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）农药是全世界使用最广泛的害虫防治剂之一。在美国，马拉硫磷和毒死蜱占每年使用的数百万磅有机磷农药的 50% 以上。越来越多的流行病学研究报告称，母亲在怀孕期间接触过有机磷农药（包括毒死蜱和马拉硫磷）的儿童，其认知障碍、注意力缺陷/多动症和自闭症谱系障碍的发生率高于未接触过的儿童。尽管动物研究已证实，在子宫内或产后早期接触毒死蜱会损害大鼠和小鼠的大脑发育，但大脑发育的独特时间过程和高水平的循环羧酸酯酶（使 OP 化合物失活的酶）使这些啮齿类动物不适合作为模型人类OP毒性。此外，尽管OPs对发育中大脑的毒性的担忧已经通过胎盘的迅速渗透得到证实，但还没有动物研究解决马拉硫磷的潜在发育毒性。本项目旨在测试以下中心假设：马拉硫磷和毒死蜱对豚鼠（人类OP中毒的最佳非灵长类动物模型）的发育神经毒性可以被加兰他敏抵消，并且很大程度上是通过表观遗传机制来解释的。加兰他敏是一种被批准用于治疗阿尔茨海默病的药物，已知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]。加兰他敏还可以预防因豚鼠单次接触亚毒剂量的有机磷农药而导致的迟发性认知功能障碍。该项目采用涉及电生理学、行为学、磁共振成像和分子生物学测定的多学科方法来实现三个具体目标：(i) 确定几内亚在不同出生后年龄的神经学、结构和神经行为相关性与子宫内暴露的相关性猪对马拉硫磷或毒死蜱的影响，(ii) 确定加兰他敏产后治疗的有效性，以抵消这些农药的发育毒性，以及 (iii) 检查农药发育毒性和加兰他敏治疗效果的表观遗传机制。该项目的总体目标是为评估和充分治疗马拉硫磷和毒死蜱的人类发育毒性提供基本和及时的投入。这项关于未成熟大脑接触农药所带来的潜在健康风险的高度转化性研究的结果将具有深远的影响，因为它们将为推进旨在确定治疗子宫内神经系统疾病的新治疗策略的研究奠定必要的基础。接触特定的有机磷农药。

项目成果

Spatial learning impairment in prepubertal guinea pigs prenatally exposed to the organophosphorus pesticide chlorpyrifos: Toxicological implications.

产前暴露于有机磷农药毒死蜱的青春期前豚鼠的空间学习障碍：毒理学影响。

• 发表时间: 2016-09
• 影响因子: 3.4
• 作者: Mamczarz, Jacek;Pescrille, Joseph D;Gavrushenko, Lisa;Burke, Richard D;Fawcett, William P;DeTolla Jr, Louis J;Chen, Hegang;Pereira, Edna F R;Albuquerque, Edson X
• 通讯作者: Albuquerque, Edson X

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

有机磷杀虫剂毒死蜱的发育神经毒性：从临床发现到临床前模型和潜在机制。

• 发表时间: 2017-08
• 影响因子: 4.7
• 作者: Burke, Richard D;Todd, Spencer W;Lumsden, Eric;Mullins, Roger J;Mamczarz, Jacek;Fawcett, William P;Gullapalli, Rao P;Randall, William R;Pereira, Edna F R;Albuquerque, Edson X
• 通讯作者: Albuquerque, Edson X