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

描述（由申请人提供） 产生软骨藻酸的藻类的有害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临灭绝的物种。人类处于危险之中，后果可能很严重。 尽管建立了海产品检测机制，但对人类潜在接触的担忧仍然存在，包括子宫内接触，这种接触最初可能未被发现，但会产生有害的长期后果。 先前的啮齿动物研究表明，子宫内暴露于软骨藻酸可能会导致海马神经病理学变化和癫痫的发展，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。拟议的项目是一个跨学科的合作， 野生动物兽医和生物医学科学家进行了一项研究，以检验子宫内接触软骨藻酸会导致颞叶癫痫的假设，尽管这种癫痫比成人接触软骨藻酸引起的癫痫要轻。 目的1是测试在子宫内暴露于软骨藻酸是否会导致小鼠颞叶癫痫，并将神经病理学与成年暴露的小鼠进行比较。 目的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来检验加州海狮的假设，预后不良。结果将表明子宫内暴露是否会导致颞叶癫痫的发展，如果是这样，它是否与成人暴露后发展的一样严重。 研究结果将为未来决定是否以及如何进一步评估人类子宫内暴露于软骨藻酸的风险提供信息。此外，Aim 2将从具有大的脑回和自然发生的颞叶癫痫的动物中生成罕见的灌注固定的定量全脑数据，这可以深入了解癫痫发生的机制。 公共卫生相关性：拟议的项目解决了人们日益关注的问题，即当孕妇食用含有天然毒素的海产品时，人类胚胎可能处于危险之中，其水平低于目前的监管限制。研究人员将确定怀孕期间的暴露是否会导致实验室小鼠和自然暴露的海狮的颞叶癫痫。

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. Public Health Relevance: The proposed project addresses growing concerns that human embryos might be at risk when pregnant women consume seafood containing naturally occurring toxins at levels below current regulatory limits. The investigators will determine whether or not exposure during pregnancy can cause temporal lobe epilepsy in laboratory mice and naturally exposed sea lions.