Developmental Neurotoxicity of Superfund Pesticides

超级基金农药的发育神经毒性

• 批准号: 6900493
• 负责人: THEODORE A SLOTKIN
• 金额: $ 24.89万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6900493
• 关键词: apoptosis; axon; biological signal transduction; biomarker; cell differentiation; cell line; cholinesterase inhibitors; developmental disease /disorder; developmental neurobiology; environmental exposure; environmental toxicology; neurogenesis; neurons; neurotoxicology; oxidative stress; phenotype; physostigmine

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.

有机磷(OP)农药在全球范围内使用，是超级基金的一个处置问题。在……里面 在前一阶段，我们展示了毒死蜱是一种发育神经毒剂，从大脑形成的雏形一直延伸到出生后的晚期，它的作用范围是一个窗口。重要的是，除了胆碱酯酶抑制外，这些不良反应还受到一系列机制的影响，胆碱酯酶抑制是介导成人全身毒性的过程。这提出了两个重要的问题：我们可以用什么类型的生物标记物来表征这种机制 这些药物潜在的发育神经毒性，以及我们如何评估相关和 不相关的毒物会有相同类型的影响吗？有四个目标： 一、确定其发育神经毒性的细胞/分子机制 毒死蜱：神经细胞复制分化、递质选择的基本机制 表型，信号转导，轴突发生，氧化应激，细胞凋亡，功能反应。 二、毒死蜱与其他有机磷农药和非农药的作用机制比较 胆碱酯酶抑制剂(毒扁豆碱)：所有的OP或胆碱酯酶抑制剂是相同的吗？ 使用相同的方法评估其他超级基金的发育神经毒性 化学品(在其他项目中也进行了研究)：狄氏剂、镍、伊丽莎白河沉积物提取物、 毒死蜱光解产物。PC12模型能用来筛选神经毒物吗？ 发展一个基因组阵列“指纹”，在细胞发育的不同阶段易受神经毒性的影响，并与特定的表型和终点相联系。对不同发育阶段(未分化、早期分化、末期分化)的细胞周期、分化、神经递质表型、氧化应激、细胞凋亡的基因簇随时间的变化进行评估，选择与毒死蜱相关的毒物(毒死蜱、 对硫磷)或无关的(镍、狄氏剂)作用机制。