Chlorpyrifos and chlorpyrifos oxon impair the transport of membrane bound organelles in rat cortical axons

• Published in: Neurotoxicology (Park Forest South) 2017-09, Vol.62, p.111-123
• Main Authors: Gao, Jie, Naughton, Sean X., Beck, Wayne D., Hernandez, Caterina M., Wu, Guangyu, Wei, Zhe, Yang, Xiangkun, Bartlett, Michael G., Terry, Alvin V.
• Format: Article
• Language: English
• Subjects: Acetylcholine receptors; Acetylcholinesterase; Acetylcholinesterase - metabolism; Acute toxicity; Agrochemicals; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Animals; Atropine - pharmacology; Axonal transport; Axonal Transport - drug effects; Axons; Cell culture; Cell Survival - drug effects; Cells, Cultured; Cerebral Cortex - cytology; Chlorpyrifos; Chlorpyrifos - analogs & derivatives; Chlorpyrifos - pharmacology; Cholinesterase Inhibitors - pharmacology; Cortex; Embryo, Mammalian; Embryos; Environmental health; Fluorescence; Fluorescent indicators; Ganglionic Blockers - pharmacology; Gulf war illness; L-Lactate Dehydrogenase - metabolism; Mecamylamine - pharmacology; Membranes; Metabolites; Microtubule-Associated Proteins - metabolism; Mitochondria; Muscarinic Antagonists - pharmacology; Nerves; Neurodevelopment; Neurons; Neurons - drug effects; Neuropeptides - metabolism; Organelles; Organelles - drug effects; Organelles - metabolism; Organophosphate; Organophosphates; Organophosphorus pesticides; Pesticide; Pesticides; Public health; Rats; Rats, Sprague-Dawley; Studies; Toxicity; Transport
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2017.06.003

•Chlorpyrifos and Chlorpyrifos oxon impair axonal transport in embryonic neurons.•The transport deficits were not blocked by muscarinic or nicotinic antagonists.•Deficits occurred at concentrations below the threshold for cholinesterase inhibition. Chlorpyrifos (CPF) is an extensively used organophosphorus pesticide that has recently come under increasing scrutiny due to environmental health concerns particularly its association with neurodevelopmental defects. While the insecticidal actions and acute toxicity of CPF are attributed to its oxon metabolite (CPO) which potently inhibits the cholinergic enzyme acetylcholinesterase (AChE), there is significant evidence that CPF, CPO, and other organophosphates may affect a variety of neuronal targets and processes that are not directly related to AChE. Previously, in adult rat sciatic nerves ex vivo and postnatal neurons from rats in vitro we observed that CPF and CPO impaired the movements of vesicles and mitochondria in axons. Here, in embryonic neurons from rats in culture, we evaluated 24h exposures to CPF and CPO across picomolar to micromolar concentrations for effects on fast axonal transport of membrane bound organelles (MBOs) that contained the amyloid precursor protein (APP) tagged with the fluorescent marker, Dendra2 (APPDendra2). The most notable observations of this study were concentration-dependent decreases in the velocity and percentage of MBOs moving in the anterograde direction, an increase in the number of stationary MBOs, and an increased frequency of pauses associated with both CPF and CPO. These effects occurred at concentrations that did not significantly inhibit AChE activity, they were not blocked by cholinergic receptor antagonists, and they were not associated with compromised cell viability. These effects of CPF and CPO may be significant given the importance of axonal transport to neuronal development as well the function of fully developed neurons.