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

软骨藻酸(DA)是一种由有害藻华产生的毒素。软骨藻酸在海产品中积累，会对海洋哺乳动物和食用受污染贝类的人类造成伤害。在高剂量下，DA会导致被称为遗忘性贝类中毒(ASP)的神经毒性疾病，其临床症状包括癫痫发作、记忆丧失、昏迷和死亡。人们对长期暴露在较低剂量下的影响知之甚少。该研究小组最近的海鲜消费研究显示，一些休闲采摘者超过了目前规定的剂量限制和/或每周至少连续六个月长期接触DA，而且这一群体中的大多数人超过60岁。衰老是多种慢性疾病的最大风险因素，包括那些影响大脑、心脏和肾脏功能的疾病，所有这些都是DA毒性的目标。这项研究将调查软骨藻酸暴露的影响如何随着年龄的变化而变化。随着海洋条件的变化，由于产生毒素的水华的频率和严重性增加，通过海鲜消费接触DA的情况可能会增加。因此，更好地了解DA暴露对慢性疾病风险的影响以及长期健康问题的潜在机制，特别是在老年人口中，对于监管机构更好地管理这些风险和改善与利益攸关方的沟通至关重要。这项研究是由美国国家科学基金会和美国国家环境健康科学研究所(NIEHS)共同支持的。该研究有三个具体目标。首先，为了验证衰老增加对急性DA毒性易感性的假设，研究人员将测量急性症状性DA暴露对小鼠和老年小鼠认知、心脏和肾功能的影响。在急性症状暴露后，他们将量化已知的DA诱导的三个系统-认知系统、心脏系统和肾脏系统-的组织病理和功能障碍。其次，为了验证衰老增加对慢性DA毒性易感性的假设，他们将测量长期低水平DA暴露对年轻和老年小鼠的认知、心脏和肾脏功能的影响。研究人员此前已经证明，长期低水平的DA暴露会导致可逆的认知障碍。然而，衰老是否会影响慢性DA毒性对认知、心脏和肾功能的易感性和可逆性还没有得到研究。最后，为了测试线粒体氧化应激是认知、心脏和肾脏系统慢性DA毒性的基础的假设，他们将在小鼠模型(MCAT)中使用慢性DA暴露范例(AIM 2)，在线粒体中过度表达过氧化氢酶。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Domoic acid (DA) is a toxin produced by a type of harmful algal bloom. Domoic acid accumulates in seafood products and can harm marine mammals and humans who consume contaminated shellfish. At high doses, DA is responsible for the neurotoxic illness known as amnesic shellfish poisoning (ASP), with clinical symptoms that include seizures, memory loss, coma, and death. The effects of chronic exposure to lower doses are less well understood. Recent seafood consumption studies by this research team revealed that some recreational harvesters exceeded the current regulated dose limit 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 brain, heart, and kidney function, all of which are also targets of DA toxicity. This study will investigate how the effects of domoic acid exposure change with age. As ocean conditions change, exposure to DA through seafood consumption is likely to increase as a result of increased frequency and severity of toxin producing blooms. Thus a better understanding of the effect of DA exposure on the risk of developing chronic disease and the mechanisms underlying long term health problems, especially in the elderly population, is critical for better management of these risks by regulatory bodies and improved communication with stakeholders. The research is jointly supported by NSF and by the National Institute for Environmental Health Sciences (NIEHS).The study has three specific aims. First, in order to test the hypothesis that aging increases susceptibility to acute DA toxicity the investigators will measure the effects of acute symptomatic DA exposure on cognitive, cardiac and renal function in young and old mice. Following an acute symptomatic exposure, they will quantify tissue pathology and dysfunction in three systems with known DA induced pathology - cognitive, cardiac, and kidney systems. Second, in order to test the hypothesis that aging increases the susceptibility to chronic DA toxicity they will measure the effects of chronic low-level DA exposure on cognitive, cardiac and renal function in young and old mice. The investigators have previously demonstrated that chronic low-level DA exposure caused reversible cognitive deficits. However, whether aging affects the susceptibility to and reversibility of chronic DA toxicity to cognitive, cardiac and renal function has not been examined. Finally, in order to test the hypothesis that mitochondrial oxidative stress underlies chronic DA toxicity in cognitive, cardiac and renal systems they will use the chronic DA exposure paradigm (aim 2) in a mouse model (mCAT) overexpressing catalase, a key antioxidant enzyme, in the mitochondria.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.