Does in utero exposure to domoic acid cause temporal lobe epilepsy?

描述(由申请人提供) 产生软骨藻酸的有害藻类大量繁殖是一个日益严重的问题。受影响的物种包括一些受到威胁或濒危的物种。人类正处于危险之中，后果可能是严重的。尽管建立了海鲜检测机制，但对潜在的人类接触的担忧依然存在，包括在子宫接触中，这可能在一开始没有被发现，但会产生有害的长期后果。以前的啮齿动物研究表明，宫内暴露于软骨藻酸可能会导致海马区的神经病理变化和癫痫的发生，但缺乏自发性癫痫发作的直接证据。调查人员将试图填补这一关键空白。拟议的项目是以下各方之间的跨学科合作 野生动物兽医和生物医学科学家测试这一假说，即宫内暴露于软骨藻酸会导致颞叶癫痫，尽管形式比成人暴露引起的轻微。第一个目的是测试宫内暴露于软骨藻酸是否会导致小鼠的颞叶癫痫，并将其神经病理与成年暴露的小鼠进行比较。目标2是通过评估因软骨藻酸中毒而被安乐死的动物的脑组织，在加州海狮身上验证这一假说，这些动物的预后很差。结果将表明，宫内暴露是否会导致颞叶癫痫的发生，如果是，其严重程度是否与成人暴露后的严重程度相同。这些发现将为未来决定是否以及如何进一步评估宫内暴露于人类软骨藻酸的风险提供依据。此外，Aim 2将生成罕见的、灌流固定的、定量的全脑数据，这些数据来自具有大的脑回回和自然发生的颞叶癫痫的动物，这可能为癫痫发生的机制提供洞察力。

DESCRIPTION (provided by applicant) Harmful blooms of domoic acid-producing algae are a growing problem. Species affected include some that are threatened or endangered. Humans are at risk, and consequences can be severe. Despite established seafood testing mechanisms, concerns about potential human exposures persist, including in utero exposure, which might go undetected initially but have detrimental long-term consequences. Previous rodent studies suggest in utero exposure to domoic acid might cause neuropathological changes in the hippocampus and the development of epilepsy, but direct evidence of spontaneous seizures is lacking. The investigators will attempt to fill this critical gap. The proposed project is an interdisciplinary collaboration among wildlife veterinarians and biomedical scientists to test the hypothesis that in utero exposure to domoic acid causes temporal lobe epilepsy, albeit a milder form than that caused by adult exposure. Aim 1 is to test whether in utero exposure to domoic acid causes temporal lobe epilepsy in mice and to compare the neuropathology to that of mice exposed as adults. Aim 2 is to test the hypothesis in California sea lions by evaluating brain tissue from animals euthanized because of domoic acid toxicosis with a poor prognosis. Results will indicate whether or not in utero exposure can cause temporal lobe epilepsy to develop, and if so, whether it is as severe as that which develops after adult exposure. Findings will inform future decisions on whether and how to further evaluate risks of in utero exposure to domoic acid in humans. In addition, Aim 2 will generate rare, perfusion-fixed, quantitative whole-brain data from animals that have a large, gyrencephalic brain and naturally occurring temporal lobe epilepsy, which could provide insight into mechanisms of epileptogenesis.