Neurotoxicity of organophosphorus pesticides in developing guinea pigs

描述（由申请人提供）：有机磷（OP）农药是世界上使用最广泛的害虫防治剂之一。在美国，每年使用的数百万磅有机磷农药中，马拉硫磷和毒死蜱占了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杀虫剂（包括毒死蜱和马拉硫磷）的儿童，其认知障碍、注意力缺陷/多动障碍和自闭症谱系障碍的发生率高于未接触过杀虫剂的儿童。虽然动物研究已经证实，在子宫内或产后早期暴露于毒死蜱会损害大鼠和小鼠的大脑发育，但大脑发育的不同时间过程和高水平的循环羧酸酯酶（使OP化合物失活的酶）使这些啮齿动物不适合作为人类OP毒性的模型。此外，尽管对OPs对发育中的大脑的毒性的担忧已经通过其迅速渗透胎盘得到证实，但还没有针对马拉硫磷潜在发育毒性的动物研究。目前的项目旨在验证一个中心假设，即马拉硫磷和毒死蜱对豚鼠（人类OP中毒的最佳非灵长类模型）的发育性神经毒性可以被加兰他明抵消，并且在很大程度上是由表观遗传机制造成的。加兰他明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: 1322, 2006]。加兰他敏还可以预防由于豚鼠单次接触亚毒性剂量的OPs而导致的迟发性认知功能障碍。该项目采用多学科方法，包括电生理、行为、磁共振成像和分子生物学分析，以解决三个具体目标：(1)确定在不同出生年龄的豚鼠子宫内暴露于马拉硫磷或毒死蜱的神经、结构和神经行为相关性；(2)确定用加兰他敏产后治疗以抵消这些农药的发育毒性的有效性；(3)检查表观遗传机制对农药发育毒性的贡献以及加兰他敏的治疗效果。该项目的总体目标是为马拉硫磷和毒死蜱的人体发育毒性评估和适当治疗提供基本和及时的投入。这项对未成熟大脑暴露于农药相关的潜在健康风险的高度转化性研究的结果将具有深远的意义，因为它们将为推进旨在确定治疗子宫内暴露于特定OP农药引起的神经系统疾病的新治疗策略的研究奠定必要的基础。

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. PUBLIC HEALTH RELEVANCE: The overarching goal of this project is to provide fundamental and timely input for assessment of the human developmental toxicity of malathion and chlorpyrifos and identification of lead compounds for adequate treatment of neurological diseases that result from in-uterus exposure to these pesticides.