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

描述(由申请人提供) 关于长期低水平暴露于常见环境毒素的影响，如神经毒性氨基酸、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，存在严重的知识差距。DA在食物网中的积累对人类和野生动物的健康构成了重大威胁，并导致了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。事实上，该调查小组的一名成员最近的研究结果表明，与非含DA贝类消费者相比，沿海贝类消费者中出现了显著的认知障碍和癫痫患病率增加。慢性毒性的亚临床健康影响和潜在机制很难阐明，主要是因为缺乏专门针对慢性暴露的生物标记物。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记物，它是慢性低水平DA暴露的特异性标志，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。在这里，他们测试了一种假设，即DA特异性抗体是低水平慢性暴露的持久生物标记物，即使在没有急性暴露的明显神经行为症状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记物，从而确保在与环境相关的暴露条件下哺乳动物产生抗体反应。这项研究的总体目标是1)开发和验证长期低水平接触DA的生物标记物，2)将该生物标记物与可量化的亚临床神经毒性联系起来 3)在哺乳动物模型系统中量化慢性暴露对整体动物毒素敏感性(即，增加的敏感性或抵抗力)的影响。这是 为制定评估长期低水平DA暴露对健康影响的可行诊断测试迈出了坚实的一步，并将成为监测与不断变化的海洋状况有关的暴露风险变化的重要工具。 公共卫生相关性：长期接触低水平的藻毒素软骨藻酸可能对经常食用软骨藻酸污染的海鲜的人类和野生动物种群构成重大健康威胁。该研究小组发现了一种抗体反应，这是慢性软骨藻酸暴露的特定生物标志物，并建议使用小鼠模型来进一步确定与抗体水平有关的毒性健康影响。这项研究的结果将为用于人类和野生动物健康评估的慢性暴露提供第一个诊断测试。

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. Public Health Relevance: Chronic exposure to low levels of the algal toxin domoic acid may pose significant health threats to human and wildlife populations that regularly consume domoic acid contaminated seafood. This research team has discovered an antibody response that is a specific biomarker for chronic domoic acid exposure and proposes to use mouse model to further identify toxic health impacts that can be linked to antibody levels. Results from this stud would provide the first diagnostic test for chronic exposure for use in human and wildlife health assessments.