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

摘要 这项建议是基于海鲜毒素软骨藻酸(DA)的新暴露范例，我们已经 在与亚临床慢性DA暴露相关的实验室模型中发现了显著的学习缺陷。 这一点很重要，因为随着有害藻华在#年继续增加，接触DA的风险正在增加。 由于海洋条件变暖，其规模、持续时间和地理范围。众所周知，DA是一种 强烈的兴奋性毒素，对中枢神经系统有严重影响，导致癫痫发作和急性 在人类和野生动物海鲜消费者中都有暴露。暴露于DA的实验室研究和诊断 海洋哺乳动物还证明了对认知、心脏和肾脏系统的永久性影响。这个 随着目前海鲜的实施，急性接触的人类健康风险已降至最低 以急性参考剂量(ARfD)为基础的单次接触20微克DA/g海鲜的监管限值 旨在防止癫痫发作。然而，ARFD没有考虑亚临床效应，重复 以及年龄对DA易感性的影响。我们团队最近的海鲜消费研究显示 一些休闲收割机超过了ARfD和/或每周长期暴露在DA中 至少连续六个月，而且这一群体的大多数人都在60岁以上。衰老是单身 多种慢性疾病的最大风险因素，包括影响认知、心脏和肾脏的疾病 功能，所有这些也是DA毒性的目标。迫切需要了解这种相互作用是如何 DA暴露和衰老之间的关系会增加罹患慢性病和毒素敏感性的风险 在海鲜资源上变得更加持久。为了解决目标1和目标2中的这一知识差距，我们将测试 衰老是否会增加急性症状和慢性低水平无症状毒性的易感性 通过量化组织病理学和组织病理学方法，研究DA暴露以及对幼年和老年小鼠的毒性影响的持久性 认知、心脏和肾脏系统功能障碍。我们的初步数据表明，长期的低水平DA 暴露会影响这些系统中的线粒体功能。在目标3中，我们将检验假设 线粒体氧化应激是认知、心脏和肾脏系统慢性DA毒性的基础 过度表达过氧化氢酶的转基因小鼠模型(MCAT)，过氧化氢酶是线粒体中的一种关键抗氧化酶。 这项研究的结果将明确地为亚临床水平有多低提供新的机械性见解 慢性接触会影响健康寿命，导致慢性疾病，并表明新的 线粒体靶向干预可能有效地降低DA暴露的健康风险。

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.