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ISOTONIC DOSE-RESPONSE MODELING OF THE TRANSCRIPTIONAL RESPONSE OF RAT CEREBROCORTICAL TISSUE AFTER ACUTE PYRETHROID EXPOSURE IN VIVO.
Citation:
HARRILL, J., F. A. WRIGHT, AND K. M. CROFTON. ISOTONIC DOSE-RESPONSE MODELING OF THE TRANSCRIPTIONAL RESPONSE OF RAT CEREBROCORTICAL TISSUE AFTER ACUTE PYRETHROID EXPOSURE IN VIVO. Presented at Society of Toxicology, Charlotte, NC, March 25 - 29, 2007.
Description:
Pyrethroid insecticides produce neurotoxicity in mammals by disrupting ion channel function in excitable nerve membranes. Pyrethroid use has increased as regulatory guidelines have restricted the use of other pesticide classes. Currently, a sensitive, specific, and dose-responsive biomarker of effect that correlates with pyrethroid-induced disruption of nervous system function is not available. This study used a novel combination of statistical methods to identify dose-responsive transcripts from a microarray data set. Our goal was to characterize potential biochemical markers of pyrethroid effects. Long-Evans rats (n = 8-12 / group) were orally dosed with permethrin (1, 10, 100 mg/kg), deltamethrin (0.3, 1.0, 3.0 mg/kg) or corn-oil vehicle and cerebrocortical tissue was collected at 6 hours. Affymetrix Rat 230 2.0 GeneChip® microarrays were used to obtain global transcriptional profiles. Dose-responsive transcripts were identified using an isotonic regression model that assumes a monotonic dose-response relationship, but otherwise makes no assumptions about the precise form of the dose-response curve (M-score, Hu et al. 2005). In conjunction with this method, a permutation based calculation of false discovery rates was used to provide multiple comparison error control. These analyses revealed several candidate transcript commonly regulated by both compounds. qRT-PCR was used to confirm dose-responsive relationships for: increased expression of Camk1¿¿¿ and decreased expression of Abcb1a, prominin 1 and dopa decarboxylase (Ddc), for both deltamethrin and permethrin. Future work will validate the use of these transcripts, their corresponding proteins, or components of cellular signaling pathways in which they are involved, as specific biomarkers of effect for pyrethroids. This abstract does not necessarily represent EPA policies.