Delayed reduction of hippocampal synaptic transmission and spines following exposure to repeated subclinical doses of organophosphorus pesticide in adult mice.
Delayed reduction of hippocampal synaptic transmission and spines following exposure to repeated subclinical doses of organophosphorus pesticide in adult mice.
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成年小鼠反复接触亚临床剂量的有机磷农药后，海马突触传递和棘的延迟减少。
DOI：
10.1093/toxsci/kfr253
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Powell,CraigM
中科院分区：
文献类型：
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作者：
Speed,HaleyE;Blaiss,CoryA;Kim,Ahleum;Haws,MichaelE;Melvin,NealR;Jennings,Michael;Eisch,AmeliaJ;Powell,CraigM
农业和家用有机磷农药抑制乙酰胆碱酯酶（AchE），导致中枢神经系统乙酰胆碱（Ach）升高。在成人中，急性和长时间暴露于高剂量乙酰胆碱酯酶抑制剂会引起严重的临床明显症状，随后是持久的记忆损伤和认知功能障碍。在环境中反复暴露于低剂量、亚临床剂量的OP农药对成人的神经毒性尚未得到充分研究。然而，反复暴露于乙酰胆碱酯酶抑制剂，如毒死蜱（CPF）、吡哆斯的明和沙林神经毒剂，在流行病学上与海湾战争病的迟发性症状有关，并且可能与农场工人等的环境暴露有关。以亚临床剂量（5 mg/kg） CPF连续5天治疗成年小鼠，观察CPF给药后早期（2-7天）和晚期（3个月）海马突触传递和脊柱密度。在治疗期间或治疗后的任何时间均未观察到胆碱能毒性的迹象。在最后一次注射后2-7天，我们发现cpf处理小鼠海马CA3-CA1区突触传递比对照组增加。相比之下，在CPF给药3个月后，我们观察到突触传递减少了50%，这可能是由于CA1锥体神经元突触棘密度相应减少了50%。这项研究首次确定了反复暴露于OP后突触异常的双相进展，并表明即使在没有急性胆碱能毒性的情况下，反复暴露于CPF也会对体内成人大脑造成延迟的持续性损伤。
Agricultural and household organophosphorus (OP) pesticides inhibit acetylcholinesterase (AchE), resulting in increased acetylcholine (Ach) in the central nervous system. In adults, acute and prolonged exposure to high doses of AchE inhibitors causes severe, clinically apparent symptoms, followed by lasting memory impairments and cognitive dysfunction. The neurotoxicity of repeated environmental exposure to lower, subclinical doses of OP pesticides in adults is not as well studied. However, repeated exposure to acetylcholinesterase inhibitors, such as chlorpyrifos (CPF), pyridostigmine, and sarin nerve agent, has been epidemiologically linked to delayed onset symptoms in Gulf War Illness and may be relevant to environmental exposure in farm workers among others. We treated adult mice with a subclinical dose (5 mg/kg) of CPF for 5 consecutive days and investigated hippocampal synaptic transmission and spine density early (2–7 days) and late (3 months) after CPF administration. No signs of cholinergic toxicity were observed at any time during or after treatment. At 2–7 days after the last injection, we found increased synaptic transmission in the CA3-CA1 region of the hippocampus of CPF-treated mice compared with controls. In contrast, at 3 months after CPF administration, we observed a 50% reduction in synaptic transmission likely due to a corresponding 50% decrease in CA1 pyramidal neuron synaptic spine density. This study is the first to identify a biphasic progression of synaptic abnormalities following repeated OP exposure and suggests that even in the absence of acute cholinergic toxicity, repeated exposure to CPF causes delayed persistent damage to the adult brainin vivo.