Peng Y G, Clayton E C, Means L W, Ramsdell J S
Marine Biotoxins Program, NOAA Southeast Fisheries Science Center Charleston Laboratory, South Carolina, USA.
Fundam Appl Toxicol. 1997 Nov;40(1):63-7. doi: 10.1006/faat.1997.2360.
Domoic acid (DA) is an environmental neurotoxin to humans. This work examines whether repeated exposure to subsymptomatic or symptomatic nonlethal doses of domoic acid leads to enhanced symptomatic toxicity in ICR outbred and DBA inbred strains of laboratory mice. A multiple independent exposure paradigm was designed in which doses were administered intraperitoneally every other day for 7 days to achieve four separate exposures to domoic acid. We first examined the effect of repeated exposure on serum clearance of domoic acid. Serum domoic acid levels did not differ following a single or repeated exposure. We next examined the effect of repeated exposure on symptomatic toxicity. The mean toxicity scores did not show a significant difference between single and repeated exposures of either subsymptomatic (0.5 mg/kg) or symptomatic sublethal (2.0 mg/kg) doses of domoic acid. We then examined the effects of repeated domoic acid exposure on a second strain of mouse. DBA mice were chosen based upon their sensitivity to kainic acid-induced seizures; however, the ICR mice were more sensitive to low-dose domoic acid toxicity, particularly in terms of onset and duration of stereotypic scratching behavior. Our results indicate that both strains of mice have comparable concentration-dependent toxic responses to domoic acid; however, differences exist in the magnitude of the response and in specific symptoms. The mean toxicity scores did not show a significant difference when a single exposure (1.0 and 2.0 mg/kg domoic acid) and repeated exposure of the same dose were compared in the DBA mice. This study provides no evidence that short-term repeated exposure to domoic acid in laboratory mice alters domoic acid clearance from the serum, or leads to a more sensitive or a greater neurotoxic response.
软骨藻酸（DA）是一种对人类具有环境毒性的神经毒素。本研究旨在探讨反复暴露于亚症状或症状性非致死剂量的软骨藻酸是否会导致ICR远交系和DBA近交系实验小鼠的症状性毒性增强。设计了一种多组独立暴露范式，每隔一天腹腔注射给药，持续7天，以实现对软骨藻酸的四次单独暴露。我们首先研究了反复暴露对软骨藻酸血清清除率的影响。单次或反复暴露后血清软骨藻酸水平无差异。接下来，我们研究了反复暴露对症状性毒性的影响。对于亚症状剂量（0.5mg/kg）或症状性亚致死剂量（2.0mg/kg）的软骨藻酸，单次暴露和反复暴露之间的平均毒性评分没有显著差异。然后，我们研究了反复暴露于软骨藻酸对另一品系小鼠的影响。选择DBA小鼠是基于它们对 kainic 酸诱导的癫痫发作的敏感性；然而，ICR小鼠对低剂量软骨藻酸毒性更敏感，特别是在刻板抓挠行为的发作和持续时间方面。我们的结果表明，两种品系的小鼠对软骨藻酸都有类似的浓度依赖性毒性反应；然而，在反应程度和特定症状方面存在差异。在DBA小鼠中，当比较单次暴露（1.0和2.0mg/kg软骨藻酸）和相同剂量的反复暴露时，平均毒性评分没有显著差异。本研究没有提供证据表明实验小鼠短期反复暴露于软骨藻酸会改变血清中软骨藻酸的清除率，或导致更敏感或更大的神经毒性反应。
