Chlorpyrifos is used increasingly in the home and in agriculture because of its persistence and its relatively poor ability to elicit organophosphate (OP)-induced delayed neuropathy. Nevertheless, concern has been raised about exposure of pregnant women, infants and children. Animal studies indicate that chlorpyrifos is up to 100-fold more toxic in the newborn and that mechanisms other than cholinesterase inhibition may contribute to developmental neurotoxicity. This proposal will identify the cellular mechanisms underlying the developmental neurotoxicity of chlorpyrifos, as well as the adverse behavioral outcomes consequent to developmental exposure, so as to provide appropriate biomarkers with which to estimate the NOAEL and to identify the window of vulnerability. We will examine two models, one of mammalian neurotoxicity (rat) and one for piscine neurotoxicity (zebrafish). The mammalian model will provide a closer model for human health effects and the piscine model will provide a potential biomarker for environmental monitoring. The health effects and the piscine model will provide a potential biomarker for environmental monitoring. The zebrafish model is also valuable because the processes of neurodevelopment are readily observable since the embryo is also valuable because the processes of neurodevelopment are readily observable since the embryo is transparent. In both cases we will concentrate on the specific targeting of brain development at exposure levels below the threshold for dysmorphogenesis or standard teratogenesis. There are three Aims: I. To determine the cellular mechanisms by which chlorpyrifos disrupts mammalian neural cell replication and differentiation: signaling cascades that control nuclear transcription factors involved in cell replication, differentiation and apoptosis; comparison to cholinesterase inhibition. II. To determine the functional consequences of chlorpyrifos' effects on cell development: behavioral responses and their corresponding, underlying neurochemical mechanisms; we will concentrate on neural pathways and neurotransmitter systems already identified in our preliminary results as likely targets. III. To develop a non-mammalian model of developmental neurotoxicity of chlorpyrifos for estimation of NOAEL in ecotoxicologic settings: zebrafish provides a relevant piscine species for ecotoxicologic risk determination while at the same time providing transgenic models for specific molecular/cellular events in neurodevelopment. Molecular mechanisms of developmental neurotoxicity can be determined and linked to eventual alterations in behavioral performance.
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