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Jason P. Magby
B.A. Rutgers University - 2006
Thesis Advisor: Jason R. Richardson Ph.D.
Graduate Program in Toxicology
Conference Room C
Wednesday, May 8, 2013
Voltage gated sodium channels (Nav) are responsible for the generation and propagation of action potentials in neurons. Alteration of Nav expression or function alters neuronal excitability, which can manifest as behavioral abnormalities, pain disorders, paralysis and seizures. Therefore, exposure to environmental contaminants that alter Nav has the potential to cause neurological impairment. Pyrethroid insecticides are widely used in agricultural and household settings and cause toxicity by delaying Nav inactivation, causing hyperexcitability in neurons. Because there is increasing use and the young are more susceptible to their toxic effects, there is concern that pyrethroids, such as deltamethrin, could cause developmental neurotoxicity. In this project, we examined the potential for developmental exposure to deltamethrin to alter expression of Nav protein and mRNA expression. We first show that in utero exposure to deltamethrin causes long-term (10-12 months) decreases in Nav expression that is the result of persistent calpain activation. Next, acute administration of deltamethrin down-regulated Nav protein in an age-dependent manner. In young rats (12 days), Nav protein down-regulation was associated with increased proteasome activity. However, exposure at 30 days of age resulted in Nav cleavage and increased calpain activation. Finally, repeated postnatal exposure to deltamethrin caused decreased Nav protein levels that resulted in decreased glutamate release in the hippocampus. Taken in concert, these data demonstrate disruption of Nav mRNA and protein following exposure to deltamethrin that is age-dependent and results in altered neurotransmission. The persistent nature of these disruptions suggests early exposure to deltamethrin could have long lasting impacts on neuronal excitability and function.