Developmental Neurotoxicity of Superfund Pesticides

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Organophosphate (OP) pesticides are used worldwide and are a Superfund disposal problem. In the previous period, we showed that chlorpyrifos is a developmental neurotoxicant that acts over a window extending from the rudiments of brain formation all the way through late postnatal stages. Importantly, these adverse effects are exerted by a family of mechanisms in addition to cholinesterase inhibition, the process that mediates adult systemic toxicity. This raises two important questions: what types of biomarkers can we use to characterize the mechanisms underlying developmental neurotoxicity of these agents, and how do we assess related and unrelated toxicants for the same types of effects? There are four aims: I. To identify cellular/molecular mechanisms underlying the developmental neurotoxicity of chlorpyrifos: the basic machinery of neural cell replication/differentiation, selection of transmitter phenotype, signal transduction, axonogenesis, oxidative stress, apoptosis, functional responses. II. To compare the mechanisms for chlorpyrifos with those of other OPs and non-OP cholinesterase inhibitors (physostigmine): are all OPs or cholinesterase inhibitors the same? III. To use the same approach to evaluate the developmental neurotoxicity of other Superfund chemicals (also studied in other projects): dieldrin, nickel, Elizabeth River Sediment Extracts, chlorpyrifos photolytic products. Can the PC12 model be used to screen neurotoxicants? IV. To develop a genomic array "fingerprint" for vulnerability to neurotoxicity in different phases of cell development, with a link to specific phenotypes and endpoints. Evaluations of time-dependent changes in gene clusters for cell cycle, differentiation, neurotransmitter phenotype, oxidative stress, apoptosis for different developmental phases (undifferentiated, early differentiation, terminal differentiation), for selected toxicants with related (chlorpyrifos, parathion) or unrelated (nickel, dieldrin) mechanisms.