to PFHxA during gestation and lactation. The first aim will investigate how gestational and lactational exposure to PFHxA affects neuron and glia phenotypes using RNA sequencing and immunohistochemistry (IHC). This aim will also investigate how this exposure affects animal behaviors, especially those related to the cerebellum. The second will determine if microglia are altered at the genetic, protein, and dynamic level by using RNA sequencing, IHC, and two-photon microscopy. These experiments will show, for the first time, whether PFHxA exposure during brain development is neurotoxic and will also guide regulators from multiple agencies when considering PFHxA exposure to humans.

项目概要 全氟己酸 (PFHxA) 是一种短链全氟烷基物质 (PFAS)，用于工业 和消费品，例如水成膜泡沫 (AFFF)、食品包装纸、家具防污剂、 和化妆。 PFHxA 的使用在美国不受监管。 PFHxA 在环境中无处不在 严重污染土壤和水，导致人类通过摄入而暴露。流行病学 文献报道PFHxA存在于母体血清和母乳中，并且PFHxA可穿过胎盘。一起， 这些数据表明，胎儿通过胎盘接触，婴儿通过母乳喂养接触。在 在人类中，PFHxA 在小脑中的积累量高于大多数其他大脑区域。小脑很关键 对运动和认知功能都有影响，是 50% 神经元的所在地，具有独特的细胞结构，并且 发育晚于其他区域，使其成为发育毒物背景下研究的重要区域 曝光。虽然 PFHxA 对健康的影响在很大程度上尚未得到研究，但众所周知，遗留的 PFAS 改变免疫功能，包括抑制外周免疫反应。然而，PFHxA 对 大脑的免疫细胞小胶质细胞尚未得到研究。小胶质细胞具有相同的中胚层 起源于外周免疫细胞，表明发育暴露可能针对小胶质细胞功能。 有趣的是，与小胶质细胞相比，小脑中的小胶质细胞可能对神经毒物特别敏感 在其他大脑区域，因为它们具有独特的转录组特征。除了免疫功能外，小胶质细胞还发挥作用 通过帮助血管生成、为髓磷脂发育提供因子，在大脑发育中发挥关键作用，以及 修剪突触从而重塑神经回路。因此，发育阶段的 PFHxA 暴露可能会影响他们 免疫和神经解剖功能。尽管小胶质细胞在大脑发育中很重要并且有证据表明 虽然 PFHxA 进入大脑，但尚未在哺乳动物神经系统中研究 PFHxA。基于 根据 PFHxA 和长链 PFAS 流行病学研究的证据，我假设妊娠期和 小鼠模型中哺乳期接触 PFHxA 会扰乱小脑发育，影响神经元和胶质细胞 表型以及运动活动。小胶质细胞可能会受到这种暴露的独特影响，成为 免疫抑制。为了检验这个假设，我将使用代表人类的小鼠模型来追求两个目标 妊娠和哺乳期间接触 PFHxA。第一个目标将调查妊娠期和哺乳期如何 使用 RNA 测序和免疫组织化学研究接触 PFHxA 会影响神经元和神经胶质细胞表型 （免疫组化）。该目标还将调查这种暴露如何影响动物行为，特别是与 小脑。第二个将通过使用确定小胶质细胞是否在遗传、蛋白质和动态水平上发生改变 RNA 测序、IHC 和双光子显微镜。这些实验将首次表明，是否 大脑发育过程中接触 PFHxA 具有神经毒性，也将为多个机构的监管机构提供指导 在考虑人类接触 PFHxA 时。