Microbial mechanisms of methylmercury metabolism in humans
人体甲基汞代谢的微生物机制
基本信息
- 批准号:10020407
- 负责人:
- 金额:$ 56.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-19 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AntibioticsArsenicBiological AssayBiological MarkersBloodCohort StudiesCommunitiesConsumptionDNADiagnosisDietDietary ProteinsDietary SupplementationDoseEatingEcologyEngineeringEscherichia coliExcretory functionExhibitsExposure toFecesFishesGenesGenomeGenomicsGerm-FreeGnotobioticGuidelinesHairHalf-LifeHazardous SubstancesHealthHealth BenefitHumanHuman MicrobiomeHuman VolunteersHuman bodyIndividualIntakeInterventionKineticsKnowledgeLaboratory AnimalsLeadMeasurementMeasuresMediatingMercuryMetabolicMetabolic BiotransformationMetabolismMetagenomicsMethylmercury CompoundsMicrobeMusNutrientPoisonPredispositionProbioticsResearchRiskRoleRunningSamplingSequence AnalysisSourceSupplementationTestingTimeToxic effectToxicokineticsUncertaintyValidationVariantbasedemethylationdesigndietary supplementsdisease registryenzyme activityexperienceexperimental studyexposure routefeedinggut bacteriagut microbesgut microbiomehuman DNAhumanized mouseimprovedin vivointer-individual variationmembermethylmercury exposuremicrobialmicrobiomemicrobiome compositionmouse modelprebioticsstemtooltrait
项目摘要
Abstract
Mercury (Hg) continues to pose a significant risk to human health reflected by its #3 ranking on the U.S. Agency
of Toxic Substances and Disease Registry priority list of hazardous substances, behind only arsenic and lead.
Of greatest concern is exposure to the more toxic methylmercury (MeHg) that comes with eating fish. Four billion
people world-wide rely on fish as a significant source of dietary protein and essential nutrients. Thus, the
“mercury problem” cannot be solved by simply avoiding the major source of exposure. On the other hand, what
constitutes a harmful level of MeHg exposure remains considerably uncertain. For example, federal (US EPA)
guidelines for fish consumption are based on a Reference Dose (RfD) value for intake of MeHg, which
incorporates 10-fold “uncertainty factor”. It is known that much of this uncertainty stems from the fact that people
metabolize MeHg at widely variable rates and as a result two similarly sized individuals consuming equal
amounts of fish could experience as much as a four-fold difference in accumulated MeHg. A solution to this
problem lies in developing the knowledge and tools to determine an individual’s predisposition to accumulate
MeHg. Yet, several fundamental gaps in the knowledge of how the human body metabolizes and eliminates
MeHg remain. Prior research, largely in laboratory animals, supports the notion that microbes in the gut are
required for the efficient biotransformation (demethylation) and excretion of toxic MeHg. We have recently
obtained substantiating evidence that the rate of MeHg elimination in the human body is reliant on gut microbes.
Importantly, we discovered that MeHg elimination rate in a given individual can vary significantly over time and,
furthermore, is significantly slowed with exposure to antibiotics. With this evidence, we will test the hypothesis
that an individual’s susceptibility for reaching harmful levels of MeHg in the body is regulated by a select number
of microbes common to the human gut. We predict these microbes will be present in variable amounts in different
individuals, and thus could serve as a biomarker for MeHg metabolism disposition. We also predict a change in
abundance of these microbes can be achieved with a probiotic diet supplement. We will test our hypothesis in
a coordinated team effort involving experts in MeHg exposure and metabolism in humans, gut microbial ecology
in mouse models, and microbial Hg biotransformation and genomics. In three Specific Aims we will: establish
gut microbiome samples that exhibit “fast” and “slow” MeHg kinetics in humans (Aim1), validate the microbiome’s
role in MeHg kinetics using germ free mouse modeling (Aim2) and identify and isolate microbial species
responsible for MeHg demethylation in the human gut (Aim3). With knowledge from this study we intend to
improve human health practices by: 1) deriving non-invasive tools to identify individuals susceptible to
accumulating MeHg and 2) identifying dietary supplement approaches to enhance an individual’s capacity to
metabolize and excrete toxic MeHg.
