Spatial learning impairment in prepubertal guinea pigs prenatally exposed to the organophosphorus pesticide chlorpyrifos: Toxicological implications
Spatial learning impairment in prepubertal guinea pigs prenatally exposed to the organophosphorus pesticide chlorpyrifos: Toxicological implications
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DOI：
10.1016/j.neuro.2016.06.008
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发表时间：
2016-09-01
期刊：
影响因子：
3.4
通讯作者：
Albuquerque, Edson X.
中科院分区：
文献类型：
--
作者：
Mamczarz, Jacek;Pescrille, Joseph D.;Albuquerque, Edson X.
发育中的大脑暴露于毒死蜱（CPF），一种在世界各地农业中广泛使用的有机磷（OP）农药，与儿童，特别是男孩认知缺陷的患病率增加有关。本研究的目的是测试的假设，产前暴露于亚急性剂量的CPF引起的认知缺陷可以复制早熟的小物种。为了解决这一假设，将妊娠豚鼠每天注射CPF（25 mg/kg，s.c.）或溶剂（花生油），从推定妊娠日（GD）53-55开始给药10天。后代在GD 65左右出生，在出生后第20天（PND）断奶，并在PND 30左右开始接受行为测试。在出生当天，丁酰胆碱酯酶（BuChE），OP生物清除剂作为OP暴露的生物标志物，和乙酰胆碱酯酶（AChE），OP化合物的主要分子靶点，显着抑制在血液中的CPF暴露后代。在他们的大脑中，BuChE，而不是AChE，被显著抑制。产前CPF暴露对自发活动或自发习惯没有显着影响，这是一种在开放领域评估的非联想记忆形式。在Morris水迷宫（MWM）中，豚鼠的空间导航被发现是两性异形的，雄性表现优于雌性。产前CPF暴露受损的空间学习更显着的男性比女性豚鼠，因此，减少了任务的性别二型性。这里给出的结果，这有力地支持了测试假设，表明豚鼠是一个有价值的动物模型的OP农药的发育神经毒性的临床前评估。这些发现意义深远，因为它们为未来的研究奠定了基础，旨在确定治疗干预措施，以治疗和/或预防CPF在发育中的大脑中的神经毒性作用。(C)2016由Elsevier B. V.出版
Exposure of the developing brain to chlorpyrifos (CPF), an organophosphorus (OP) pesticide used extensively in agriculture worldwide, has been associated with increased prevalence of cognitive deficits in children, particularly boys. The present study was designed to test the hypothesis that cognitive deficits induced by prenatal exposure to sub-acute doses of CPF can be reproduced in precocial small species. To address this hypothesis, pregnant guinea pigs were injected daily with CPF (25 mg/kg, s.c.) or vehicle (peanut oil) for 10 days starting on presumed gestation day (GD) 53-55. Offspring were born around GD 65, weaned on postnatal day (PND) 20, and subjected to behavioral tests starting around PND 30. On the day of birth, butyrylcholinesterase (BuChE), an OP bioscavenger used as a biomarker of OP exposures, and acetylcholinesterase (AChE), a major molecular target of OP compounds, were significantly inhibited in the blood of CPF-exposed offspring. In their brains, BuChE, but not AChE, was significantly inhibited. Prenatal CPF exposure had no significant effect on locomotor activity or on locomotor habituation, a form of non-associative memory assessed in open fields. Spatial navigation in the Morris water maze (MWM) was found to be sexually dimorphic among guinea pigs, with males outperforming females. Prenatal CPF exposure impaired spatial learning more significantly among male than female guinea pigs and, consequently, reduced the sexual dimorphism of the task. The results presented here, which strongly support the test hypothesis, reveal that the guinea pig is a valuable animal model for preclinical assessment of the developmental neurotoxicity of OP pesticides. These findings are far reaching as they lay the groundwork for future studies aimed at identifying therapeutic interventions to treat and/or prevent the neurotoxic effects of CPF in the developing brain. (C) 2016 Published by Elsevier B.V.