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.

摘要