Developmental neurotoxicity of chlorpyrifos--Mechanism and consequences

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，引起有机磷（OP）诱导的迟发性神经病。然而，人们对孕妇、婴儿和儿童的接触表示关切。动物研究表明，毒死蜱对新生儿的毒性高出100倍，抑制胆碱酯酶以外的机制可能导致发育神经毒性。该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，以便提供适当的生物标志物，用于估计NOAEL并确定脆弱性窗口。我们将研究两种模型，一种是哺乳动物神经毒性模型（大鼠），另一种是鱼类神经毒性模型（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，鱼类模型将为环境监测提供潜在的生物标志物。该生物标志物的健康效应和鱼类模型将为环境监测提供潜在的生物标志物。斑马鱼模型也是有价值的，因为神经发育的过程很容易观察，因为胚胎也是有价值的，因为神经发育的过程很容易观察，因为胚胎是透明的。在这两种情况下，我们将集中在特定的目标，在暴露水平低于阈值的畸形或标准致畸的大脑发育。有三个目标：一。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：控制细胞复制、分化和凋亡中涉及的核转录因子的信号级联;与胆碱酯酶抑制的比较。二.为了确定毒死蜱对细胞发育的影响的功能后果：行为反应及其相应的潜在神经化学机制;我们将集中于我们的初步结果中已经确定为可能目标的神经通路和神经递质系统。三.开发一种非哺乳动物的毒死蜱发育神经毒性模型，用于估计生态毒理学环境中的NOAEL：斑马鱼为生态毒理学风险确定提供了相关鱼类物种，同时为神经发育中的特定分子/细胞事件提供了转基因模型。可以确定发育神经毒性的分子机制，并将其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 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.