ToxSci Advance Access published online on December 22, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh038
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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1 Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195-7234
* To whom correspondence should be addressed. E-mail: zxia{at}u.washington.edu.
Chlorpyrifos, an acetylcholinesterase (AChE) inhibitor, is a widely used organophosphate pesticide. Recent concern has focused on its neurotoxicity that not attributable to AChE inhibition. Here, we report that chlorpyrifos and chlorpyrifos-oxon, but not 3,5,6-trichloro-2-pyridinol (TCP; the breakdown product of chlorpyrifos and chlorpyrifos-oxon), induce apoptosis in primary cortical neurons cultured from embryonic day 17 or newborn rats. It is generally agreed that chlorpyrifos-oxon is approximately three orders of magnitude more potent than chlorpyrifos in inhibition of brain acetylcholinesterase activity. However, our data demonstrate that chlorpyrifos-oxon is only slightly more potent than chlorpyrifos in inducing apoptosis. This indicates that chlorpyrifos-induced apoptosis may occur independently of AChE inhibition, although AChE activity was not measured in this study. Furthermore, chlorpyrifos activates the ERK1/2 and p38 MAP kinases. Surprisingly, blocking ERK1/2 activation by the MEK inhibitor SL327 caused a small but statistically significant inhibition of apoptosis, while blocking p38 with SB202190 significantly accelerated apoptosis induced by chlorpyrifos. This suggests a pro- and anti-apoptotic role for ERK1/2 and p38, respectively. Although chlorpyrifos did not stimulate total JNK activity, it caused a sustained activation of a sub-pool of JNK in the nucleus and stimulated phosphorylation of c-Jun, a downstream target of JNK. Transient expression of a dominant negative c-Jun mutant inhibited chlorpyrifos-induced apoptosis, suggesting a role for JNK and JNK-mediated transcription in this cell death. Together, our data suggest apoptosis as a novel toxic endpoint of chlorpyrifos neurotoxicity in the brain that may be independent of AChE inhibition. Furthermore, activation of the ERK1/2 and JNK MAP kinases contributes to, while activation of the p38 MAP kinase counteracts chlorpyrifos-induced apoptosis in cortical neurons.
© 2003 Society of Toxicology
Neurotoxicology
Chlorpyrifos Induces Apoptosis in Rat Cortical Neurons That Is Regulated by a Balance between p38 and ERK/JNK MAP Kinases
2 Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195-7234; Department of Pharmacology, University of Washington, Seattle, Washington 98195-7234
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