Mechanisms of Pesticide Neuro- and Immunotoxicity in Children

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Children living in agricultural communities are exposed to mixtures of pesticides and allergens, which may have adverse immunologic and neurotoxic effects. We aim to elucidate the potential mechanisms for these adverse effects on respiratory disease and neurodevelopment. We will: 1) examine the in vitro effects of pesticides (chlorpyrifos and maneb) and house dust mite allergen (Der pl), alone and in combinations, on the production of Thl/Th2 cytokines; 2) determine whether pesticide and allergen exposures differentially affect cytokine expression in lymphocytes of children versus those of adults in vitro; 3) establish a new mechanism-based enzymatic assay for "neuropathy target esterase" (NTE) in human adult lymphocytes, 4) determine the ontogenetic changes in NTE activity in humans at different ages from birth to adulthood; 5) determine the sensitivities of NTE in children and adult lymphocytes to known NTE inhibitors, as well as to pesticides commonly found in our agricultural community in the Salinas Valley. This project will take advantage of our large repository of biological samples from the CHAMACOS cohort of pregnant women and children. We will use in vitro cultures of human cells to examine the effects of individual and combined exposures to pesticides and allergens on cytokine response. Cytokine dose responses will be determined by Taqman? realtime PCR, flow cytometric detection of intracellular cytokines, and ELISA. Using these methods, we will elucidate mechanisms of pesticide-induced immunotoxicity, which may be related to respiratory disease in children. We will examine the role of NTE activity in neurotoxity in a neuroblastoma cell line and in human lymphocytes using a new method based on interaction with a cellular target (lysophospholipids). This method may have important clinical uses in assessing adverse health outcomes in cases of pesticide poisonings and chemical warfare, and in understanding the mechanism of neurobehavioral effects of pesticide exposure in children. These studies will help to inform future policy decisions regarding allowable pesticide exposure to children and pregnant women.