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Protection against Arsenic-Induced Neurologic Defects by Brain DHA Enrichment

通过富含大脑 DHA 预防砷诱发的神经系统缺陷

基本信息

批准号：
10018911
负责人：
Robert M Sargis
金额：
$ 23.99万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
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：
2019-09-17 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018911
关键词：
Address Adult Adult Children Adverse effects Affect Animal Model Anxiety Arsenic Behavior Biology Blood - brain barrier anatomy Brain Brain Diseases Brain-Derived Neurotrophic Factor Cardiovascular Diseases Clinical Clinical Trials Cognition Cognitive deficits Consumption Data Defect Development Diabetes Mellitus Diet Disease Docosahexaenoic Acids Docosahexaenoic acid supplement Docosahexaenoic acid supplementation Dose Elderly Epidemiology Esters Euphausiacea Exposure to Fatty acid glycerol esters Fish Oils Fishes Functional disorder Homeostasis Human Impairment Individual Intake Intervention Lactation Learning Life Link Lipids Liver Low Prevalence Lysophosphatidylcholines Major Depressive Disorder Malignant Neoplasms Mediating Memory Mental Depression Mental disorders Methods Modification Molecular Molecular Analysis Mood Disorders Mus Neurocognition Neurocognitive Neurocognitive Deficit Neurologic Neurons Nutraceutical Oils Omega-3 Fatty Acids Outcome Pathway interactions Penetrance Phospholipids Placenta Plasma Polyunsaturated Fatty Acids Population Pregnancy Prevention Public Health Resistance Risk Factors Rodent Model Role Route Saturated Fatty Acids Source Testing Toxic Environmental Substances Triglycerides Weaning World Health Organization adverse outcome contaminated drinking water cost depression model dietary supplements feeding fetal improved inflammatory marker innovation modifiable risk neurobehavioral neurocognitive disorder neuropsychiatry novel offspring pregnant prenatal stress prevent remediation stressor

项目摘要

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.

项目总结: