Pesticide Exposure and Adult Neurogenesis: Role of ER Stress

自从限制拟除虫菊酯杀虫剂的使用以来，近年来拟除虫菊酯杀虫剂的使用一直在增加 家用有机磷。溴氰菊酯是一种高效的第二类拟除虫菊酯，在农业上用途广泛。 和住宅应用。在这些人的尿液中发现了可检测到的拟除虫菊酯代谢物 在普通人群中，在杀虫剂施用者中观察到的水平要高得多。最近，神经学 已有报告称，高度接触拟除虫菊酯的个人出现症状。累积暴露于低水平 据推测，杀虫剂的使用会导致神经损伤，但与其影响相关的数据很少 关于认知功能的存在。事实上，对拟除虫菊酯对神经发生的影响进行了严格的定量评估 没有进行过，神经发生和行为的分析也没有同时进行。我们的 初步调查表明，成年小鼠反复暴露于溴氰菊酯，剂量接近最低 可观察到的不良反应水平，导致海马区内质网应激和学习记忆障碍 老鼠。这些效应伴随着齿状回细胞死亡的显著增加和干细胞的减少。 细胞增殖，提示对成人神经发生的潜在影响。基于这些发现，这项研究的目标是 项目包括(1)确定溴氰菊酯对成人神经发生的影响：海马区的形态分析 干细胞增殖及其定位、分化、迁移和命运，(2)探讨干细胞增殖的机制 通过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)从药理学和生物学角度研究内质网应激与海马神经发生的关系 遗传方法。

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.