Transcriptional response of rat frontal cortex following acute In Vivo exposure to the pyrethroid insecticides permethrin and deltamethrin

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  • Harrill, Joshua A
    • Affiliation: School of Medicine, Curriculum in Toxicology
  • Li, Zhen
    • Affiliation: Gillings School of Global Public Health, Department of Biostatistics
    • Other Affiliation: Carolina Environmental Bioinformatics Center
  • Wright, Fred A.
    • Affiliation: Gillings School of Global Public Health, Department of Biostatistics
    • Other Affiliation: Carolina Environmental Bioinformatics Center
  • Radio, Nicholas M
    • Other Affiliation: Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, United State Environmental Protection Agency, Research Triangle Park, North Carolina, USA
  • Mundy, William R
    • Other Affiliation: Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, United State Environmental Protection Agency, Research Triangle Park, North Carolina, USA
  • Tornero-Velez, Rogelio
    • Other Affiliation: Human Exposure and Atmospheric Sciences Division, National Exposure Research Laboratory, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina, USA
  • Crofton, Kevin M
    • Other Affiliation: Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, United State Environmental Protection Agency, Research Triangle Park, North Carolina, USA
Abstract
  • 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 (~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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  • Article
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  • In Copyright
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  • Joshua A Harrill et al.; licensee BioMed Central Ltd.
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Journal title
  • BMC Genomics
Journal volume
  • 9
Journal issue
  • 1
Page start
  • 546
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1471-2164
Bibliographic citation
  • BMC Genomics. 2008 Nov 18;9(1):546
Publisher
  • BioMed Central Ltd
Access right
  • Open Access
Date uploaded
  • January 15, 2016

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