Biomarkers of neurotoxicant exposure & neurodegeneration

神经毒物暴露的生物标志物

• 批准号: 6577805
• 负责人: MOHAMMAD SABRI
• 金额: $ 10.08万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6577805
• 关键词: analytical chemistry; benzene; biomarker; carbopolycyclic compound; chemical kinetics; environmental contamination; environmental exposure; environmental health; environmental toxicology; hazardous substances; laboratory rat; neural degeneration; neurotoxicology; solvents; urinalysis

Superfund sites commonly contain organic solvents with neurotoxic potential. These substances include aromatic hydrocarbons, such as benzene and toluene and aliphatic hydrocarbons, such as 2-butanone (methyl ethyl ketone). Neurotic benzene derivatives, such as a 1,2- diethylbenzene (1,2-DEB) and its putative metabolite 1,2-diacetylbenzene (1,2-DAB), cause a blue-green coloration (chromogenicity) of tissues and urine. The chromogenic compound 1,2-DAB is a potent neurotoxicant that induces neuropathological changes (neurofilament-filled giant axonal swellings) comparable to those found in humans and animals repeatedly exposed to the aliphatic hydrocarbon solvent n-hexane or its keto metabolite 2,5-hexanedione (2,5-HD), respectively. In concert with components of the Analytical Core, we will use male and female young adult rats, and biochemical, analytical, and morphological methods, to test the following hypotheses: (a) that a relationship exists between the structural and toxicological properties of 1,2-DAB and 2,5-HD, (b) that the chromogenic and neurotoxic properties of 1,2-DAB are directly interrelated, (c) that 1,2-DAB is the neurotoxic metabolic of 1,2-DEB, and (d) that 2-butanone and toluene, which respectively enhance and suppress the neurotoxic potential of n-hexane by altering its metabolism to 2,5-HD, modulate the neurotoxic potency of 1,2-DEB by altering its metabolism to 1,2-DAB. The major goal of this research project is to determine if the urinary chromogen (known to form in humans as well as rodents) can be used as a sensitive and specific biomarker of exposure to, and impending neuropathic effect of, aromatic hydrocarbons with neurotoxic potential. This biomarker may prove to be less invasive and more sensitive than an existing red blood cell spectrin-based biomarker of exposure to aliphatic gamma-diketones (2,5-HD). This project will also support studies in a companion research project (see Withers and Wallace, A4) that seek to determine if 1,2-DAB impacts brain development and plasticity. The long-term objective is to develop an ultra-sensitive biomarker of exposure to non-chlorinated organic solvents that can be used to identify individuals/populations at risk for neurotoxicity.

超级基金场所通常含有具有潜在神经毒性的有机溶剂。这些物质包括芳香烃，如苯和甲苯，以及脂肪烃，如2-丁酮（甲乙酮）。神经质苯衍生物，例如 1,2-二乙苯 (1,2-DEB) 及其假定的代谢物 1,2-二乙酰苯 (1,2-DAB)，会导致组织和尿液呈蓝绿色（显色）。显色化合物 1,2-DAB 是一种强效神经毒剂，可引起神经病理学变化（充满神经丝的巨型轴突肿胀），与反复暴露于脂肪烃溶剂正己烷或其酮代谢物 2,5- 的人类和动物中发现的变化相当。分别为己二酮（2,5-HD）。与分析核心的组成部分相一致，我们将使用雄性和雌性年轻成年大鼠以及生化、分析和形态学方法来测试以下假设：（a）1的结构和毒理学特性之间存在关系， 2-DAB 和 2,5-HD，(b) 1,2-DAB 的显色特性和神经毒性特性直接相关，(c) 1,2-DAB 是 2,5-HD 的神经毒性代谢物1,2-DEB 和 (d) 2-丁酮和甲苯分别通过改变其代谢为 2,5-HD 来增强和抑制正己烷的神经毒性潜力，调节 1,2-DEB 的神经毒性效力通过将其代谢改变为 1,2-DAB。该研究项目的主要目标是确定尿色原（已知在人类和啮齿动物中形成）是否可以用作暴露于具有潜在神经毒性的芳香烃以及其即将产生的神经病变效应的敏感和特异性生物标志物。与现有的基于红细胞血影蛋白的暴露于脂肪族伽马二酮（2,5-HD）的生物标志物相比，该生物标志物可能被证明侵入性更小且更敏感。 该项目还将支持一个配套研究项目（参见 Withers 和 Wallace，A4）的研究，该项目旨在确定 1,2-DAB 是否会影响大脑发育和可塑性。长期目标是开发一种超灵敏的非氯化有机溶剂暴露生物标志物，可用于识别有神经毒性风险的个人/人群。