| Pyrethroids interfere with nervous system function by increasing neuronal excitability. Increased excitability underlies the toxicity observed at the whole organism level following an acute pyrethroid exposure. However, changes in neuronal excitability also trigger de novo gene expression which may impact neuronal function. This aspect of pyrethroid toxicity has not been extensively examined. The present studies test the hypothesis that in vivo pyrethroid exposures, at doses surrounding the threshold for neurobehavioral effects, result in changes in gene expression in the rat cortex. In the first aim, adult rats were orally dosed with deltamethrin (DLT: 0.3, 1, 3 mg/kg), permethrin (PERM: 1, 10, 100 mg/kg) or vehicle. Frontal cortex was collected at 6 hr and global transcriptional profiles were generated. Dose-dependent changes in gene expression were identified using penalized linear and isotonic regressions. A set of altered transcripts were then confirmed by qRT-PCR. In addition, rats were dosed with either DLT (3 mg/kg), PERM (100 mg/kg) or vehicle and cortical tissue collected at 1,3,6 and 9 hr. Expression of transcripts examined by qRT-PCR in the dose-response studies were investigated in this time course cohort. Functional category analysis identified 'branching morphogenesis' as a biological process potentially sensitive to pyrethroids. This prediction was confirmed in an in vitro model of neuronal morphogenesis. The time course of expression for Camk1g was further examined by qRT-PCR and Western blot. Expression of the Camk1g1 mRNA splice variant changed in response to pyrethroids with no detectable change in Camk1g1 protein. The second aim determined if Type I and Type II pyrethroids produce similar effects on gene transcription in the cortex. Rats were dosed with vehicle or either a Type I or Type II pyrethroid at doses that produce the same effect on an apical behavior. Cortex was sampled at 3 and 6 hr and global transcriptional profiles were generated. Qualitatively similar but quantitatively different patterns of expression between Type I and Type II pyrethroids were observed that is consistent with increases in neuronal excitability. These data contribute to a comprehensive mode-of-action model for pyrethroids. |
