Developmental Neurotoxicity of Domoic Acid in a Nonhuman Primate Model

说明(申请人提供)：软骨藻酸(DA)是一种天然存在的海洋刺激性毒素，可污染生活在海水中的贝类和鳍类，是健忘性贝类中毒的原因。由有毒藻类产生的DA水平升高正变得越来越频繁，人类接触已成为食用高水平贝类的人群的一个重大公共卫生问题。人类的急性大剂量症状包括呕吐、抽筋、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中断(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，并影响影响的严重程度。虽然关于发育过程中暴露的一些信息是已知的，但研究很少，仅限于啮齿动物模型，还没有使用与人类健康问题最相关的途径--口腔暴露。软骨藻酸很容易通过胎盘进入胎儿大脑。软骨藻酸与暴露的后代的先天性变形障碍无关，但与持续性神经行为变化有关，如高反应性、多动症、社交减少、退缩和情绪性增加以及空间学习和记忆障碍。与发育性DA相关的功能丧失可能是持续性的，单次暴露后对中枢神经系统的损伤可能是进行性的和严重的。我们提出了第一项使用非人类灵长类动物模型来研究怀孕期间长期、低水平口服DA对母婴影响的研究。我们的实验方法包括母婴毒代动力学研究、婴儿神经行为评估和后代成像研究，以评估DA在发育中的大脑的变化。我们的非人类灵长类动物模型提供了一个无与伦比的机会，在受控的实验室环境中研究这种亚毒性水平的新出现的兴奋性毒素。我们的具体目标是：1)描述怀孕期间DA的母胎转移和处置2)确定孕前和怀孕期间母亲暴露于DA对后代的神经行为影响，特别强调评估行为反应性、情绪性、体力活动、社会行为和空间记忆以及3)表征 用脑电生理(EEG)和最先进的神经成像技术研究子代神经行为效应与中枢神经系统结构和功能变化的关系。结果将填补我们对这种海洋化合物的了解的重大数据空白，以及对于高贝类消费者来说，低水平的母体接触可能对发育中的胎儿构成的危险。

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.