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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：
9806012
负责人：
Robert M Sargis
金额：
$ 19.99万
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 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9806012
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 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 Supplementation 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.

项目概要：砷是一种常见的环境毒物，威胁着全球一亿多人。在除了与心血管疾病、糖尿病和癌症相关之外，砷还与多种神经认知障碍。这些流行病学联系得到啮齿动物模型的支持证明砷介导的脑生物学破坏。由于重要的个人和精神健康疾病的社会负担，新的预防和治疗方法正在出现迫切需要。虽然环境修复为解决这种可改变的风险带来了希望因素、暴露程度及其遗留问题需要采取额外措施来解决与砷相关的问题神经认知缺陷。二十二碳六烯酸 (DHA) 是一种必需的多不饱和脂肪酸维持正常的神经功能；然而，神经元无法合成 DHA。此外，一个脂质生物学的中心法则是大脑 DHA 池是在发育过程中建立的，并且是对以后的生活操纵有抵抗力。这也许可以解释奇怪的二分法：虽然 DHA 摄入量低与精神健康障碍有关，DHA 干预措施（如甘油三酯 [例如鱼油]）具有失望的。我们提出另一种假设：甘油三酯-DHA (TG-DHA) 不太适合用于跨血脑屏障 (BBB) 输送 DHA。相比之下，特定的识别 BBB (Mfsd2a) 上的溶血磷脂酰胆碱 (LPC) 转运蛋白为大脑提供了替代途径 DHA浓缩。虽然内源性 LPC 含有很少的 DHA (LPC-DHA)，但营养保健品方法可以丰富血浆LPC-DHA。事实上，我们的数据表明成人大脑 DHA 可以使用 LPC-DHA 可以增加一倍，并且这种丰富可以改善学习和记忆。这一点至关重要，因为我们的数据还显示砷会消耗大脑 DHA。因此，本申请的中心假设是砷介导的大脑 DHA 消耗会导致晚年神经认知缺陷，并且 LPC-DHA 的针对性救援可以防止这些不良后果。重要的是，由于 Mfsda2 是在胎盘和 BBB 中均表达，将询问两种策略。在目标 1 中，我们将使用一种预防范式，用于检验发育性 DHA 补充剂可以抵消这一假设砷引起的 DHA 消耗并预防晚年认知缺陷。在目标2中，我们将挑战成人大脑 DHA 停滞的教条并质疑断奶后干预的假设可以恢复 DHA 水平并挽救神经认知功能。在每个目标中，新颖的 LPC-DHA 干预措施将与经典的 TG-DHA 方法进行比较，并进行探索性机制研究将研究砷暴露与神经认知功能障碍之间的联系途径。鉴于双砷和精神健康障碍的全球威胁，新颖的、可扩展的干预策略，例如 LPC-DHA 有望减少个人和社会的重大痛苦。