Vulnerability of the Adolescent Brain to Organophosphorus Pesticides

描述(由申请人提供)：尽管来自人类和动物研究的证据清楚地将神经毒性确定为主要的不利终点；但反复接触有机磷杀虫剂(OP)的职业和环境长期影响仍然知之甚少。还迫切需要调查儿童和青少年对杀虫剂的敏感性，因为发育中的大脑可能对这些药物的神经毒性影响特别敏感。我们与埃及梅努菲亚大学的同事合作，对为农业部工作的青少年进行了一项试点研究，他们是棉花作物的杀虫剂施用者。在这些初步发现的基础上，我们建议进行一项纵向研究，以调查农药暴露、影响和易感性的敏感和特定生物标记物与这一独特队列中神经行为功能的多项指标之间的关系，以评估累积和潜在的可逆影响。 我们的主要假设是，发育中的青春期大脑的固有可塑性将允许从与短期和长期接触杀虫剂相关的选定神经行为缺陷中恢复。三个目标是解决这一假设，扩大在R21项目中开始的成功努力，在Menoufia建立研究技能，与农业部合作确定易感人群并采取适当措施减少农药暴露。目的1在职业(施药者)或环境(非施药者)暴露的青少年队列中进行纵向研究，以确定农药暴露与神经行为功能之间的关系，以检验以下假设：与短期暴露相关的神经行为表现缺陷发生在施药季节，但选定的神经行为功能领域在夏季喷洒季节结束后会恢复。有些缺陷可能会持续到喷雾季节之后或反复出现夏季喷雾季节之后。以生物为基础的暴露评估将纳入尿毒死磷、丙硫磷(OP)和α-氯氰菊酯(拟除虫菊酯)代谢物的水平，以及OP代谢关键酶(CYP2B6、CYP2C19和PON1)的功能多态，作为生物有效剂量的修饰物。AIM 2将通过建立一个研究所来扩大梅努菲亚大学的研究能力，该研究所将：(A)建立流行病学研究能力；(B)在当地举办的Sort课程和通过视频会议教授赠款撰写和研究技能；(C)提供指导和国际教育经验；以及(D)实施试点项目研究方案。这是为了在梅努菲亚大学创造一种有竞争力的研究文化。目标3将为农业部工人(包括施用者)制定一项培训方案，介绍如何通过卫生、行为(工作惯例)改变和使用防护设备减少暴露，解决环境(家庭)和职业暴露问题。随机对照试验设计将评估训练计划对反应、行为和知识(学习和保持)的影响。

DESCRIPTION (provided by applicant): Despite evidence from human and animal studies that clearly identifies neurotoxicity as the primary adverse endpoint; the long-term effects of repeated occupational and environmental exposures to organophosphorus pesticides (OPs) remain poorly understood. There is also a critical need to investigate the susceptibility of children and adolescents to pesticides, since the developing brain may be uniquely sensitive to the neurotoxic effects of these agents. Partnering with colleagues at Egypt's Menoufia University, we conducted a pilot study of adolescents working for the Ministry of Agriculture as pesticide applicators for the cotton crop. Building on these preliminary findings, we propose a longitudinal study to investigate the relationship between sensitive and specific biomarkers of pesticide exposure, effect and susceptibility and multiple measures of neurobehavioral function in this unique cohort over a 5 year period to assess cumulative and potentially reversible effects. Our overarching hypothesis is that the inherent plasticity of the developing adolescent brain will allow recovery from selected neurobehavioral deficits associated with short- and long-term exposures to pesticides. Three aims address this hypothesis, expand on the successful efforts begun in the R21 project, to build research skills at Menoufia and work with the Ministry of Agriculture to identify susceptible populations and put into place appropriate measures to reduce pesticide exposure. Aim 1 will determine the association between pesticide exposure and neurobehavioral function in a longitudinal study among adolescent cohorts with occupational (applicators) or environmental (non-applicators) exposures to test the hypothesis that neurobehavioral performance deficits associated with short-term exposure occur during the application season but that there is recovery of selected neurobehavioral functional domains after the summer spray season ends. Some deficits may persist beyond the spray season or after repeated summer spray seasons. A biologically- based exposure assessment will incorporate levels of urinary metabolites of chlorpyrifos and profenophos (OPs) and alpha-cypermethrin (pyrethroid) and functional polymorphisms in key enzymes involved in OP metabolism (CYP2B6, CYP2C19, and PON1) as modifiers of bioeffective dose. Aim 2 will expand the research capacity at Menoufia University by establishing a Research Institute that will: (a), build epidemiologic research capacity (b) teach grant writing and research skills in shot courses held locally and through videoconferences, (c) provide mentoring and international education experiences, and (d) implement a pilot project research program. This is designed to create a competitive research culture at Menoufia University. Aim 3 will develop a training program for the Ministry of Agriculture workers (including applicators) on ways to reduce exposure through hygiene, behavior (work practice) change and use of protective equipment, addressing both environmental (home) and occupational exposures. A randomized controlled trial design will evaluate the impact of the training program on reaction, behavior, and knowledge (learning and retention).