MECHANISMS OF CHLORPYRIFOS DEVELOPMENTAL NEUROTOXICITY

毒死蜱发育神经毒性机制

• 批准号: 6635508
• 负责人: THEODORE A SLOTKIN
• 金额: $ 19.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6635508
• 关键词: apoptosis; behavior test; cell cycle; cell differentiation; cholinesterase inhibitors; cholinesterases; chordate locomotion; developmental neurobiology; disease /disorder model; environmental toxicology; histogenesis; laboratory rat; learning disorders; memory disorders; model design /development; neurogenesis; neurotoxicology; neurotoxins; organophosphorus insecticide; pesticide biological effect; reflex disorder; synaptogenesis; transcription factor; zebrafish

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.

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弱的诱导有机磷(OP)诱导的迟发性神经病变的能力。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达100倍，除胆碱酯酶抑制外，其他机制可能导致发育神经毒性。这项建议将确定发育神经毒性的细胞机制。这项建议将确定毒死蜱发育神经毒性的潜在细胞机制，以及发育暴露所导致的不良行为后果，以便提供适当的生物标志物来估计NOAEL和识别脆弱窗口。我们将检查两个模型，一个是哺乳动物神经毒性(大鼠)，另一个是鱼类神经毒性(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。斑马鱼的模型也很有价值，因为胚胎是透明的，神经发育的过程很容易观察到。在这两种情况下，我们将集中于大脑发育的特定靶点，暴露水平低于畸形发育或标准畸形的阈值。有三个目的：1.确定毒死蜱扰乱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；与胆碱酯酶抑制进行比较。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；我们将集中研究在我们的初步结果中已被确定为可能的靶标的神经通路和神经递质系统。建立毒死蜱发育神经毒性的非哺乳动物模型，用于体外毒理学环境中NOAEL的评估：斑马鱼为体外毒理学风险测定提供相关的鱼类物种，同时为神经发育中的特定分子/细胞事件提供转基因模型。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有关。