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
基本信息
- 批准号:10205069
- 负责人:
- 金额:$ 13.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAddressAffectAgeAge-YearsAgingCardiacCessation of lifeChronicChronic DiseaseCognitiveCognitive deficitsCommunicationConsumptionDataDiagnosticDoseElderlyExcitatory NeurotoxinsExposure toFrequenciesFunctional disorderFundingGeographyHealthHumanInterventionKidneyKnowledgeLaboratoriesLaboratory StudyLearningMammalsMeasuresMitochondriaModelingMorbidity - disease rateMusNational Institute of Environmental Health SciencesNeuraxisOxidative StressPacific OceanPathologyPopulationPredispositionPublic HealthRenal functionResearchResourcesRiskRisk FactorsRisk ManagementSeafoodSeizuresSeveritiesSystemTestingTissuesToxic effectToxinTransgenic Miceacute toxicityage effectagedantioxidant enzymebasebiological systemscatalasecognitive functiondesigndomoic acidexperimental studyharmful algal bloomshealthspanheart functionimprovedinsightmouse modelocean ecosystemsoverexpressionpreventpublic health relevance
项目摘要
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
该建议是基于一个新的海鲜毒素软骨藻酸(DA)的暴露模式,我们有
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,因为随着有害藻华的持续增加,
规模、持续时间和由于海洋变暖而造成的地理范围。众所周知,A是一个
强效兴奋性毒素,对中枢神经系统有严重影响,导致急性癫痫发作和死亡
人类和野生动物海产品消费者的接触。DA暴露的实验室研究和诊断
海洋哺乳动物对认知、心脏和肾脏系统的永久性影响也有进一步的记录。的
实施现行的海产食品标准,
基于单次接触急性参考剂量(ARfD)的20 ug DA/g海产品的监管限值
用来防止癫痫发作然而,急性参考剂量不考虑亚临床效应、重复性
暴露,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,
一些娱乐性收割机超过了ARfD和/或每周长期暴露于DA,
至少连续六个月,而且这一群体的大多数年龄在60岁以上。衰老是唯一
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。有一个关键需要了解如何相互作用
DA暴露和衰老之间的关系有助于慢性疾病和毒素易感性的风险,
在海产品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
衰老是否会增加对急性症状性和慢性低水平无症状性毒性的易感性
通过定量组织病理学和免疫组织化学方法,
认知、心脏和肾脏系统功能障碍。我们的初步数据表明,长期低水平DA
暴露影响这些系统中的线粒体功能。在目标3中,我们将检验以下假设:
线粒体氧化应激是认知、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,线粒体中的关键抗氧化酶。
这项研究的结果将明确提供新的机制见解,以了解低水平亚临床
长期接触会影响健康寿命并导致慢性疾病,并表明是否有新的
线粒体靶向干预可能有效降低DA暴露的健康风险。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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David J. Marcinek其他文献
Reversible Inhibition of Mitochondrial Function by Oxidative Stress Contributes to Age-Related Mitochondrial Deficits
- DOI:
10.1016/j.freeradbiomed.2012.10.311 - 发表时间:
2012-11-01 - 期刊:
- 影响因子:
- 作者:
David J. Marcinek;Shane E. Kruse;Michael P. Siegel;Hazel H. Szeto - 通讯作者:
Hazel H. Szeto
Urolithin A provides cardioprotection and mitochondrial quality enhancement preclinically and improves human cardiovascular health biomarkers
尿石素 A 在临床前具有心脏保护作用和线粒体质量增强作用,并改善人类心血管健康生物标志物。
- DOI:
10.1016/j.isci.2025.111814 - 发表时间:
2025-02-21 - 期刊:
- 影响因子:4.100
- 作者:
