Project 3: Cellular and Molecular Mechanisms Underlying Long-term Effects of Early Life Exposure to HAB Toxins

项目 3：生命早期接触 HAB 毒素造成长期影响的细胞和分子机制

• 批准号: 10223309
• 负责人: Mark E Hahn
• 金额: $ 14.15万
• 依托单位: WOODS HOLE OCEANOGRAPHIC INSTITUTION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223309
• 关键词: Acute; Address; Adult; Affect; Agonist; Animal Model; Animals; Axon; Behavior; Behavioral; Behavioral Assay; Brain; Cell Lineage; Cells; Chemicals; Climate; Collaborations; Communication; Community Outreach; Defect; Development; Disease; Dose; Elderly; Embryo; Environment; Environmental Exposure; Epidemiology; Exposure to; Gene Expression; Gene Expression Profile; Genetic Transcription; Glutamate Receptor; Health; Human; Ion Channel; Larva; Life; Life Cycle Stages; Long-Term Effects; Measures; Modeling; Molecular; Motor Neurons; Nervous system structure; Neuraxis; Neuroglia; Neurons; Neurotransmitter Receptor; Oceans; Oligodendroglia; Perinatal Exposure; Physiological; Protein Family; Public Health; Regulation; Research; Risk; Rodent; Safety; Saxitoxin; Seafood; Signal Transduction; Sodium Channel; Testing; Toxic effect; Toxin; Transgenic Organisms; Visualization; Wood material; Zebrafish; acute toxicity; axon growth; base; climate change; cognitive function; community engagement; design; developmental neurotoxicity; developmental toxicity; domoic acid; early life exposure; experimental study; exposed human population; harmful algal blooms; human model; inhibitor/antagonist; migration; myelination; neurobehavior; neurobehavioral; neurodevelopment; neurotoxicity; neurotoxicology; novel; oligodendrocyte lineage; oligodendrocyte myelination; prenatal; prevent; stressor; voltage

The overall objective of the proposed research is to elucidate the cellular and molecular mechanisms by which early-life exposure to harmful algal bloom (HAB) toxins may interfere with neurodevelopment to cause persistent neurobehavioral changes later in life. The HAB toxins domoic acid and saxitoxin occur in seafood and levels are regulated to prevent acute toxicity. However, human exposure to these toxins at levels below regulatory limits is common, widespread, and may be increasing, posing risks to vulnerable subpopulations such as developing humans. It is now well known that the early life environment can profoundly influence health throughout the life course (the developmental origins of health and disease). However, the mechanisms by which developmental exposures elicit effects later in life are not well understood. The central hypothesis of this research is that early life, low-level exposure to domoic acid and saxitoxin targets neurotransmitter receptors and ion channels, leading to altered gene expression, functional changes in glial and neural cells, and long-term changes in neurobehavioral function in adults. These studies will be conducted using zebrafish, a powerful model organism in developmental neurotoxicology research. In Aim 1, we will test the hypothesis that embryonic exposure to low levels of domoic acid, a glutamate receptor agonist, targets developing oligodendrocytes (OLs), thereby disrupting myelination of axons. We will measure the effects on OL-lineage cells using a variety of transgenic zebrafish lines that allow visualization of developing OLs and myelination. We will elucidate the functional consequences of these changes by assessing larval behavior. In addition, we will determine later life consequences of developmental exposure to domoic acid on neurobehavior using a battery of well-established behavioral assays and characterizing the gene expression patterns in the adult brain. In Aim 2, we will test the hypothesis that developmental exposure to saxitoxin, an inhibitor of voltage- gated sodium channels, targets developing neurons, leading to defects in axonal growth. We will visualize the changes in axonal growth in motor neurons and determine functional changes in larval and adult behavior. In Aim 3, we will test the hypothesis that combined early life exposure to low levels of domoic acid and saxitoxin targets OLs and neuronal cells, interfering with activity-dependent myelination and causing enhanced deficits in myelination and neurobehavior. We will also test the hypothesis that domoic acid and saxitoxin can cause silent neurotoxicity that can be unmasked later in life by secondary stressors. Research in collaboration with Projects 1 and 2 and the Community Outreach Core will model human exposure and how it may change with a changing climate. This research will identify the cellular and molecular bases for neurobehavioral effects following early-life exposure to prominent HAB toxins, contributing to an understanding of the potential long- term health consequences of developmental exposure to domoic acid and saxitoxin in humans, critical for assessing public health risks associated with the possibly increasing exposure to these toxins.

拟议研究的总体目标是阐明细胞和分子机制 生命早期接触有害藻华 (HAB) 毒素可能会干扰神经发育，导致 晚年持续的神经行为变化。海鲜中存在HAB毒素软骨藻酸和石房蛤毒素 并调节水平以防止急性毒性。然而，人类接触这些毒素的水平低于 监管限制是常见、广泛的，并且可能不断增加，给弱势群体带来风险 比如人类的发展。现在众所周知，早期的生活环境可以深刻地影响 整个生命过程的健康（健康和疾病的发育起源）。然而，这些机制 发育暴露如何对以后的生活产生影响尚不清楚。中心假设为 这项研究表明，生命早期，低水平接触软骨藻酸和石房蛤毒素会靶向神经递质 受体和离子通道，导致基因表达改变、神经胶质细胞和神经细胞功能变化， 以及成人神经行为功能的长期变化。这些研究将使用斑马鱼进行， 发育神经毒理学研究中强大的模型生物。在目标 1 中，我们将检验假设 胚胎暴露于低水平的软骨藻酸（一种谷氨酸受体激动剂）会导致发育 少突胶质细胞（OL），从而破坏轴突的髓鞘形成。我们将测量对 OL 谱系的影响 使用各种转基因斑马鱼系的细胞，可以可视化发育​​中的 OL 和髓鞘形成。 我们将通过评估幼虫的行为来阐明这些变化的功能后果。此外，我们 将使用以下方法确定发育暴露于软骨藻酸对神经行为的晚年影响 一系列完善的行为测定并表征成人的基因表达模式 脑。在目标 2 中，我们将检验以下假设：发育过程中接触石房蛤毒素（一种电压抑制剂） 门控钠通道，针对发育中的神经元，导致轴突生长缺陷。我们将可视化 运动神经元轴突生长的变化并确定幼虫和成虫行为的功能变化。在 目标 3，我们将检验将生命早期接触低水平软骨藻酸和石房蛤毒素相结合的假设 以 OL 和神经元细胞为目标，干扰活动依赖性髓鞘形成并导致缺陷增强 髓鞘形成和神经行为。我们还将检验软骨藻酸和石房蛤毒素可引起的假设 无声的神经毒性可能会在以后的生活中被二次压力源所掩盖。与以下机构合作研究 项目 1 和 2 以及社区外展核心将模拟人类接触情况以及它如何随 气候变化。这项研究将确定神经行为效应的细胞和分子基础 在生命早期接触主要的 HAB 毒素后，有助于了解潜在的长期危害 人类发育过程中暴露于软骨藻酸和石房蛤毒素的长期健康后果，对 评估与可能增加接触这些毒素相关的公共卫生风险。