Pesticide Exposure and Adult Neurogenesis: Role of ER Stress

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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.