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Transcriptional response of rat frontal cortex following acute in vivo exposure to the pyrethroid insecticides permethrin and deltamethrin.

Harrill JA, Li Z, Wright FA, Radio NM, Mundy WR, Tornero-Velez R, Crofton KM - BMC Genomics (2008)

Bottom Line: In the present study, pyrethroids induced changes in gene expression in the frontal cortex near the threshold for decreases in ambulatory motor activity in vivo.Finally, SAFE analysis of gene expression data identified branching morphogenesis as a biological process sensitive to pyrethroids and subsequent in vitro experiments confirmed this predicted effect.The novel findings regarding pyrethroid effects on branching morphogenesis indicate these compounds may act as developmental neurotoxicants that affect normal neuronal morphology.

View Article: PubMed Central - HTML - PubMed

Affiliation: Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. harrill.josh@epa.gov

ABSTRACT

Background: Pyrethroids are neurotoxic pesticides that interact with membrane bound ion channels in neurons and disrupt nerve function. The purpose of this study was to characterize and explore changes in gene expression that occur in the rat frontal cortex, an area of CNS affected by pyrethroids, following an acute low-dose exposure.

Results: Rats were acutely exposed to either deltamethrin (0.3 - 3 mg/kg) or permethrin (1 - 100 mg/kg) followed by collection of cortical tissue at 6 hours. The doses used range from those that cause minimal signs of intoxication at the behavioral level to doses well below apparent no effect levels in the whole animal. A statistical framework based on parallel linear (SAM) and isotonic regression (PIR) methods identified 95 and 53 probe sets as dose-responsive. The PIR analysis was most sensitive for detecting transcripts with changes in expression at the NOAEL dose. A sub-set of genes (Camk1g, Ddc, Gpd3, c-fos and Egr1) was then confirmed by qRT-PCR and examined in a time course study. Changes in mRNA levels were typically less than 3-fold in magnitude across all components of the study. The responses observed are consistent with pyrethroids producing increased neuronal excitation in the cortex following a low-dose in vivo exposure. In addition, Significance Analysis of Function and Expression (SAFE) identified significantly enriched gene categories common for both pyrethroids, including some relating to branching morphogenesis. Exposure of primary cortical cell cultures to both compounds resulted in an increase (approximately 25%) in the number of neurite branch points, supporting the results of the SAFE analysis.

Conclusion: In the present study, pyrethroids induced changes in gene expression in the frontal cortex near the threshold for decreases in ambulatory motor activity in vivo. The penalized regression methods performed similarly in detecting dose-dependent changes in gene transcription. Finally, SAFE analysis of gene expression data identified branching morphogenesis as a biological process sensitive to pyrethroids and subsequent in vitro experiments confirmed this predicted effect. The novel findings regarding pyrethroid effects on branching morphogenesis indicate these compounds may act as developmental neurotoxicants that affect normal neuronal morphology.

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Comparison of probe sets identified by PIR or SAM between pyrethroids. Panels A and B plot the -log10 (empirical p-value) for deltamethrin (x-axis) against the -log10 (empirical p-value) for permethrin (y-axis) for probe sets identified during PIR or SAM regression analyses, respectively. All probe sets that had a Benjamini-Hochberg adjusted p-value < 0.05 in a one-way ANOVA for either permethrin or deltamethrin are included in the plot. Dashed boxes represent empirical p-value thresholds of p < 0.05. All points in the upper right of the figures, within the dashed boxes, meet the respective p-value criteria for both pyrethroids. 27.2% and 27.8% of all probe sets identified during PIR or SAM analysis, respectively, had empirical p-values of p < 0.05 for both compounds.
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Figure 3: Comparison of probe sets identified by PIR or SAM between pyrethroids. Panels A and B plot the -log10 (empirical p-value) for deltamethrin (x-axis) against the -log10 (empirical p-value) for permethrin (y-axis) for probe sets identified during PIR or SAM regression analyses, respectively. All probe sets that had a Benjamini-Hochberg adjusted p-value < 0.05 in a one-way ANOVA for either permethrin or deltamethrin are included in the plot. Dashed boxes represent empirical p-value thresholds of p < 0.05. All points in the upper right of the figures, within the dashed boxes, meet the respective p-value criteria for both pyrethroids. 27.2% and 27.8% of all probe sets identified during PIR or SAM analysis, respectively, had empirical p-values of p < 0.05 for both compounds.

Mentions: A comparison of the probe sets identified as dose-responsive in the PIR and SAM regression analyses demonstrates that the transcriptional response elicited by the two pyrethroids has some common characteristics. The panels in Figures 3 plot the -log10 of the empirical p-values associated with the PIR regression (3A) or SAM regression (3B) for each probe set identified as dose-responsive for either deltamethrin or permethrin. Data from the PIR regression analyses demonstrate that expression of 27.2% of all probe sets identified as dose-responsive for either pyrethroid are significantly altered by both compounds at an empirical p-value threshold of p < 0.05 (Figure 3A). Likewise, SAM analyses demonstrated that 27.8% of all dose-responsive transcripts are altered by both pyrethroids (Figure 3B). Differences in the global transcriptional response profiles between pyrethroids are also apparent.


