title: Hippocampal ER stress and learning deficits following repeated pyrethroid exposure.
abstract: Endoplasmic reticulum (ER) stress is implicated as a significant contributor to neurodegeneration and cognitive dysfunction. Previously, we reported that the widely used pyrethroid pesticide deltamethrin causes ER stress-mediated apoptosis in SK-N-AS neuroblastoma cells. Whether or not this occurs in vivo remains unknown. Here, we demonstrate that repeated deltamethrin exposure (3 mg/kg every 3 days for 60 days) causes hippocampal ER stress and learning deficits in adult mice. Repeated exposure to deltamethrin caused ER stress in the hippocampus as indicated by increased levels of C/EBP-homologous protein (131%) and glucose-regulated protein 78 (96%). This was accompanied by increased levels of caspase-12 (110%) and activated caspase-3 (50%). To determine whether these effects resulted in learning deficits, hippocampal-dependent learning was evaluated using the Morris water maze. Deltamethrin-treated animals exhibited profound deficits in the acquisition of learning. We also found that deltamethrin exposure resulted in decreased BrdU-positive cells (37%) in the dentate gyrus of the hippocampus, suggesting potential impairment of hippocampal neurogenesis. Collectively, these results demonstrate that repeated deltamethrin exposure leads to ER stress, apoptotic cell death in the hippocampus, and deficits in hippocampal precursor proliferation, which is associated with learning deficits.
authors.affiliation: *Department of Environmental and Occupational Medicine, Rutgers-Robert Wood Johnson Medical School, and Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey 08854; and Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Hossain
authors.affiliation: *Department of Environmental and Occupational Medicine, Rutgers-Robert Wood Johnson Medical School, and Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey 08854; and Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
authors.forename: Emanuel
authors.initials: E
authors.lastname: DiCicco-Bloom
authors.affiliation: *Department of Environmental and Occupational Medicine, Rutgers-Robert Wood Johnson Medical School, and Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey 08854; and Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854 jricha3@eohsi.rutgers.edu.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Richardson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D053454:Caspase 12 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007306:Insecticides / Q000633:toxicity*; D007859:Learning Disabilities / Q000139:chemically induced* / Q000503:physiopathology / Q000523:psychology; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects; D009570:Nitriles / Q000633:toxicity*; D011722:Pyrethrins / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007306:Insecticides; D009570:Nitriles; D011722:Pyrethrins; D051742:Transcription Factor CHOP; C017180:decamethrin; C506440:Casp12 protein, mouse; C505409:Casp3 protein, mouse; D053454:Caspase 12; D053148:Caspase 3
keywords: ER stress; adult neurogenesis; deltamethrin; hippocampus; water maze