Neurotoxicity of organophosphorus pesticides in developing guinea pigs

有机磷农药对发育中豚鼠的神经毒性

• 批准号: 8497688
• 负责人: Edson X Albuquerque
• 金额: $ 55.42万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-06 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8497688
• 关键词: 3 year old; Accounting; Acetylcholinesterase Inhibitors; Acute; Address; Affect; Age; Alzheimer' s Disease; Animal Behavior; Animal Testing; Animals; Antidotes; Area; Attention deficit hyperactivity disorder; Behavioral; Biological Assay; Birth; Brain; Carboxylic Ester Hydrolases; Cavia; ChIP-on-chip; Child; Chlorpyrifos; Cognitive; Development; Dicarboxylic Acids; Dose; Effectiveness; Electroencephalogram; Emotional; Enzymes; Epidemiologic Studies; Epigenetic Process; Exposure to; Female; Galantamine; Gene Expression; Goals; Health; Histone Acetylation; Histopathology; Human; Image; Immunohistochemistry; Impaired cognition; Impairment; Incidence; Intoxication; Laboratory Animals; Lead; Magnetic Resonance Imaging; Malathion; Maternal Exposure; Medical; Metabolic; Metabolism; Microarray Analysis; Modeling; Molecular; Molecular Target; Monitor; Mothers; Mus; Nervous system structure; Neurologic; Oral; Organophosphorus Compounds; Pest Control; Pesticides; Pharmaceutical Preparations; Phosphorylation; Placenta; Poisoning; Pregnancy; Rattus; Reporting; Research; Risk; Rodent; Rodent Model; Soman; Structure; Synaptic Transmission; Synaptic plasticity; Testing; Toxic effect; Treatment Effectiveness; Urine; Uterus; Western Blotting; abnormal reflex; autism spectrum disorder; brain electrical activity; carboxylesterase; chromatin immunoprecipitation; design; developmental neurotoxicity; histone modification; interdisciplinary approach; male; mental development; mind control; mouse development; neonate; nervous system disorder; neurobehavioral; neurobehavioral test; neurodevelopment; neurotoxicity; novel therapeutics; offspring; pesticide poisoning; postnatal; pregnant; prenatal exposure; prevent; public health relevance; research study; sex; synaptic function; therapeutic effectiveness; translational study

DESCRIPTION (provided by applicant): Organophosphorus (OP) pesticides are among the most heavily used pest control agents worldwide. In the US, malathion and chlorpyrifos account for more than 50% of the millions of pounds of OP pesticides used yearly. An ever growing body of epidemiological studies report that children whose mothers have been exposed to OP pesticides, including chlorpyrifos and malathion, during pregnancy present higher incidence of cognitive impairments, attention deficit/hyperactivity disorder, and autism spectrum disorders than non-exposed children. Although animal studies have confirmed that in-uterus or early postnatal exposure to chlorpyrifos compromises the brain development of rats and mice, the distinct temporal course of brain development and high levels of circulating carboxylesterases (enzymes that inactivate OP compounds) make these rodents inadequate models of human OP toxicity. In addition, even though concerns regarding the toxicity of OPs to the developing brain have been substantiated by their prompt permeation through the placenta, there have been no animal studies addressing the potential developmental toxicity of malathion. The present project is designed to test the central hypothesis that the developmental neurotoxicity of malathion and chlorpyrifos in guinea pigs - the best non-primate model of human OP intoxication - can be counteracted by galantamine and is largely accounted for by epigenetic mechanisms. Galantamine, a drug approved to treat Alzheimer's disease, is known to safely and effectively protect guinea pigs against the acute toxicity of OP compounds [PNAS 103: 13220, 2006]. Galantamine can also prevent the delayed cognitive dysfunctions that result from a single exposure of guinea pigs to sub-toxic doses of OPs. This project uses a multidisciplinary approach that involves electrophysiological, behavioral, magnetic resonance imaging and molecular biological assays to address three specific aims: (i) to identify, at various postnatal ages, neurological, structural, and neurobehavioral correlates of in-uterus exposure of guinea pigs to malathion or chlorpyrifos, (ii) to determine the effectiveness of postnatal treatment with galantamine to counteract the developmental toxicity of those pesticides, and (iii) to examine the contribution of epigenetic mechanisms to the developmental toxicity of the pesticides and the therapeutic effectiveness of galantamine. The overarching goal of this project is to provide fundamental and timely input for assessment and adequate treatment of the human developmental toxicity of malathion and chlorpyrifos. The results of this highly translational study of the potential health risks associated with exposure of the immature brain to pesticides will be far reaching as they will lay the groundwork necessary to advance research aimed at identifying novel therapeutic strategies to treat neurological diseases derived from in-uterus exposure to specific OP pesticides.

描述（由申请人提供）：有机磷（OP）农药是全球使用最严重的害虫控制剂之一。在美国，马拉硫翁和毒死rif占每年使用的数百万磅农药的50％以上。越来越多的流行病学研究报告说，在怀孕期间，母亲暴露于包括毒死rif虫和马拉硫化在内的OP农药的孩子表现出比无暴露儿童更高的认知障碍，注意力不足/多动障碍以及自闭症谱系障碍的发生率更高。尽管动物研究已经证实，乌田内或早期暴露于毒死rif的暴露会损害大鼠和小鼠的大脑发育，脑发育的独特时间过程以及高水平的循环羧酸酯酶（灭活OP化合物）使这些啮齿动物不足的模型不足人类OP毒性。此外，即使对OP对发育大脑的毒性的担忧已经通过胎盘的迅速渗透来证实，但没有动物研究来解决马拉硫磷的潜在发育毒性。本项目旨在检验中心假设：豚鼠中马拉硫酮和毒性rif的发育神经毒性 - 人类OP中毒的最佳非青调模型 - 可以由甘兰氨基氨酸来抵消，并由表观遗传机制在很大程度上解释。众所周知，Galantamine是一种批准治疗阿尔茨海默氏病的药物，可以安全有效地保护豚鼠免受OP化合物的急性毒性[PNAS 103：13220，2006]。甘氨酸还可以防止由豚鼠单次暴露于OP的毒性剂量的延迟认知功能障碍。该项目使用涉及电生理，行为，磁共振成像和分子生物学测定的多学科方法来解决三个具体目标：（i）在各种产后年龄，神经学，结构和神经行为群体中识别几内亚几内亚内属内部的神经行为相关性猪到马拉硫磷或毒性里利，（ii）确定使用甘氨酸后产后治疗以抵消这些农药的发育毒性的有效性，以及（iii）检查表观遗传机制对农药和农药发育毒性的贡献甘坦明。该项目的总体目标是提供基本和及时的投入，以评估和适当治疗马拉硫磷和毒死rif的人类发育毒性。这项对与未成熟大脑接触农药相关的潜在健康风险的高度转化研究的结果将是遥不可及的，因为它们将为促进旨在识别识别从乌塔鲁斯造成的神经系统疾病的新型治疗策略提供必要的基础研究。暴露于特定的OP农药。

项目成果

Developmental neurotoxicity of the organophosphorus insecticide chlorpyrifos: from clinical findings to preclinical models and potential mechanisms.

• DOI: 10.1111/jnc.14077
• 发表时间: 2017-08
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Burke RD;Todd SW;Lumsden E;Mullins RJ;Mamczarz J;Fawcett WP;Gullapalli RP;Randall WR;Pereira EFR;Albuquerque EX
• 通讯作者: Albuquerque EX