Transcriptional response of rat frontal cortex following acute in vivo exposure to the pyrethroid insecticides permethrin and deltamethrin.

Harrill JA, Li Z, Wright FA, Radio NM, Mundy WR, Tornero-Velez R, Crofton KM - BMC Genomics (2008)

Comparison of probe sets identified by PIR or SAM between pyrethroids. Panels A and B plot the -log10 (empirical p-value) for deltamethrin (x-axis) against the -log10 (empirical p-value) for permethrin (y-axis) for probe sets identified during PIR or SAM regression analyses, respectively. All probe sets that had a Benjamini-Hochberg adjusted p-value < 0.05 in a one-way ANOVA for either permethrin or deltamethrin are included in the plot. Dashed boxes represent empirical p-value thresholds of p < 0.05. All points in the upper right of the figures, within the dashed boxes, meet the respective p-value criteria for both pyrethroids. 27.2% and 27.8% of all probe sets identified during PIR or SAM analysis, respectively, had empirical p-values of p < 0.05 for both compounds.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2626604&req=5

Figure 3: Comparison of probe sets identified by PIR or SAM between pyrethroids. Panels A and B plot the -log10 (empirical p-value) for deltamethrin (x-axis) against the -log10 (empirical p-value) for permethrin (y-axis) for probe sets identified during PIR or SAM regression analyses, respectively. All probe sets that had a Benjamini-Hochberg adjusted p-value < 0.05 in a one-way ANOVA for either permethrin or deltamethrin are included in the plot. Dashed boxes represent empirical p-value thresholds of p < 0.05. All points in the upper right of the figures, within the dashed boxes, meet the respective p-value criteria for both pyrethroids. 27.2% and 27.8% of all probe sets identified during PIR or SAM analysis, respectively, had empirical p-values of p < 0.05 for both compounds.
Mentions: A comparison of the probe sets identified as dose-responsive in the PIR and SAM regression analyses demonstrates that the transcriptional response elicited by the two pyrethroids has some common characteristics. The panels in Figures 3 plot the -log10 of the empirical p-values associated with the PIR regression (3A) or SAM regression (3B) for each probe set identified as dose-responsive for either deltamethrin or permethrin. Data from the PIR regression analyses demonstrate that expression of 27.2% of all probe sets identified as dose-responsive for either pyrethroid are significantly altered by both compounds at an empirical p-value threshold of p < 0.05 (Figure 3A). Likewise, SAM analyses demonstrated that 27.8% of all dose-responsive transcripts are altered by both pyrethroids (Figure 3B). Differences in the global transcriptional response profiles between pyrethroids are also apparent.

Bottom Line: In the present study, pyrethroids induced changes in gene expression in the frontal cortex near the threshold for decreases in ambulatory motor activity in vivo.Finally, SAFE analysis of gene expression data identified branching morphogenesis as a biological process sensitive to pyrethroids and subsequent in vitro experiments confirmed this predicted effect.The novel findings regarding pyrethroid effects on branching morphogenesis indicate these compounds may act as developmental neurotoxicants that affect normal neuronal morphology.

View Article: PubMed Central - HTML - PubMed

Affiliation: Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. harrill.josh@epa.gov

ABSTRACT

Background: Pyrethroids are neurotoxic pesticides that interact with membrane bound ion channels in neurons and disrupt nerve function. The purpose of this study was to characterize and explore changes in gene expression that occur in the rat frontal cortex, an area of CNS affected by pyrethroids, following an acute low-dose exposure.

Results: Rats were acutely exposed to either deltamethrin (0.3 - 3 mg/kg) or permethrin (1 - 100 mg/kg) followed by collection of cortical tissue at 6 hours. The doses used range from those that cause minimal signs of intoxication at the behavioral level to doses well below apparent no effect levels in the whole animal. A statistical framework based on parallel linear (SAM) and isotonic regression (PIR) methods identified 95 and 53 probe sets as dose-responsive. The PIR analysis was most sensitive for detecting transcripts with changes in expression at the NOAEL dose. A sub-set of genes (Camk1g, Ddc, Gpd3, c-fos and Egr1) was then confirmed by qRT-PCR and examined in a time course study. Changes in mRNA levels were typically less than 3-fold in magnitude across all components of the study. The responses observed are consistent with pyrethroids producing increased neuronal excitation in the cortex following a low-dose in vivo exposure. In addition, Significance Analysis of Function and Expression (SAFE) identified significantly enriched gene categories common for both pyrethroids, including some relating to branching morphogenesis. Exposure of primary cortical cell cultures to both compounds resulted in an increase (approximately 25%) in the number of neurite branch points, supporting the results of the SAFE analysis.

Conclusion: In the present study, pyrethroids induced changes in gene expression in the frontal cortex near the threshold for decreases in ambulatory motor activity in vivo. The penalized regression methods performed similarly in detecting dose-dependent changes in gene transcription. Finally, SAFE analysis of gene expression data identified branching morphogenesis as a biological process sensitive to pyrethroids and subsequent in vitro experiments confirmed this predicted effect. The novel findings regarding pyrethroid effects on branching morphogenesis indicate these compounds may act as developmental neurotoxicants that affect normal neuronal morphology.

Show MeSH
Related in: MedlinePlus