MECHANISMS OF CHLORPYRIFOS DEVELOPMENTAL NEUROTOXICITY

毒死蜱在家庭和农业中的使用越来越多，因为它的持久性和相对较差的能力引发有机磷（OP）诱导的延迟性神经病变。然而，人们对孕妇、婴儿和儿童的暴露表示关注。动物研究表明，毒死蜱对新生儿的毒性高达100倍，而且除了胆碱酯酶抑制外，其他机制也可能导致发育性神经毒性。本研究将确定发育性神经毒性的细胞机制。本提案将确定毒死蜱发育神经毒性的细胞机制，以及发育暴露后的不良行为结果，从而提供适当的生物标志物来估计NOAEL并确定脆弱性窗口。我们将研究两种模型，一种用于哺乳动物神经毒性（大鼠），一种用于鱼类神经毒性（斑马鱼）。哺乳动物模型将为人类健康影响提供更接近的模型，而鱼类模型将为环境监测提供潜在的生物标志物。斑马鱼模型也很有价值，因为神经发育过程很容易观察到，因为胚胎是透明的。在这两种情况下，我们将集中在大脑发育的具体目标暴露水平低于畸形或标准畸形的阈值。有三个目的：1 .确定毒死蜱破坏哺乳动物神经细胞复制和分化的细胞机制；控制参与细胞复制、分化和凋亡的核转录因子的信号级联；胆碱酯酶抑制的比较。2。确定毒死蜱对细胞发育影响的功能后果：行为反应及其相应的潜在神经化学机制；我们将集中在神经通路和神经递质系统已经确定在我们的初步结果作为可能的目标。3。为了建立一种非哺乳动物的毒死蜱发育性神经毒性模型，用于在生态毒理学环境中评估NOAEL：斑马鱼为生态毒理学风险确定提供了相关的鱼类物种，同时为神经发育中特定的分子/细胞事件提供了转基因模型。发育神经毒性的分子机制可以确定并与行为表现的最终改变联系起来。

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. 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 for 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 zebrafish model 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 of 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 consequence 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 ectotoxicologic settings: zebrafish provides a relevant piscine species for ectotoxicologic 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.