Developmental Neurotoxicity of Domoic Acid in a Nonhuman Primate Model

描述（由申请人提供）：软骨藻酸（DA）是导致贝类中毒的原因，是一种天然存在的海洋兴奋性毒素，可污染生活在海洋沃茨的贝类和有鳍鱼类。由有毒藻类产生的DA水平升高变得越来越频繁，人类接触DA已成为食用大量贝类的人群的一个重大公共卫生问题。人类的急性高剂量中毒包括呕吐、痉挛、昏迷和死亡。实验动物研究和人类神经心理学/尸检医学报告共同表明，DA暴露主要影响大脑的海马区，并与癫痫发作和认知过程的中断（例如幻觉，混乱以及短暂和永久性记忆丧失）有关。DA暴露的途径很重要，影响效应的严重程度。虽然已知一些关于发育接触的信息，但研究很少，仅限于啮齿动物模型，并且没有使用与人类健康问题最相关的口服接触途径。软骨藻酸很容易穿过胎盘进入胎儿大脑。软骨藻酸与暴露后代的先天性畸形无关，但与持续的神经行为变化有关，如高反应性、多动性、社会接触减少、退缩和情绪化增加以及空间学习和记忆缺陷。与发育性DA相关的功能丧失可能是持续性的，单次暴露后对CNS的损伤可能是进行性的和严重的。我们提出了第一项研究，使用非人灵长类动物模型，以研究孕产妇和婴儿的影响与慢性，低水平的口服暴露于DA在怀孕期间。我们的实验方法包括母胎毒理学研究、婴儿神经行为评估和后代成像研究，以评估DA诱导的发育中大脑变化。我们的非人灵长类动物模型提供了一个无与伦比的机会，研究这种新兴的兴奋性毒素在亚毒性水平在受控的实验室环境。我们的具体目标是：1）描述妊娠期间DA的母胎转移和处置; 2）确定妊娠前和妊娠期间母体DA暴露对后代出生后神经行为的影响，特别强调对行为反应性、情绪性、体力活动、社会行为和空间记忆的评价; 3）描述 采用脑电生理学（EEG）和最先进的神经影像学技术测量后代神经行为效应与CNS结构和功能变化之间的关系。研究结果将填补我们对这种海洋化合物的认识中的重大数据空白，以及低水平母体暴露可能对高贝类消费者发育中的胎儿造成的危险。

DESCRIPTION (provided by applicant): Domoic acid (DA), the cause of Amnesic Shellfish Poisoning, is a naturally occurring marine excitotoxin that can contaminate shellfish and finfish living in marine waters. Produced by toxic algae, elevated levels of DA are becoming more frequent and human exposure has become a significant public health concern for populations who consume high levels of shellfish. Acute high-dose symptomology in humans includes vomiting, cramping, coma and death. Experimental animal studies and human neuropsychological/autopsy medical reports have collectively shown that DA exposure primarily affects the hippocampal regions of the brain and is associated with seizures and the disruption of cognitive processes (e.g. hallucinations, confusion and both transient and permanent memory loss). The route of DA exposure is important and influences the severity of effects. While some information on developmental exposure is known, studies are few, limited to rodent models and have not used oral exposure, the route most relevant to human health concerns. Domoic Acid readily crosses the placenta and enters the fetal brain. Domoic acid is not associated with congenital dysmorphia in exposed offspring but is linked to persistent neurobehavioral changes such as hyperreactivity, hyperactivity, reduced social contact, increased withdrawal and emotionality and deficits in spatial learning and memory. The functional losses associated with developmental DA can be persistent and injuries to the CNS after a single exposure can be progressive and severe. We propose the first study using a nonhuman primate model to study maternal and infant effects associated with chronic, low-level oral exposure to DA during pregnancy. Our experimental approach includes studies of maternal-fetal toxicokinetics, neurobehavioral assessments of infants and offspring imaging studies to evaluate DA-induced changes in the developing brain. Our nonhuman primate model provides an unmatched opportunity to study this emerging excitotoxin at subtoxic levels in a controlled laboratory setting. Our specific aims are to: 1) characterize the maternal-fetal transfer and disposition of DA during pregnancy 2) determine the offspring postnatal neurobehavioral effects of maternal DA exposure prior to and during pregnancy with special emphasis on evaluation of behavioral reactivity, emotionality, physical activity, social behavior and spatial memory and 3) characterize the relationship between the offspring neurobehavioral effects and structural and functional changes in the CNS with measures of brain electrophysiology (EEG) and state-of-the-art neuroimaging techniques. Results will fill significant data gaps in our knowledge of this marine compound and the danger that low-level maternal exposure may pose to the developing fetus for high shellfish consumers.