Protection against Arsenic-Induced Neurologic Defects by Brain DHA Enrichment
Protection against Arsenic-Induced Neurologic Defects by Brain DHA Enrichment
批准号:
9806012
负责人:
Robert M Sargis
金额:
$19.99万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-09-17 至 2021-08-31
关键词:
AddressAdultAdult ChildrenAdverse effectsAffectAnimal ModelAnxietyArsenicBehaviorBiologyBlood - brain barrier anatomyBrainBrain DiseasesBrain-Derived Neurotrophic FactorCardiovascular DiseasesClinicalClinical TrialsCognitionCognitive deficitsConsumptionDataDefectDevelopmentDiabetes MellitusDietDiseaseDocosahexaenoic AcidsDoseElderlyEpidemiologyEstersEuphausiaceaExposure toFatty acid glycerol estersFish OilsFishesFunctional disorderHomeostasisHumanImpairmentIndividualIntakeInterventionLactationLearningLifeLinkLipidsLiverLow PrevalenceLysophosphatidylcholinesMajor Depressive DisorderMalignant NeoplasmsMediatingMemoryMental DepressionMental disordersMethodsModificationMolecularMolecular AnalysisMood DisordersMusNeurocognitionNeurocognitiveNeurocognitive DeficitNeurologicNeuronsNutraceuticalOilsOmega-3 Fatty AcidsOutcomePathway interactionsPenetrancePhospholipidsPlacentaPlasmaPolyunsaturated Fatty AcidsPopulationPregnancyPreventionPublic HealthResistanceRisk FactorsRodent ModelRoleRouteSaturated Fatty AcidsSourceSupplementationTestingToxic Environmental SubstancesTriglyceridesWeaningWorld Health Organizationadverse outcomecontaminated drinking watercostdepression modeldietary supplementsfeedingfetalimprovedinflammatory markerinnovationmodifiable riskneurobehavioralneurocognitive disorderneuropsychiatrynoveloffspringpregnantprenatal stresspreventremediationstressor
中文摘要
项目总结:
英文摘要
Project Summary:
Arsenic is a common environmental toxicant that threatens over 100 million people globally. In
addition to associations with cardiovascular disease, diabetes, and cancer, arsenic is linked to
multiple neurocognitive disorders. These epidemiological links are supported by rodent models
demonstrating arsenic-mediated disruptions in brain biology. Because of the significant individual and
societal burden of mental health disorders, new prevention and treatment approaches are
desperately needed. While environmental remediation offers hope for addressing this modifiable risk
factor, the extent of exposure and its legacy demand additional means to address arsenic-associated
neurocognitive deficits. Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid that is essential
for normal neuronal functioning; however, neurons are incapable of synthesizing DHA. Moreover, a
central dogma of lipid biology is that the brain DHA pool is established during development and is
resistant to later life manipulation. This may explain the curious dichotomy that while low DHA intake
is associated with mental health disorders, DHA interventions (as triglyceride [e.g. fish oil]) have
disappointed. We propose an alternative hypothesis that triglyceride-DHA (TG-DHA) is poorly suited
for DHA delivery across the blood brain barrier (BBB). In contrast, the identification of a specific
lysophosphatidylcholine (LPC) transporter at the BBB (Mfsd2a) offers an alternative route for brain
DHA enrichment. While endogenous LPC contains very little DHA (LPC-DHA), nutraceutical
approaches can enrich plasma LPC-DHA. Indeed, our data indicate that adult brain DHA can be
doubled using LPC-DHA, and this enrichment improves learning and memory. This is critical since
our data also show arsenic depletes brain DHA. Thus, the central hypothesis of this application is
that arsenic-mediated brain DHA depletion causes later life neurocognitive deficits, and
targeted rescue with LPC-DHA prevents these adverse outcomes. Importantly, since Mfsda2 is
expressed in both the placenta and the BBB, two strategies will be interrogated. In Aim 1, we will use
a prevention paradigm to test the hypothesis that developmental DHA supplementation counteracts
arsenic-induced DHA depletion and prevents later life cognitive deficits. In Aim 2, we will challenge
the dogma of adult brain DHA stasis and interrogate the supposition that intervention after weaning
can restore DHA levels and rescue neurocognitive function. In each Aim, the novel LPC-DHA
intervention will be compared to the classical TG-DHA approach, and exploratory mechanistic studies
will investigate pathways linking arsenic exposure to neurocognitive dysfunction. Given the dual
global threats of arsenic and mental health disorders, novel, scalable intervention strategies such as
LPC-DHA may hold great promise for reducing significant individual and societal suffering.
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会议论文
Protection against Arsenic-Induced Neurologic Defects by Brain DHA Enrichment
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批准号:10018911
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项目类别:
-
资助金额:$23.99万
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财政年份:2019
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负责人:Robert M Sargis
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依托单位:
Selenoproteins in Arsenic-Induced Metabolic Dysfunction
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批准号:10091436
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项目类别:
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资助金额:$49.94万
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财政年份:2018
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负责人:Robert M Sargis
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依托单位:
Selenoproteins in Arsenic-Induced Metabolic Dysfunction
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批准号:10328235
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项目类别:
-
资助金额:$49.94万
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财政年份:2018
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负责人:Robert M Sargis
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依托单位:
Metabolic Impact of Fetal or Adult Exposure to Environmental Endocrine Disruptors
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批准号:8723826
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项目类别:
-
资助金额:$23.46万
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财政年份:2013
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负责人:Robert M Sargis
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依托单位:
Metabolic Impact of Fetal or Adult Exposure to Environmental Endocrine Disruptors
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批准号:8582434
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项目类别:
-
资助金额:$19.75万
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财政年份:2013
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负责人:Robert M Sargis
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依托单位:
Environmental Endocrine Disruption of Adipocyte Metabolism
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批准号:8265337
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项目类别:
-
资助金额:$16.02万
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财政年份:2010
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负责人:Robert M Sargis
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依托单位:
Environmental Endocrine Disruption of Adipocyte Metabolism
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批准号:7953162
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项目类别:
-
资助金额:$15.68万
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财政年份:2010
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负责人:Robert M Sargis
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依托单位:
Environmental Endocrine Disruption of Adipocyte Metabolism
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批准号:8462609
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项目类别:
-
资助金额:$16.02万
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财政年份:2010
-
负责人:Robert M Sargis
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依托单位:
Environmental Endocrine Disruption of Adipocyte Metabolism
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批准号:8144891
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项目类别:
-
资助金额:$16.02万
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财政年份:2010
-
负责人:Robert M Sargis
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依托单位:
Environmental Endocrine Disruption of Adipocyte Metabolism
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批准号:8660690
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项目类别:
-
资助金额:$16.02万
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财政年份:2010
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负责人:Robert M Sargis
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依托单位:
Environmental Endocrine Disruptors and Adipocyte Biology
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批准号:7674978
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项目类别:
-
资助金额:$5.34万
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财政年份:2009
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负责人:Robert M Sargis
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依托单位:
海外基金