Persistent locomotor and behavioral effects resulting from developmental exposure to pyrethroid pesticide deltamethrin are mediated by dopaminergic and serotonergic system dysfunction

Pyrethroid pesticides are generally considered to be a safer alternative to other classes of insecticides. However, there is increasing concern that children are more susceptible to the adverse effects of pesticides. The hypothesis tested in this thesis is that exposure to pyrethroid pesticide deltamethrin, at concentrations below the LOAEL, during the critical developmental period would result in persistent behavioral deficits, which are due, in part, to changes in dopamine and serotonin system gene expression and neurochemistry. Zebrafish embryos were treated with deltamethrin (0.25 µg/L - 0.5 μg/L) during the embryonic period (3-72hpf), and then reared in treatment free water until the larval (2-week) and adult stages. Deltamethrin exposure during development resulted in increased locomotor activity, decreased drd1 and drd2a transcripts, and increased levels of dopamine (DA) metabolite, homovanillic acid, at the larval stage. Manipulating the DA system by concomitant knockdown of the dopamine transporter (DAT) during exposure rescued deltamethrin induced locomotor activity. Acute methylphenidate (DAT inhibitor) exposure increased locomotor activity in control larvae but reduced locomotor activity in larvae previously exposed to deltamethrin. These studies indicate that dopaminergic dysfunction mediates the behavioral effects observed in larval zebrafish following deltamethrin exposure during development. Behavioral characterization of adult zebrafish revealed a sex specific response in fish that had been exposed to deltamethrin during development, including increased distance travelled, velocity, bouts of high mobility, and aggression in males, and increased swim velocity, thigmotaxis, and altered rates of habituation in females. In adult males, transcript levels of serta, sertb, and drd2a, positively correlated with the magnitude of aggression. However, this correlation was lost in the population of male fish that had been developmentally exposed to deltamethrin. Fluoxetine exposure attenuated aggression exhibited by dominant male zebrafish demonstrating the involvement of the serotonin system in mediating aggressive behavior. In conclusion, this research demonstrates that environmental influences during critical neurodevelopmental stages results in persistent neurobehavioral deficits. Also, we add to zebrafish ethology using the experimental behavioral paradigms adapted for our laboratory. Finally, we provide a mode of action for deltamethrin induced behavioral deficits which can assist in the cumulative risk assessment of this class of compounds.Ph.D.Includes bibliographical referencesby Tiffany S. Kun