Protection against Arsenic-Induced Neurologic Defects by Brain DHA Enrichment

项目总结： 砷是一种常见的环境毒物，威胁着全球超过1亿人。在……里面 除了与心血管疾病、糖尿病和癌症有关外，砷还与 多发性神经认知障碍。这些流行病学联系得到了啮齿动物模型的支持 展示了砷对大脑生物学的破坏作用。因为这位重要的个人 精神健康障碍的社会负担，新的预防和治疗方法是 迫切需要。虽然环境补救措施为解决这种可改变的风险带来了希望 因数、暴露程度及其遗留问题需要更多手段来解决与砷有关的问题 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 对于正常的神经元功能；然而，神经元不能合成DHA。此外，一个 脂质生物学的中心教条是大脑DHA池在发育过程中建立，并 抵抗晚年生活的操控。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]) 很失望。我们提出了另一种假设，即甘油三酯-DHA(TG-DHA)不太适合 用于通过血脑屏障(BBB)传递DHA。相比之下，识别特定的 溶血磷脂酰胆碱(LPC)血脑屏障转运蛋白(Mfsd2a)为大脑提供了另一种途径 DHA浓缩。而内源性LPC含有很少的DHA(LPC-DHA)，营养食品 可通过多种途径富集血浆LPC-DHA。事实上，我们的数据表明，成人大脑DHA可以 使用LPC-DHA加倍，这种丰富改善了学习和记忆。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，该应用程序的中心假设是 砷介导的脑DHA耗竭会导致晚年神经认知障碍，并且 使用LPC-DHA进行有针对性的救援可防止这些不良后果。重要的是，由于Mfsda2是 在胎盘和血脑屏障中都有表达，我们将询问两种策略。在目标1中，我们将使用 一种预防范式，以检验发育中补充DHA会抵消这一假说 砷可导致DHA耗竭，并防止晚年认知障碍。在《目标2》中，我们将挑战 成人脑DHA停滞学说及断奶后干预的设想 可以恢复DHA水平，挽救神经认知功能。在每个目标上，新的LPC-DHA 干预将与经典的TG-DHA方法和探索性机制研究进行比较 将研究砷暴露与神经认知功能障碍之间的联系。在给定的双重条件下 砷和精神健康疾病的全球威胁，新的、可扩展的干预战略，如 LPC-DHA可能在减少重大的个人和社会痛苦方面大有可为。

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.