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.

这项研究的总体目标是阐明细胞和分子机制， 生命早期暴露于有害藻华（HAB）毒素可能会干扰神经发育， 在以后的生活中持续的神经行为变化。赤潮毒素软骨藻酸和石房蛤毒素存在于海产品中 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 监管限制是常见的、广泛的，并且可能会增加，对脆弱的亚群构成风险 比如发展人类。现在大家都知道，早期的生活环境可以深刻地影响 健康贯穿整个生命过程（健康和疾病的发展起源）。然而，机制 发育性接触对以后生活的影响尚不清楚。的中心假设 这项研究表明，生命早期，低水平暴露于软骨藻酸和石房蛤毒素的目标神经递质 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的功能变化， 以及成年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的一种强有力的模式生物。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）， 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，其允许发育中的OL和髓鞘形成的可视化。 我们将通过评估幼虫的行为来阐明这些变化的功能后果。另外我们 将使用一种方法来确定软骨藻酸对神经行为的发育暴露对以后生活的影响。 一组成熟的行为测定和表征成人中的基因表达模式 个脑袋在目标2中，我们将检验以下假设：发育期暴露于蛤蚌毒素（一种电压抑制剂）- 门控钠通道，靶向发育中的神经元，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，并决定幼虫和成虫行为的功能变化。在 目的3，我们将检验早期暴露于低水平软骨藻酸和石房蛤毒素 靶向OL和神经元细胞，干扰活动依赖性髓鞘形成并导致增强的缺陷 在髓鞘形成和神经行为方面。我们还将测试软骨藻酸和石房蛤毒素可以导致 沉默的神经毒性，可以在以后的生活中被二次压力所掩盖。研究与合作 项目1和2以及社区外展核心将模拟人类接触以及它如何随着时间的推移而变化。 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 在生命早期暴露于主要的HAB毒素之后，有助于了解潜在的长期- 软骨藻酸和石房蛤毒素对人类发育的长期健康影响， 评估与可能增加的这些毒素接触有关的公共健康风险。