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.2009 Mar 31:1263:23-32.
doi: 10.1016/j.brainres.2009.01.049. Epub 2009 Feb 5.

Protein kinase C is a target for diverse developmental neurotoxicants: transcriptional responses to chlorpyrifos, diazinon, dieldrin and divalent nickel in PC12 cells

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Protein kinase C is a target for diverse developmental neurotoxicants: transcriptional responses to chlorpyrifos, diazinon, dieldrin and divalent nickel in PC12 cells

Theodore A Slotkin et al. Brain Res..

Abstract

Unrelated developmental neurotoxicants can elicit similar functional outcomes, whereas agents in the same class may differ. We compared two organophosphate insecticides (chlorpyrifos, diazinon) with an organochlorine (dieldrin) and a metal (Ni(2+)) for similarities and differences in their effects on gene expression encoding subtypes of protein kinase C and their modulators, a cell signaling cascade that integrates the actions of neurotrophic factors involved in brain development. We conducted evaluations in PC12 cells, a model for neuronal development, with each agent introduced at 30 microM for 24 or 72 h, treatments devoid of cytotoxicity. Chlorpyrifos evoked by far the largest effect, with widespread upregulation of multiple genes; the effects were greater during neurodifferentiation than when cells were exposed prior to differentiation. Diazinon had smaller and less widespread effects, consistent with its lesser long-term impact on synaptic function and behavior noted for in vivo exposures in developing rats. Surprisingly, the effects of diazinon, dieldrin and Ni(2+) showed basic similarities despite the fact that all three come from different classes of toxicants. Our findings provide some of the first evidence for a specific mechanistic cascade contributing to the cholinesterase-independent developmental neurotoxicant actions of chlorpyrifos and its differences from diazinon, while at the same time identifying mechanistic convergence between otherwise unrelated toxicants that provides predictions about common neurodevelopmental outcomes. These results further show how combined use of cell cultures and microarray technology can guide future in vivo work on diverse developmental neurotoxicants.

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Figures

Figure 1
Figure 1
Effects of chlorpyrifos exposure in undifferentiated (A) and differentiating (B) PC12 cells. Asterisks shown below each gene denote a significant main treatment effect. Daggers denote genes for which a treatment × time interaction was detected and show the individual times for which treatment effects were present. Multivariate ANOVA (treatment, differentiation state, gene, time) indicates a significant main treatment effect (chlorpyrifos > control, p< 0.02) and interactions of treatment × gene (p< 0.0002), treatment × state × time (p< 0.02), treatment × gene × time (p< 0.05) and treatment × state × gene (p< 0.05).
Figure 2
Figure 2
Effects of diazinon in differentiating PC12 cells. Asterisks shown below each gene denote a significant main treatment effect. Daggers denote genes for which a treatment × time interaction was detected and show the individual times for which treatment effects were present. Multivariate ANOVA (treatment, gene, time) indicates a significant treatment × gene interaction (p< 0.02).
Figure 3
Figure 3
Effects of dieldrin in differentiating PC12 cells. Asterisks shown below each gene denote a significant main treatment effect. Daggers denote genes for which a treatment × time interaction was detected and show the individual times for which treatment effects were present. Multivariate ANOVA (treatment, gene, time) indicates a significant treatment × gene × time interaction (p< 0.05).
Figure 4
Figure 4
Effects of Ni2+ in differentiating PC12 cells. Asterisks shown below each gene denote a significant main treatment effect. Daggers denote genes for which a treatment × time interaction was detected and show the individual times for which treatment effects were present. Multivariate ANOVA (treatment, gene, time) indicates significant interactions of treatment × time (p < 0.04), treatment × gene (p < 0.004) and treatment × gene × time (p < 0.02).
Figure 5
Figure 5
Correlation between changes in gene expression evoked by dieldrin and those caused by Ni2+ exposure.
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References

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