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Transcriptional response of rat cerebrocortical tissue following acute in vivo exposure to the pyrethroid insecticides permethrin and deltamethrin
Citation:
Harrill, J. A., L. Zhen, F. A. Wright, AND K. M. CROFTON. Transcriptional response of rat cerebrocortical tissue following acute in vivo exposure to the pyrethroid insecticides permethrin and deltamethrin. BMC Genomics. BioMed Central Ltd, London, Uk, 18(9):546, (2008).
Impact/Purpose:
To support criteria for MYP
Description:
Pyrethroids are neurotoxic pesticides that interact with membrane bound ion channels in neurons. The physiological result is disruption of nerve membrane excitability. A current focus of pyrethroid research is examination of the molecular mechanisms-of-action of pyrethroids, including perturbation of intracellular signaling pathways and adaptive neuronal responses downstream of the pharmacological actions of these compounds. The present study uses statistical regression methods to identify dose-responsive changes in mRNA levels in cerebrocortical tissue from rats treated with pyrethroids in vivo. Rats were orally exposed to acute doses of either deltamethrin (0.3 – 3 mg/kg) or permethrin (1 – 100 mg/kg) followed by collection of cortical tissue at 6 hours. Global gene expression profiles were generated using Affymetrix GeneChips®. The doses used range from those that cause minimal signs of intoxication in a behavioral test to doses well below apparent no effect levels (Wolansky et al. 2006). Penalized linear regression (SAM) and penalized isotonic regression (PIR) ranked similar sub-sets of genes within each compound as being the most dose-responsive. A group of dose-responsive transcripts identified with microarray analysis were confirmed by qRT-PCR, and the time course of transcript expression examined, in independent cohorts of test subjects. Both differences and similarities in the transcriptional response were observed when comparing permethrin and deltamethrin. Changes in Camk1g, Ddc and Prom1 mRNA levels were consistently observed across multiple test cohorts for both compounds while increased expression of Gpd1 and Fkbp51 were specific to deltamethrin. In addition, Significance Analysis of Function and Expression (SAFE) identified significantly enriched gene categories common for both pyrethroids including some related to neuronal morphology and intracellular Ca+2 signaling. This study identifies several transcripts that may be useful as biochemical markers for pyrethroid effects on the nervous system and some sensitive biological processes that may be previously unrecognized aspects of pyrethroid neurotoxicity.