Sophia Liu;Julie Faitg;Charlotte Tissot;Dimitris Konstantopoulos;Ross Laws;Guillaume Bourdier;Pénélope A. Andreux;Tracey Davey;Hector Gallart-Ayala;Julijana Ivanisevic;Anurag Singh;Chris Rinsch;David J. Marcinek;Davide D’Amico - 通讯作者:
Davide D’Amico
280 - Reducing Oxidative Stress Restores Thiol Proteome and Improves Energetics and Performance in Aged Mouse Skeletal Muscle
- DOI:
10.1016/j.freeradbiomed.2015.10.329 - 发表时间:
2015-10-01 - 期刊:
- 影响因子:
- 作者:
Matthew D. Campbell;Gary M. Knowles;Matthew J. Gaffrey;Richard P. Beyer;Hazel S. Szeto;Wei-Jun Qian;David J. Marcinek - 通讯作者:
David J. Marcinek
Contemporary insights into elamipretide’s mitochondrial mechanism of action and therapeutic effects
依拉米肽线粒体作用机制及治疗效果的当代见解
- DOI:
10.1016/j.biopha.2025.118056 - 发表时间:
2025-06-01 - 期刊:
- 影响因子:7.500
- 作者:
Hani N. Sabbah;Nathan N. Alder;Genevieve C. Sparagna;James E. Bruce;Brian L. Stauffer;Luke H. Chao;Robert D.S. Pitceathly;Christoph Maack;David J. Marcinek - 通讯作者:
David J. Marcinek
75 Protective effect of mitochondrial catalase on AZT mitochondrial toxicity
- DOI:
10.1016/j.mito.2009.12.070 - 发表时间:
2010-03-01 - 期刊:
- 影响因子:
- 作者:
David J. Marcinek;Jonathan Wanagat;Peter S. Rabinovitch;Joachim Voss - 通讯作者:
Joachim Voss
David J. Marcinek的其他文献
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{{ truncateString('David J. Marcinek', 18)}}的其他基金
Redox stress resilience in aging skeletal muscle
衰老骨骼肌的氧化还原应激恢复能力
- 批准号:
10722970 - 财政年份:2023
- 资助金额:
$ 13.06万 - 项目类别:
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:
10438785 - 财政年份:2018
- 资助金额:
$ 13.06万 - 项目类别:
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:
9702219 - 财政年份:2018
- 资助金额:
$ 13.06万 - 项目类别:
Preventing Skeletal and Cardiac Muscle Aging by Restoring Mitochondrial Function
通过恢复线粒体功能预防骨骼肌和心肌老化
- 批准号:
9564597 - 财政年份:2017
- 资助金额:
$ 13.06万 - 项目类别:
SS peptides: a new approach to improve mitochondrial and skeletal muscle function
SS 肽:改善线粒体和骨骼肌功能的新方法
- 批准号:
8444893 - 财政年份:2012
- 资助金额:
$ 13.06万 - 项目类别:
SS peptides: improve mitochondrial and skeletal muscle function with age
SS肽:随着年龄的增长改善线粒体和骨骼肌功能
- 批准号:
8554758 - 财政年份:2012
- 资助金额:
$ 13.06万 - 项目类别:
Mitochondrial fuction, oxidative damage, and aging
线粒体功能、氧化损伤和衰老
- 批准号:
7022219 - 财政年份:2005
- 资助金额:
$ 13.06万 - 项目类别:
Mitochondrial function, oxidative damage, and aging
线粒体功能、氧化损伤和衰老
- 批准号:
7198108 - 财政年份:2005
- 资助金额:
$ 13.06万 - 项目类别:
Mitochondrial function, oxidative damage, and aging
线粒体功能、氧化损伤和衰老
- 批准号:
6870808 - 财政年份:2005
- 资助金额:
$ 13.06万 - 项目类别:
Mitochondrial function, oxidative damage, and aging
线粒体功能、氧化损伤和衰老
- 批准号:
7369717 - 财政年份:2005
- 资助金额:
$ 13.06万 - 项目类别:
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