A novel antibody based biomarker for toxicity of chronic domoic acid exposure

一种基于抗体的新型生物标志物，用于检测慢性软骨藻酸暴露的毒性

• 批准号: 8920296
• 负责人: Kathi Lefebvre
• 金额: $ 11.91万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8920296
• 关键词: Acute; Affect; Amino Acids; Animals; Antibodies; Antibody Formation; Astrocytes; Biological Assay; Biological Markers; Biological Models; Cessation of life; Characteristics; Chronic; Cognitive; Coma; Consumption; Dendritic Spines; Detection; Development; Diagnostic tests; Disease; Dose; Ensure; Exposure to; Food Webs; Glutamate Agonist; Glutamates; Goals; Harvest; Health; Human; Impaired cognition; Individual; Knowledge; Link; Mammals; Marines; Memory Loss; Mitochondria; Modeling; Monitor; Mus; Neurotoxins; Oceans; Oxidative Stress; Phytoplankton; Poisoning; Population; Predisposition; Prevalence; Recovery; Research; Research Personnel; Resistance; Risk; Role; Sea Lions; Seafood; Seizures; Serum; Shellfish; Solid; Surveys; Symptoms; Testing; Time; Tissues; Toxic Environmental Substances; Toxic effect; Toxin; Zalophus; Zebrafish; base; brain tissue; cohort; domoic acid; excitotoxicity; harmful algal blooms; human study; insight; member; mouse model; neurobehavioral; neurotoxic; neurotoxicity; novel; public health relevance; response; tool; tribal community; uptake

DESCRIPTION (provided by applicant) There is a critical knowledge gap regarding the impacts of chronic low-level exposure to common environmental toxins such as the neurotoxic amino acid, domoic acid (DA), a phycotoxin naturally produced during harmful algal blooms (HABs). Accumulation of DA in the food web poses significant health threats to humans and wildlife and is responsible for a neurotoxic illness known as amnesic shellfish poisoning (ASP). Regular monitoring of DA levels in edible shellfish tissues has been effective in protecting human consumers from acute high-level DA exposure. However, there is no protection from chronic low-level DA exposure, which may pose significant human health risks, particularly in coastal and tribal communities that subsistence harvest shellfish known to contain low levels of the toxin. In fact, recent findings b a member of this investigative team suggest that significant cognitive impairment and increased seizure prevalence occur in a coastal cohort of shellfish consumers compared to non-consumers of DA-containing shellfish. The subclinical health effects and underlying mechanisms of chronic toxicity are difficult to elucidate primarily due to the lack of a biomarker specific for chronic exposure. The investigators' research team has discovered 1) a novel antibody based biomarker that is a specific signature for chronic low-level DA exposure, and 2) that chronic exposure increases toxin susceptibility in subsequent exposures in a zebrafish chronic exposure model. Here they test the hypothesis that a DA- specific antibody is a persistent biomarker for low-level chronic exposure that results in neurotoxicity even in the absence of the overt neurobehavioral symptoms characteristic of acute exposure. The investigators have detected the antibody biomarker in naturally DA-exposed California sea lions, thereby ensuring that the antibody response occurs in mammals under environmentally relevant exposure conditions. The overall goals of the study are to 1) develop and validate a biomarker for chronic low-level exposure to DA, 2) link this biomarker to quantifiable subclinical neurotoxic logical endpoints, and 3) quantify the effects of chronic exposure on overall whole animal toxin susceptibility (i.e., increased sensitivity or resistance) in a mammalian model system. This is the first solid step towards developing a viable diagnostic test for assessing health impacts of chronic low-level DA exposure and will be an important tool for monitoring changes in exposure risks associated with changing ocean conditions.

描述（由申请人提供） 关于长期低水平接触常见环境毒素的影响，如神经毒性氨基酸软骨藻酸（DA），这是有害藻华（HAB）期间自然产生的一种藻毒素，存在着严重的知识空白。 DA在食物网中的积累对人类和野生动物造成了重大的健康威胁，并导致了一种称为遗忘性贝类中毒（ASP）的神经毒性疾病。 定期监测可食用贝类组织中的DA水平可以有效地保护人类消费者免受急性高水平DA暴露的影响。 然而，没有保护长期低水平的DA暴露，这可能会对人类健康构成重大风险，特别是在沿海和部落社区，生存收获贝类已知含有低水平的毒素。 事实上，最近的研究结果B，这个调查小组的一名成员表明，显着的认知障碍和癫痫发作的患病率增加发生在沿海队列的贝类消费者相比，非消费者的DA含贝类。亚临床健康影响和慢性毒性的潜在机制难以阐明，主要是因为缺乏针对慢性接触的生物标志物。 研究人员的研究小组发现了1）一种新的基于抗体的生物标志物，它是慢性低水平DA暴露的特异性特征，2）在斑马鱼慢性暴露模型中，慢性暴露增加了随后暴露的毒素易感性。 在这里，他们测试了这样一种假设，即DA特异性抗体是低水平慢性暴露的持久生物标志物，即使在没有急性暴露的明显神经行为症状特征的情况下也会导致神经毒性。 研究人员在自然暴露于DA的加州海狮中检测到了抗体生物标志物，从而确保了在环境相关暴露条件下哺乳动物中发生的抗体反应。研究的总体目标是：1）开发和验证慢性低水平DA暴露的生物标志物，2）将该生物标志物与可量化的亚临床神经毒性联系起来。 逻辑终点，和3）量化慢性暴露对整体动物毒素易感性的影响（即，增加的敏感性或抗性）。这是 这是朝着开发一种可行的诊断测试方法以评估长期低水平DA暴露的健康影响迈出的坚实的第一步，并将成为监测与不断变化的海洋条件相关的暴露风险变化的重要工具。