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In mammals, pyrethroids are neurotoxicants that interfere with ion channel function in excitable neuronal membranes. Previous work demonstrated increases in the expression of Ca(2+)/calmodulin-dependent protein kinase 1-gamma (Camk1g) mRNA following acute deltamethrin and permethrin exposure. In the rat, this gene is expressed as two distinct splice variants, Camk1g1 and Camk1g2. The present study tests the hypothesis that changes in Camk1g mRNA expression in the rat following acute pyrethroid exposure are due to a specific increase in the Camk1g1 splice variant and not the Camk1g2 splice variant. Long-Evans rats were acutely exposed to permethrin, deltamethrin, or corn oil vehicle. Frontal cortex was collected at 6 h postdosing. In addition, rats were exposed to permethrin (100 mg/kg) or deltamethrin (3 mg/kg), and frontal cortex was collected at 1, 3, 6, 9, 12, or 24 h along with time-matched vehicle controls. Expression of Camk1g1 and Camk1g2 mRNA was measured by quantitative real-time RT-PCR and quantified using the 2(-Delta Delta C)T method. Dose-dependent increases in Camk1g1 mRNA expression were observed for both pyrethroids at 6 h. In addition, a dose-dependent increase in Camk1g2 was observed at 6 h although it was very small in magnitude. The increases in Camk1g1 expression for deltamethrin and permethrin peak between 3 and 6 h postexposure and returns to control levels by 9 h. There was no increase in CAMK1G1 protein as measured with Western blots. The present data demonstrate that pyrethroid-induced changes in Camk1g are driven mainly by increased expression of the Camk1g1 splice variant., ((c) 2010 Wiley Periodicals, Inc.) more...

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. more...

Pyrethroids are pesticides with high selectivity for insects. In order to identify strengths and gaps in the database for pyrethroid neurobehavioral toxicology, we have critically analyzed the data from peer-reviewed literature. This review includes dose-response data that have been recently generated demonstrating consistent findings for low-dose, acute, oral exposure to pyrethroids in small rodents. All pyrethroids tested (i.e., about twenty compounds), regardless of structure, produce a decrease in motor activity in a variety of test protocols. The range of relative potencies varies more than two orders of magnitude, and thresholds for motor activity were found well below doses that produce overt signs of poisoning. Six compounds (allethrin, permethrin, cis-permethrin, deltamethrin, cypermethrin, and fenvalerate) impair schedule-controlled operant responding, seven compounds (pyrethrum, bifenthrin, S-bioallethrin, permethrin, beta-cyfluthrin, cypermethrin, and deltamethrin) decrease grip strength, and two compounds (deltamethrin and alpha-cypermethrin) produce incoordination using the rotarod. In addition, while compounds lacking an alpha-cyano group (e.g., cismethrin, permethrin, bifenthrin) induce an increase in acoustic-evoked startle response amplitude, cyano compounds (e.g., deltamethrin, cypermethrin, cyfluthrin) produce the opposite outcome. Other endpoints (e.g., tremor intensity, sensory response) have been only occasionally explored. A synthesis of the neurobehavioral evidence relating to the action of pyrethroids indicates that some differences in the experimental findings across compounds are also present in the low-effective dose range. For risk assessment purposes, a strategy that takes into account data from an array of neurobehavioral endpoints is needed to capture the heterogeneity of pyrethroid-induced adverse effects and accurately inform policy decisions. more...

A primary target of pyrethroid insecticides are the voltage-sensitive sodium channels (VSSCs). Expression of VSSCs in oocytes from Xenopus laevis is an experimental model used to study the effects of pyrethroids. A common assumption when utilizing this model is that media concentration is an accurate substitute for tissue dose. This assumption may not hold true for lipophilic chemicals. [3H]-deltamethrin (DLT) was used to test the hypothesis that media concentration is a good surrogate for tissue concentration. Accumulation of DLT (0.001-10 microM) in non-transfected oocytes exposed for 20 min was determined using liquid scintillation counting. The time course (1.0-180 min) of tissue accumulation of DLT (approximately 1.0 microM (0.50 ppm) in media) was also determined. Results demonstrate that tissue dose increases as a function of time with media concentration underestimating tissue dose at long incubation times (approximately 2.0-fold at 180 min) and overestimating tissue dose short incubation times (approximately 8.6-fold at 5 min). Tissue dose increases as a function of media concentration, with overestimation of tissue dose ranging from 1.5-fold at 0.0005 ppm to 4.1-fold at 5.0 ppm. These data suggest that media concentration does not accurately predict tissue dose at all times for a broad range of deltamethrin concentrations in X. laevis oocytes. more...