DEVELOPMENTAL NEUROTOXICITY OF OP INSECTICIDES

OP 杀虫剂的发育神经毒性

• 批准号: 6748968
• 负责人: Janice Elaine Chambers
• 金额: $ 24.4万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6748968
• 关键词: acetylcholinesterase; adenylate cyclase; choline acetyltransferase; developmental neurobiology; environmental toxicology; enzyme activity; ethology; laboratory rat; neurotoxicology; organophosphorus insecticide; parathion; phosphorylation

Organophosphorus (OP) insecticides are heavily employed in agricultural and residential uses, and have ample opportunity to expose infants and children from food and houses during critical times of their nervous system development. The mechanism of toxicity, inhibition of acetylcholinesterase (AChE), causes hyperactivity in cholinergic pathways, which can elicit compensatory neurochemical mechanisms to modulate the enhanced activity. AChE inhibition is considerably more persistent for the diethyl OP compounds than for the dimethyl OP compounds, leading to greater fluctuations in AChE activity following exposure to a dimethyl insecticide, such as methyl parathion, than to a diethyl insecticide, such as chlorpyrifos. Our preliminary results in rats have indicated more persistent whole brain muscarinic acetylcholine receptor (mAChR) decreases following early postnatal exposures to chlorpyrifos than to methyl parathion. Developmental exposures to OP insecticides cause behavioral deficits. Our preliminary results have indicated decreases in open field activity occurring only after, not during, chlorpyrifos exposures, suggesting possible permanent behavioral deficits from developmental exposures. The biochemical lesion occurs in both the central and peripheral nervous systems because of the distribution of AChE in both, so both central and peripheral effects could contribute to behavioral deficits. The possibility of permanent behavioral defects from the extended neurochemical alterations following AChE inhibition of diethyl OP insecticides has generated the following hypothesis for this project: Neurochemical aberrations and behavioral deficits will be more severe and long lasting from the more persistent phosphorylation of a diethyl OP insecticide (chlorpyrifos) during development than from a dimethyl OP insecticide (methyl parathion). The cholinergic parameters to be studied include: AChE, mAChR (total and surface), choline acetyltransferase, high affinity choline uptake, and adenylyl cyclase in brain regions, and AChE in peripheral tissues. The behavioral parameters to be studied include: developmental markers, surface righting, negative geotaxis, free-fall righting, locomotor activity, rotarod performance, grip strength, and memory and learning in two types of water mazes. The results will indicate whether certain OP insecticide chemistries elicit greater harm to the developing nervous system and whether children are likely to suffer from permanent harm to behavior, including cognition, from developmental exposures to OP insecticides.

有机磷 (OP) 杀虫剂大量用于农业和住宅用途，并且在婴儿和儿童神经系统发育的关键时期有充分的机会使他们接触食物和房屋。毒性机制是抑制乙酰胆碱酯酶（AChE），导致胆碱能通路过度活跃，从而引发补偿性神经化学机制来调节增强的活性。二乙基OP化合物的AChE抑制作用比二甲基OP化合物更持久，导致接触二甲基杀虫剂（例如甲基对硫磷）后AChE活性的波动比接触二乙基杀虫剂（例如毒死蜱）更大。我们对大鼠的初步结果表明，与甲基对硫磷相比，出生后早期接触毒死蜱后，全脑毒蕈碱乙酰胆碱受体（mAChR）下降更持久。发育过程中接触 OP 杀虫剂会导致行为缺陷。我们的初步结果表明，旷场活动仅在毒死蜱暴露后而非毒死蜱暴露期间发生减少，这表明发育暴露可能导致永久性行为缺陷。由于 AChE 在中枢和周围神经系统中的分布，生化损伤同时发生在中枢和周围神经系统中，因此中枢和周围神经系统的影响都可能导致行为缺陷。二乙基 OP 杀虫剂的 AChE 抑制作用后，神经化学物质的长期改变可能会导致永久性行为缺陷，为此项目提出了以下假设：二乙基 OP 杀虫剂的更持久的磷酸化会导致神经化学畸变和行为缺陷更加严重和持久。毒死蜱）在开发过程中的效果优于二甲基 OP 杀虫剂（甲基对硫磷）。要研究的胆碱能参数包括：脑区AChE、mAChR（总和表面）、胆碱乙酰转移酶、高亲和力胆碱摄取和腺苷酸环化酶，以及外周组织中的AChE。要研究的行为参数包括：两种类型水迷宫中的发育标记、表面扶正、负向地性、自由落体扶正、运动活动、旋转性能、握力以及记忆和学习。结果将表明某些 OP 杀虫剂化学成分是否会对发育中的神经系统造成更大的伤害，以及儿童是否可能因发育时期接触 OP 杀虫剂而对行为（包括认知）造成永久性伤害。