Effect of heavy metals on aryl hydrocarbon receptor-regulated genes

重金属对芳烃受体调节基因的影响

• 批准号: 250139-2007
• 负责人: ElKadi, Ayman
• 金额: $ 2.19万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2010
• 资助国家: 加拿大
• 起止时间: 2010-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=455583
• 关键词: Effect; heavy; metals; aryl; hydrocarbon

Co-contamination with complex mixtures of heavy metals and aryl hydrocarbon receptor (AhR)-ligands is a common environmental problem with multiple biological consequences, including birth defects, immune suppression, endocrine disruption and cancer. Both AhR ligands and heavy metals are ranked highly on the list of the most hazardous xenobiotics in the environment, prepared by the Canadian Environmental Protection Act (CEPA). The AhR plays a central role in the toxicity of numerous aromatic compounds by controlling the expression of a battery of enzymes responsible for their metabolism. The toxicity of AhR ligands is based on their bioactivation by the cytochrome P450 1A1 (CYP1A1) to yield mutagenic and carcinogenic intermediates. Many sources of environmental exposure to AhR ligands involve metal co-exposure. For example, heavy metals and AhR ligands are common contaminants of hazardous waste sites and are co-released from sources such as fossil fuel combustion and municipal waste incineration and as components of tobacco. Although environmental exposures involve co-exposure to complex mixtures, methods for assessing the potential risk to mixtures often assume additivity of responses, even though antagonism or synergy might exist. The novel aspect of this work is to understand the potential interaction between heavy metals and AhR ligands, which are common in the environment, on the expression of AhR-regulated genes to broaden our understanding of the important consequences for the toxicity of these environmental pollutants.

重金属和芳烃受体（AhR）配体的复杂混合物的共污染是一个常见的环境问题，具有多种生物后果，包括出生缺陷，免疫抑制，内分泌干扰和癌症。AhR配体和重金属都在加拿大环境保护法（CEPA）编制的环境中最危险的外源性物质清单上排名很高。AhR通过控制负责其代谢的一系列酶的表达在许多芳香族化合物的毒性中起着核心作用。AhR配体的毒性是基于它们被细胞色素P450 1A1（CYP1A1）生物活化产生致突变和致癌中间体。许多AhR配体的环境暴露源涉及金属共暴露。例如，重金属和AhR配体是危险废物场地的常见污染物，并且从诸如化石燃料燃烧和城市废物焚烧的来源以及作为烟草的组分共同释放。虽然环境接触涉及到与复杂混合物的共同接触，但评估混合物潜在风险的方法往往假定反应具有累加性，即使可能存在拮抗作用或协同作用。这项工作的新的方面是了解重金属和AhR配体之间的潜在相互作用，这是在环境中常见的，对AhR调控基因的表达，以扩大我们对这些环境污染物的毒性的重要后果的理解。