Persistent proteomic changes in glutamatergic and GABAergic signaling in the amygdala of adolescent rats exposed to chlorpyrifos as juveniles |
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| Affiliation: | 1. Department of Population Health, College of Health Sciences, Sam Houston State University, 1901 Ave I, CHSS Suite 432, Huntsville, TX, 77341, USA;2. Department of Occupational and Environmental Health Science, College of Health and Human Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, IN 47907;3. Department of Psychology and Philosophy, College of Humanities and Social Sciences, Sam Houston State University, 1905 University Ave, Huntsville, TX, 77340, USA;4. U-Chicago Research Bangladesh Ltd., House 04, Road 2B, Sector 4, Uttara, Dhaka, 1230, Bangladesh;5. Department of Environmental and Occupational Health, School of Public Health, Indiana University-Bloomington, 1025 E 7thStreet, Room 029, Bloomington, IN, 47405, USA;6. Department of Environmental Health, Mailman School of Public Health, Columbia University, 722 W, 168thStreet, New York, NY, 10032, USA;7. Department of Occupational and Environmental Health, College of Public Health, The University of Iowa, S324 CPHB, 145 N Riverside Dr, Iowa City, 52242, Iowa, USA;1. Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA;2. School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa;3. Departments of Psychiatry and Radiology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8225, St. Louis, MO, 63110, USA;4. Department of Energy, Environmental, and Chemical Engineering, Washington University, Campus Box 1180, One Brookings Drive, St. Louis, MO, 63130, USA;5. Herbert Wertheim School of Public Health, University of California, San Diego, 9500 Gilman Drive, #0725, La Jolla, CA, 92093, USA;6. Departments of Biostatistics and Environmental and Occupational Health Sciences, Box 357232, University of Washington, Seattle, WA, 98195, USA;1. Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Ain Shams University, Cairo, Egypt;2. Department of Neuropsychiatry, Faculty of Medicine, Ain Shams University, Cairo, Egypt;1. Master Program in Food Safety, College of Nutrition, Taipei Medical University, Taipei, 11031, Taiwan;2. Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan;3. School of Food Safety, College of Nutrition, Taipei Medical University, Taipei, 11031, Taiwan;4. Nutrition Research Center, Taipei Medical University Hospital, Taipei, 11031, Taiwan |
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| Abstract: | Chlorpyrifos (CPF) remains one of the most widely used organophosphorus insecticides (OPs) despite the concerns about its developmental neurotoxicity. Developmental exposure to CPF has long-lasting negative impacts, including abnormal emotional behaviors. These negative impacts are observed at exposure levels do not cause inhibition of acetylcholinesterase, the canonical target of OPs. Exposure to CPF at these levels inhibits the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) but it is not clear what the persistent effects of this inhibition are. To investigate this, male rat pups were exposed orally to either corn oil, 0.75 mg/kg CPF, or 0.02 mg/kg PF-04457845 (PF; a specific inhibitor of FAAH) daily from postnatal day 10 (PND10) - PND16. This dosage of CPF does not inhibit brain cholinesterase activity but inhibits FAAH activity. On PND38 (adolescence), the protein expression in the amygdala was determined using a label-free shotgun proteomic approach. The analysis of control vs CPF and control vs PF led to the identification of 44 and 142 differentially regulated proteins, respectively. Gene ontology enrichment analysis revealed that most of the proteins with altered expression in both CPF and PF treatment groups were localized in the synapse-related regions, such as presynaptic membrane, postsynaptic density, and synaptic vesicle. The different biological processes affected by both treatment groups included persistent synaptic potentiation, glutamate receptor signaling, protein phosphorylation, and chemical synaptic transmission. These results also indicated disturbances in the balance between glutamatergic (↓ Glutamate AMPA receptor 2, ↓ Excitatory amino acid transporter 2, and ↑ vesicular glutamate transporter 2) and GABAergic signaling (↑ GABA transporter 3 and ↑ glutamate decarboxylase 2). This imbalance could play a role in the abnormal emotional behavior that we have previously reported. These results suggest that there is a similar pattern of expression between CPF and PF, and both these chemicals can persistently alter emotional behavior as a consequence of inhibition of FAAH. |
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| Keywords: | Chlorpyrifos Organophosphates Glutamate GABA Developmental Endocannabinoid |
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