Increased Risk of Chronic Disease Due to Domoic Acid Exposure with Age

随着年龄的增长，软骨藻酸暴露导致慢性病的风险增加

• 批准号: 10205069
• 负责人: David J. Marcinek
• 金额: $ 13.06万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205069
• 关键词: Acute; Address; Affect; Age; Age-Years; Aging; Cardiac; Cessation of life; Chronic; Chronic Disease; Cognitive; Cognitive deficits; Communication; Consumption; Data; Diagnostic; Dose; Elderly; Excitatory Neurotoxins; Exposure to; Frequencies; Functional disorder; Funding; Geography; Health; Human; Intervention; Kidney; Knowledge; Laboratories; Laboratory Study; Learning; Mammals; Measures; Mitochondria; Modeling; Morbidity - disease rate; Mus; National Institute of Environmental Health Sciences; Neuraxis; Oxidative Stress; Pacific Ocean; Pathology; Population; Predisposition; Public Health; Renal function; Research; Resources; Risk; Risk Factors; Risk Management; Seafood; Seizures; Severities; System; Testing; Tissues; Toxic effect; Toxin; Transgenic Mice; acute toxicity; age effect; aged; antioxidant enzyme; base; biological systems; catalase; cognitive function; design; domoic acid; experimental study; harmful algal blooms; healthspan; heart function; improved; insight; mouse model; ocean ecosystems; overexpression; prevent; public health relevance

ABSTRACT The proposal is based on a new exposure paradigm for seafood toxin domoic acid (DA) where we have identified significant learning deficits in a laboratory models associated with sub-clinical chronic DA exposure. This is significant because exposure risks to DA are increasing as harmful algal blooms continue to increase in magnitude, duration and geographic expanse due to warming ocean conditions. It is well known that DA is a potent excitotoxin with severe effects on the central nervous system leading to seizures and death with acute exposure in both human and wildlife seafood consumers. Laboratory studies and diagnostics of DA exposed marine mammals have further documented permanent impacts on cognitive, cardiac and renal systems. The human health risks of acute exposure have been minimized with the implementation of the current seafood regulatory limit of 20 ug DA/g seafood based on an acute reference dose (ARfD) for a single exposure designed to prevent seizures. However, the ARfD does not take into account subclinical effects, repetitive exposure, and effects of age on DA susceptibility. Recent seafood consumption studies by our team revealed that some recreational harvesters exceeded the ARfD and/or were chronically exposed to DA weekly for at least six consecutive months and that the majority of this group is over 60 years of age. Aging is the single greatest risk factor for multiple chronic diseases, including those affecting cognitive, cardiac, and renal function, all of which are also targets of DA toxicity. There is a critical need to understand how the interaction between DA exposure and aging contributes to the risk of chronic disease and toxin susceptibility as DA becomes more persistent in seafood resources. To address this knowledge gap in aims 1 & 2, we will test whether aging increases susceptibility to toxicity from acute symptomatic and chronic low-level asymptomatic DA exposures as well as persistence of toxic effects in young and old mice by quantifying tissue pathology and dysfunction in cognitive, cardiac and renal systems. Our preliminary data indicate that long-term low-level DA exposure affects mitochondrial function in these systems. In aim 3 we will test the hypothesis that mitochondrial oxidative stress underlies chronic DA toxicity in cognitive, cardiac and renal systems using a transgenic mouse model (mCAT) that overexpresses catalase, a key antioxidant enzyme in the mitochondria. Results from this study will unambiguously provide new mechanistic insights into how low level subclinical chronic exposures can affect healthspan and contribute to chronic disease as well as point to whether new mitochondrial targeted interventions may be effective at reducing DA exposure health risks.

抽象的 该提案基于我们拥有的海鲜毒素domoic酸（DA）的新暴露范式 在与亚临床慢性DA暴露相关的实验室模型中发现了明显的学习缺陷。 这很重要，因为随着有害藻类的开花不断增加，对DA的接触风险正在增加 由于海洋状况变暖，大小，持续时间和地理广泛。众所周知，da是一个 有效的兴奋毒素对中枢神经系统有严重影响，导致癫痫发作和急性死亡 人类和野生动物海鲜消费者的暴露。 DA暴露的实验室研究和诊断 海洋哺乳动物进一步证明了对认知，心脏和肾脏系统的永久影响。这 通过实施当前的海鲜，人类健康的急性暴露风险已被最小化 基于一次暴露的急性参考剂量（ARFD）的20 UG DA/G海鲜的调节极限 旨在防止癫痫发作。但是，ARFD不考虑亚临床效应，重复性 暴露和年龄对DA敏感性的影响。我们的团队最近的海鲜消费研究揭示了 一些休闲收割者超过了ARFD和/或长期暴露于DA每周 至少连续六个月至少六个月，这一组中的大多数年龄超过60岁。衰老是单身 多种慢性疾病的最大危险因素，包括影响认知，心脏和肾脏的危险因素 功能，所有这些都是DA毒性的靶标。迫切需要了解互动方式 在DA暴露和衰老之间有助于慢性疾病和毒素敏感性作为DA 在海鲜资源中变得更加持久。为了解决目标1和2中的知识差距，我们将测试 衰老是否会增加急性症状和慢性低水平的毒性敏感性 通过量化组织病理学和 认知，心脏和肾脏系统的功能障碍。我们的初步数据表明长期低级DA 暴露会影响这些系统中的线粒体功能。在AIM 3中，我们将检验以下假设 线粒体氧化应激是使用A的认知，心脏和肾脏系统中慢性DA毒性的基础 转基因小鼠模型（MCAT）过表达过氧化氢酶，这是线粒体中的关键抗氧化剂酶。 这项研究的结果将明确提供有关低水平亚临床的新机械见解 慢性暴露会影响健康状态，并导致慢性疾病，并指出新的 线粒体靶向干预措施可能有效地降低DA暴露健康风险。