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

在食物链中积累神经毒性氨基酸软骨藻酸(DA)，这是一种在有害藻华(HABS)期间自然产生的藻毒素，对人类和野生动物的健康构成重大威胁，并导致一种被称为健忘性贝类中毒(ASP)的神经毒性疾病。对可食用贝类组织中DA水平的定期监测在保护人类消费者免受急性高水平DA暴露方面是有效的。然而，没有针对长期低水平DA暴露的保护措施，这可能对人类健康构成重大风险，特别是在自给自足地捕捞已知含有低水平毒素的贝类的沿海和部落社区。由于全球藻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种群中的慢性DA暴露，以及明确建立慢性DA暴露、生物标记物反应和健康影响之间关系的证据。在这项提议中，华盛顿大学科学家领导的一个研究小组将在小鼠模型系统中测试DA特异性抗体的存在是慢性低水平暴露的生物标记物，可与亚临床健康影响联系起来。最近，该团队发现了(1)一种新的基于抗体的生物标志物，它是慢性低水平DA暴露和病理的特异性标志，以及(2)在斑马鱼慢性暴露模型中，长期暴露增加了后续暴露中毒素的易感性。在这项研究中，具体目标是(1)测试小鼠在长期、低水平DA暴露后抗体反应的时间和持续时间，(2)确定这种反应是否指示亚临床神经毒性，以及(3)测试先前暴露于DA是否影响随后的毒性敏感性。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，进而是对重大健康影响的准确预测。更广泛的影响：对于经常捕捞和食用贝类的沿海和部落社区成员来说，长期、低水平接触DA是一个真正令人担忧的问题。目前，评估人类暴露在贝类中的唯一方法是通过贝类消费调查。这项研究将是开发一种评估长期低水平DA暴露对健康影响的可行诊断测试的重要第一步，也将是监测与不断变化的海洋条件有关的暴露风险变化的重要工具。JOINT由NSF和NIEHS提供资金：本项目所基于的原始提案(R01 ES021930-01)已提交给国家环境卫生科学研究所(NIH/NIEHS)，以回应由NSF联合发起的资助机会公告RFA-ES-11-013，“海洋、五大湖与人类健康(R01)”。该项目由NSF和NIEHS通过单独的奖项提供合作资金。

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.