Protection against Arsenic-Induced Neurologic Defects by Brain DHA Enrichment

项目摘要： 砷是一种常见的环境毒物，威胁着全球1亿多人。在 除了与心血管疾病、糖尿病和癌症有关外，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 证明砷介导的大脑生物学破坏。由于重要的个人和 心理健康障碍的社会负担，新的预防和治疗方法， 迫切需要的。虽然环境修复为解决这一可改变的风险带来了希望， 由于这一因素，接触的程度及其遗留问题要求采取额外手段， 神经认知缺陷二十二碳六烯酸（DHA）是一种多不饱和脂肪酸， 对于正常的神经元功能;然而，神经元不能合成DHA。而且 脂质生物学的中心法则是，大脑中的DHA库是在发育过程中建立的， 对后世的操纵有抵抗力这可能解释了奇怪的二分法，虽然低DHA摄入量 与精神健康障碍有关，DHA干预（如甘油三酯[如鱼油]） 失望我们提出了一个替代假设，即甘油三酯-DHA（TG-DHA）不适合 用于DHA穿过血脑屏障（BBB）的递送。相反，识别特定的 血脑屏障上的溶血磷脂酰胆碱（LPC）转运蛋白（Mfsd 2a）提供了一种替代途径， DHA富集。虽然内源性LPC含有非常少的DHA（LPC-DHA）， 方法可以富集血浆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，这种富集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中的DHA。因此，本申请的中心假设是 砷介导的大脑DHA消耗导致晚年神经认知缺陷， 使用LPC-DHA的靶向补救可预防这些不良后果。重要的是，由于Mfsda 2是 在胎盘和血脑屏障中表达，将询问两种策略。在目标1中，我们将使用 一种预防模式，以测试发育中补充DHA 砷引起的DHA消耗，并防止晚年认知缺陷。在目标2中，我们将挑战 成人脑DHA停滞的教条与质疑断乳后干预的假设 可以恢复DHA水平和挽救神经认知功能。在每个目标中，新型LPC-DHA 干预将与经典的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。鉴于双 砷和精神健康疾病的全球威胁，新颖的，可扩展的干预战略， LPC-DHA可能对减少重大的个人和社会痛苦有很大的希望。

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.