Project Summary (2005-2011)

A variety of chemicals on the Superfund list, such as pesticides, metals and polyhalogenated hydrocarbons have been found to impair cognitive function, including learning, memory and attention. Dr. Levin and his research team have focused on determining the neural mechanisms underlying the cognitive impairments caused by developmental pesticide exposure. Using the classic rat model of developmental neurobehavioral toxicology, they have shown in the first funding period of this center that the organophosphate insecticide chlorpyrifos causes persistent effects on working and reference memory. The researchers have taken a two-stage approach to determine the neural underpinnings of these effects. Neurochemical studies in the Slotkin lab have demonstrated the chlorpyrifos-induced disruptions of cholinergic, catecholaminergic and serotonergic transmitter systems. Neurobehavioral studies in the Levin lab have demonstrated with pharmacological probes that developmental chlorpyrifos exposure disrupts the functional role played by muscarinic acetylcholine systems in memory function. The researchers extended study of developmental chlorpyrifos effects on cognitive function to zebrafish to better understand the molecular effects underlying this impairment. They found with zebrafish that chlorpyrifos exposure during development causes persisting cognitive impairment. Initial studies with morpholino suppression of acetylcholinesterase show cognitive impairments in zebrafish. These studies are determining the neural mechanisms underlying chlorpyrifos-induced effects on learning, attention and emotional response. Specific tests of learning (repeated acquisition), attention (operant signal detection) and anxiety (elevated plus maze) are being used together with pharmacological probes of choliriergic, catecholaminergic and serotonergic transmitter receptor systems to determine not only the impact of chlorpyrifos on these neurobehavioral functions but also to determine the functional role of these transmitter systems in the persisting neurobehavioral effects of chlorpyrifos. Initial studies are being made concerning the specificity of these effects to chlorpyrifos or generality to other organophosphate pesticides. Zebrafish studies are being used to provide critical information of how pesticides affect molecular controls over cognitive development.