Department of Pharmacology and Toxicology, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
Neurotoxicol Teratol. 2012 Jan-Feb;34(1):1-8. doi: 10.1016/j.ntt.2011.08.015. Epub 2011 Oct 17.
The acute toxicity of organophosphates (OPs) has been studied extensively; however, much less attention has been given to the subject of repeated exposures that are not associated with overt signs of toxicity (i.e., subthreshold exposures). The objective of this study was to determine if the protracted spatial learning impairments we have observed previously after repeated subthreshold exposures to the insecticide chlorpyrifos (CPF) or the alkylphosphate OP, diisopropylfluorophosphate (DFP) persisted for longer periods after exposure. Male Wistar rats (beginning at two months of age) were initially injected subcutaneously with CPF (10.0 or 18.0mg/kg) or DFP (0.25 or 0.75 mg/kg) every other day for 30 days. After an extended OP-free washout period (behavioral testing begun 50 days after the last OP exposure), rats previously exposed to CPF, but not DFP, were impaired in a radial arm maze (RAM) win-shift task as well as a delayed non-match to position procedure. Later experiments (i.e., beginning 140 days after the last OP exposure) revealed impairments in the acquisition of a water maze hidden platform task associated with both OPs. However, only rats previously exposed to DFP were impaired in a second phase of testing when the platform location was changed (indicative of deficits of cognitive flexibility). These results indicate, therefore, that repeated, subthreshold exposures to CPF and DFP may lead to chronic deficits in spatial learning and memory (i.e., long after cholinesterase inhibition has abated) and that insecticide and alkylphosphate-based OPs may have differential effects depending on the cognitive domain evaluated.
有机磷化合物（OPs）的急性毒性已得到广泛研究；然而，对于没有明显毒性迹象（即阈下暴露）的重复暴露问题，关注较少。本研究的目的是确定我们之前在反复接触杀虫剂氯吡硫磷（CPF）或烷基磷酸酯 OP 二异丙基氟膦（DFP）阈下暴露后观察到的长时间空间学习障碍是否会在暴露后持续更长时间。雄性 Wistar 大鼠（从两个月大开始）最初每隔一天皮下注射 CPF（10.0 或 18.0mg/kg）或 DFP（0.25 或 0.75mg/kg），共 30 天。在延长的无 OP 洗脱期（最后一次 OP 暴露后 50 天开始进行行为测试）后，先前接触 CPF 但未接触 DFP 的大鼠在放射臂迷宫（RAM）赢移任务以及延迟非匹配位置程序中表现出障碍。后来的实验（即在最后一次 OP 暴露后 140 天开始）表明，两种 OP 都与水迷宫隐藏平台任务的获得障碍有关。然而，只有先前接触 DFP 的大鼠在第二阶段测试中表现出障碍，此时平台位置发生变化（表明认知灵活性缺陷）。因此，这些结果表明，重复的阈下接触 CPF 和 DFP 可能导致空间学习和记忆的慢性障碍（即胆碱酯酶抑制消退后很长时间），并且杀虫剂和基于烷基磷酸酯的 OP 可能根据评估的认知领域产生不同的影响。
