期刊
TOXICOLOGY AND APPLIED PHARMACOLOGY
卷 228, 期 1, 页码 32-41出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2007.11.005
关键词
organophosphorus pesticides; organophosphates; chlorpyrifos; axonal growth; acetylcholinesterase; developmental neurotoxicity; in vitro models
资金
- NIEHS NIH HHS [T32 ES007141-16, R21 ES011771-03, R21 ES011771-01, R21 ES011771, T32 ES007141, R21 ES011771-02] Funding Source: Medline
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. (c) 2007 Elsevier Inc. All rights reserved.
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