Vulnerability of the Adolescent Brain to Organophosphorus Pesticides

描述（由申请人提供）：尽管人类和动物研究的证据明确将神经毒性确定为主要不良终点;但对重复职业和环境暴露于有机磷农药（OP）的长期影响仍知之甚少。还迫切需要调查儿童和青少年对农药的敏感性，因为发育中的大脑可能对这些药剂的神经毒性作用特别敏感。我们与埃及Menoufia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，这些青少年是棉花作物的杀虫剂施用者。基于这些初步研究结果，我们提出了一项纵向研究，以调查农药暴露，影响和易感性的敏感和特异性生物标志物之间的关系，以及在这个独特的队列中，在5年内评估累积和潜在的可逆影响的神经行为功能的多种措施。 我们的总体假设是，发育中的青少年大脑的固有可塑性将允许从与短期和长期暴露于农药相关的选定神经行为缺陷中恢复。有三个目标针对这一假设，扩大在R21项目中开始的成功努力，在Menoufia建立研究技能，并与农业部合作确定易感人群，并采取适当措施减少农药接触。目的1将确定农药暴露和神经行为功能之间的关联在青少年队列与职业（施药者）或环境（非施药者）暴露的纵向研究，以测试的假设，即短期暴露相关的神经行为表现缺陷发生在应用季节，但有选定的神经行为功能域的恢复后，夏季喷洒季节结束。有些不足可能会持续到喷洒季节之后或重复的夏季喷洒季节之后。基于生物学的接触评估将包括毒死蜱和丙溴磷（OP）和甲-氯氰菊酯（拟除虫菊酯）的尿液代谢物水平以及参与OP代谢的关键酶（CYP2B6、CYP2C19和PON1）的功能多态性，作为生物有效剂量的修正剂。目标2将通过建立一个研究所来扩大Menoufia大学的研究能力，该研究所将：（a）建立流行病学研究能力（B）在当地举办的射击课程中并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个有竞争力的研究文化。目标3将为农业部工作人员（包括施药人员）制定一项培训方案，内容是如何通过卫生、行为（工作实践）改变和使用防护设备来减少接触，解决环境（家庭）和职业接触问题。随机对照试验设计将评估培训计划对反应、行为和知识（学习和记忆）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).