Pesticide Exposure and Adult Neurogenesis: Role of ER Stress

自限制使用杀虫剂以来， 家用有机磷。溴氰菊酯是一种高效的II型拟除虫菊酯，在农业上有着广泛的应用 和住宅应用。已在受试者的尿液中发现可检测水平的拟除虫菊酯代谢物。 在一般人群中，在农药施用者中观察到的水平要高得多。最近，神经学 据报告，高度接触拟除虫菊酯的个人出现了症状。低水平累积接触 农药的使用被认为会导致神经损伤，但很少有数据与其影响有关。 认知功能的存在。事实上，严格定量评估拟除虫菊酯对神经发生的影响， 尚未进行，也没有平行进行神经发生和行为的分析。我们 初步研究表明，成年小鼠重复暴露于溴氰菊酯，剂量接近最低 可观察到的不良反应水平，导致海马中的ER应激以及学习和记忆的缺陷， 小鼠这些效应伴随着齿状回细胞死亡的显著增加和干细胞减少。 细胞增殖，表明对成体神经发生的潜在影响。基于这些发现，本研究的目标 本课题包括：（1）确定溴氰菊酯对成年大鼠神经发生的影响：海马神经元的形态学分析 干细胞增殖及其定位、分化、迁移和命运，（2）探讨其机制 溴氰菊酯暴露导致海马神经发生中断和认知功能障碍，以及 3)通过药理学和生物学手段， 基因方法。

The use of pyrethroid insecticides has been increasing over recent years since the restriction of organophosphates for household use. Deltamethrin is a potent type II pyrethroid with extensive use in agriculture and residential applications. Detectable levels of pyrethroid metabolites have been found in the urine of the general population, with much higher levels observed in pesticide applicators. More recently, neurological symptoms in individuals highly exposed to pyrethroids have been reported. Cumulative exposure to low levels of pesticides has been hypothesized to contribute to neurological impairment, yet few data related to their effects on cognitive function exist. Indeed, rigorous quantitative assessment of pyrethroid effects on neurogenesis has not been performed, nor have analyses of neurogenesis and behavior been performed in parallel. Our preliminary investigations indicate that repeated exposure of adult mice to deltamethrin, at a dose near the lowest observable adverse effect level, causes ER stress in the hippocampus and deficits in learning and memory in mice. These effects were accompanied by marked increases in dentate gyrus cell death and reductions in stem cell proliferation, suggesting potential effects on adult neurogenesis. Based on these findings, the goals of this project include (1) define deltamethrin effects on adult neurogenesis: morphological analyses of hippocampal stem cell proliferation and their localization, differentiation, migration, and fate, (2) investigate the mechanisms by which deltamethrin exposure leads to disruption of hippocampal neurogenesis and cognitive dysfunction, and 3) characterize the relationship between ER stress and hippocampal neurogenesis through pharmacological and genetic approaches.