摘要
汞(Hg)继续对人类健康构成重大风险,这反映在其在美国机构中排名第三
在有毒物质和疾病登记处的危险物质优先列表中,仅次于砷和铅。
最令人担忧的是,吃鱼会接触到毒性更大的甲基汞(MeHg)。四十亿
全世界的人们依赖鱼作为膳食蛋白质和必需营养素的重要来源。因此
"汞问题"不能仅仅通过避免主要的接触源来解决。另一方面,
甲基汞接触是否达到有害水平仍然相当不确定。例如,联邦(US EPA)
鱼类消费指南是基于摄入甲基汞的参考剂量(RfD)值,
包含10倍的"不确定因素"。众所周知,这种不确定性在很大程度上源于人们
代谢甲基汞的速度差异很大,因此,两个体型相似的个体消耗相同的甲基汞,
大量的鱼类在积累的甲基汞中可能会有四倍的差异。解决这一
问题在于发展知识和工具,以确定个人的倾向,积累
甲基汞。然而,在人体如何代谢和消除的知识方面,
甲基汞残留。先前的研究,主要是在实验室动物中进行的,支持肠道中的微生物
有效的生物转化(去甲基化)和有毒甲基汞的排泄所必需的。我们最近
获得了确凿的证据,证明人体内甲基汞的消除速度取决于肠道微生物。
重要的是,我们发现,特定个体的甲基汞消除率会随着时间的推移而发生显著变化,
此外,在接触抗生素后,这种反应会显著减缓。有了这些证据,我们将检验这个假设
一个人体内甲基汞含量达到有害水平的可能性是由一个选定的数字来调节的,
人类肠道中常见的微生物。我们预测这些微生物将以不同的数量存在于不同的环境中,
个体间甲基汞代谢的差异,可作为甲基汞代谢的生物标志物。我们还预测,
这些微生物的丰度可以通过益生菌饮食补充剂来实现。我们将测试我们的假设,
由甲基汞暴露和人体代谢、肠道微生物生态学等方面的专家组成的协调小组,
以及微生物汞生物转化和基因组学。在三个具体目标中,我们将:
在人体中表现出"快"和"慢"甲基汞动力学的肠道微生物组样本(Aim 1),验证了微生物组的
使用无菌小鼠模型(Aim2),确定和分离微生物物种,
人体肠道中甲基汞的去甲基化作用(Aim 3)。通过这项研究,我们打算
通过以下方式改善人类健康实践:1)开发非侵入性工具,以识别易受
2)确定膳食补充剂的方法,以提高个人的能力,
代谢和排泄有毒的甲基汞。
项目成果
期刊论文数量(0)
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MATTHEW D RAND其他文献
MATTHEW D RAND的其他文献
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{{ truncateString('MATTHEW D RAND', 18)}}的其他基金
Microbial mechanisms of methylmercury metabolism in humans
人体甲基汞代谢的微生物机制
- 批准号:
10240601 - 财政年份:2019
- 资助金额:
$ 56.54万 - 项目类别:
Mechanisms of Methylmercury Toxicity in Neuromuscular Development
甲基汞对神经肌肉发育的毒性机制
- 批准号:
9275979 - 财政年份:2016
- 资助金额:
$ 56.54万 - 项目类别:
Mechanisms of Methylmercury Toxicity in Neuromuscular Development
甲基汞对神经肌肉发育的毒性机制
- 批准号:
9100497 - 财政年份:2016
- 资助金额:
$ 56.54万 - 项目类别:
Determination of methylmercury metabolism and elimination status in humans
人体甲基汞代谢和消除状态的测定
- 批准号:
8969362 - 财政年份:2015
- 资助金额:
$ 56.54万 - 项目类别:
Determination of methylmercury metabolism and elimination status in humans
人体甲基汞代谢和消除状态的测定
- 批准号:
9113639 - 财政年份:2015
- 资助金额:
$ 56.54万 - 项目类别:
Susceptibility to methylmercury toxicity: A role for cytochrome p450 enzymes
对甲基汞毒性的敏感性:细胞色素 p450 酶的作用
- 批准号:
8588603 - 财政年份:2012
- 资助金额:
$ 56.54万 - 项目类别:
Susceptibility to methylmercury toxicity: A role for cytochrome p450 enzymes
对甲基汞毒性的敏感性:细胞色素 p450 酶的作用
- 批准号:
8516513 - 财政年份:2012
- 资助金额:
$ 56.54万 - 项目类别:
Neurotoxicity of methylmercury in Drosophila embryo development
甲基汞对果蝇胚胎发育的神经毒性
- 批准号:
8590009 - 财政年份:2012
- 资助金额:
$ 56.54万 - 项目类别:
Neurotoxicity of methylmercury in Drosophila embryo development
甲基汞对果蝇胚胎发育的神经毒性
- 批准号:
8474760 - 财政年份:2012
- 资助金额:
$ 56.54万 - 项目类别:
Neurotoxicity of methylmercury in Drosophila embryo development
甲基汞对果蝇胚胎发育的神经毒性
- 批准号:
8284610 - 财政年份:2012
- 资助金额:
$ 56.54万 - 项目类别:
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