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

神经毒性氨基酸软骨藻酸（DA）是有害藻华（HAB）期间自然产生的藻毒素，在食物网中的积累对人类和野生动物构成重大健康威胁，并导致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。由于全球范围内藻类毒素暴露威胁的增加，迫切需要快速可靠的诊断测试来评估人类和野生动物群体中的慢性DA暴露，并需要明确建立慢性DA暴露、生物标志物反应、在这项提案中，由华盛顿大学的一位科学家领导的一个研究小组将测试一个假设，即DA-特异性抗体是慢性低水平暴露的生物标志物，可以与小鼠模型系统中的亚临床健康影响联系起来。 最近，该团队发现了（1）一种基于抗体的新型生物标志物，它是慢性低水平DA暴露和病理学的特异性特征，以及（2）在斑马鱼慢性暴露模型中，慢性暴露会增加后续暴露中的毒素易感性。在研究中，具体目标是（1）检测小鼠长期低水平DA暴露后抗体反应的时间和持续时间，（2）确定该反应是否指示亚临床神经毒性，以及（3）检测既往DA暴露是否影响随后的毒性易感性。 新的见解将是DA特异性抗体的存在是否是以前无法检测到的慢性DA暴露的可靠指标，进而是显著健康影响的准确预测因子。更广泛的影响：长期、低水平的DA暴露是沿海和部落社区成员真正关心的问题，他们经常收获和消费贝类。 目前，评估人类接触的唯一方法是通过贝类消费调查。这项研究将是朝着开发一种可行的诊断测试来评估长期低水平DA暴露对健康的影响迈出的重要的第一步，也将是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。本项目所依据的原始提案（R 01 ES 021930 -01）已提交给美国国立环境健康科学研究院（NIH/NIEHS）响应资助机会公告RFA-ES-11-013，“海洋、五大湖和人类健康（R 01）"，这是NSF联合赞助的一个机会。 该项目通过NSF和NIEHS的单独奖励合作资助。

Accumulation of the neurotoxic amino acid domoic acid (DA), a phycotoxin naturally produced during harmful algal blooms (HABs), 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. Due to increasing algal toxin exposure threats globally, there is a critical need for rapid and reliable diagnostic tests for assessing chronic DA exposure in human and wildlife populations, and for evidence that clearly establishes the relationship between chronic DA exposure, biomarker response, and health impacts.In this proposal a research team led by a scientist at the University of Washington will test the hypothesis that the presence of a DA-specific antibody is a biomarker for chronic low-level exposure that can be linked to subclinical health impacts in a mouse model system. Recently, this team has discovered (1) a novel antibody based biomarker that is a specific signature for chronic low-level DA exposure and pathology, and (2) that chronic exposure increases toxin susceptibility in subsequent exposures in a zebrafish chronic exposure model. In study the specific objectives are (1) to test the timing and duration of the antibody response following chronic, low-level DA exposure in mice, (2) to determine whether this response is indicative of subclinical neurotoxicity, and (3) to test whether previous exposures to DA affect subsequent toxic susceptibility. The new insight will be whether the presence of a DA-specific antibody is a reliable indicator of previously undetectable chronic DA exposures, and in turn an accurate predictor of significant health effects. Broader Impacts: Chronic, low-level exposure to DA is a genuine concern for members of coastal and tribal communities who routinely harvest and consume shellfish. Currently, the only way to assess exposure in humans is through shellfish consumption surveys. This study will be an important first 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.JOINT FUNDING BY NSF AND NIEHS: The original proposal on which this project is based (R01 ES021930-01) was submitted to the National Institutes of Environmental Health Sciences (NIH/NIEHS) in response to Funding Opportunity Announcement RFA-ES-11-013 , "Oceans, Great Lakes and Human Health (R01)", an opportunity jointly sponsored by NSF. This project is cooperatively funded through separate awards from NSF and NIEHS.