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.

项目摘要 全氟己酸(PFHxA)是一种用于工业生产的短链全氟烷基物质(PFAS) 和消费品，如水性成膜泡沫(AFFF)、食品包装、家具上的防污剂、 还有化妆。在美国，PFHxA的使用不受监管。PFHxA在环境中无处不在 严重污染土壤和水，导致人类通过摄入暴露在空气中。流行病学 文献报道了母体血清和母乳中的PFHxA，并且PFHxA穿过胎盘。一起， 这些数据表明，胎儿通过胎盘暴露，婴儿通过母乳喂养。在……里面 在人类，PFHxA在小脑中的积聚比在大多数其他大脑区域都要高。小脑很关键 运动和认知功能，是50%的神经元的家园，具有独特的细胞结构， 发展晚于其他地区，是在发育毒物背景下研究的重要地区 曝光。虽然PFHxA对健康的影响在很大程度上仍未得到研究，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，还没有被研究过。小胶质细胞具有相同的中胚层 起源于外周免疫细胞，表明发育中的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，因为它们有一个独特的转录图谱。除了免疫功能外，小胶质细胞还发挥着 通过帮助血管生成，为髓鞘发育提供因子，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，发育中的PFHxA暴露可能会影响他们的 免疫和神经解剖功能。尽管小胶质细胞在大脑发育和证据中的重要性 对于PFHxA进入大脑，尚未在哺乳动物神经系统中进行研究。基于 来自PFHxA和长链PFAS的流行病学研究的证据，我假设怀孕和 哺乳期暴露于PFHxA的小鼠模型扰乱小脑发育，影响神经元和神经胶质细胞 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。为了验证这一假设，我将使用代表人类的老鼠模型来实现两个目标 孕期和哺乳期暴露于PFHxA。第一个目标将调查妊娠和哺乳期 用RNA测序和免疫组织化学方法研究PFHxA暴露对神经元和神经胶质细胞表型的影响 (IHC)。这个目标还将调查这种暴露如何影响动物的行为，特别是那些与 小脑。第二个将确定小胶质细胞是否在遗传、蛋白质和动态水平上通过使用 RNA测序、免疫组化和双光子显微镜。这些实验将首次表明， 在大脑发育期间接触PFHxA是神经毒性的，也将指导来自多个机构的监管机构 当考虑将PFHxA暴露于人类时。