title: Chlorpyrifos and chlorpyrifos-oxon inhibit axonal growth by interfering with the morphogenic activity of acetylcholinesterase.
abstract: A primary role of acetylcholinesterase (AChE) is regulation of cholinergic neurotransmission by hydrolysis of synaptic acetylcholine. In the developing nervous system, however, AChE also functions as a morphogenic factor to promote axonal growth. This raises the question of whether organophosphorus pesticides (OPs) that are known to selectively bind to and inactivate the enzymatic function of AChE also interfere with its morphogenic function to perturb axonogenesis. To test this hypothesis, we exposed primary cultures of sensory neurons derived from embryonic rat dorsal root ganglia (DRG) to chlorpyrifos (CPF) or its oxon metabolite (CPFO). Both OPs significantly decreased axonal length at concentrations that had no effect on cell viability, protein synthesis or the enzymatic activity of AChE. Comparative analyses of the effects of CPF and CPFO on axonal growth in DRG neurons cultured from AChE nullizygous (AChE -/-) versus wild type (AChE +/+) mice indicated that while these OPs inhibited axonal growth in AChE+/+ DRG neurons, they had no effect on axonal growth in AChE -/- DRG neurons. However, transfection of AChE -/- DRG neurons with cDNA encoding full-length AChE restored the wild type response to the axon inhibitory effects of OPs. These data indicate that inhibition of axonal growth by OPs requires AChE, but the mechanism involves inhibition of the morphogenic rather than enzymatic activity of AChE. These findings suggest a novel mechanism for explaining not only the functional deficits observed in children and animals following developmental exposure to OPs, but also the increased vulnerability of the developing nervous system to OPs.
authors: Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Dongren
authors: D
authors: Yang
authors: Angela
authors: A
authors: Howard
authors: Donald
authors: D
authors: Bruun
authors: Mispa
authors: M
authors: Ajua-Alemanj
authors: Cecile
authors: C
authors: Pickart
authors: Pamela J
authors: PJ
authors: Lein
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004390:Chlorpyrifos / Q000031:analogs & derivatives* / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D017930:Genes, Reporter / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009434:Neural Pathways / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D014162:Transfection
chemical_list: D002800:Cholinesterase Inhibitors; D007306:Insecticides; D009419:Nerve Tissue Proteins; D049452:Green Fluorescent Proteins; C009618:O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; D000110:Acetylcholinesterase; D004390:Chlorpyrifos