Effect of heavy metals on aryl hydrocarbon receptor-regulated genes

重金属和芳烃受体(AhR)配体的复合污染是一种常见的环境问题，具有多种生物学后果，包括出生缺陷、免疫抑制、内分泌干扰和癌症。AhR配体和重金属在加拿大环境保护法(CEPA)编制的环境中最危险的外来生物名单上排名很高。AhR通过控制一系列负责其新陈代谢的酶的表达，在许多芳香族化合物的毒性中发挥核心作用。AhR配体的毒性是基于它们被细胞色素P450 1A1(CyP1A1)激活而产生诱变和致癌的中间体。在环境中暴露于AhR配体的许多来源涉及金属共暴露。例如，重金属和AhR配体是危险废物场地的常见污染物，从化石燃料燃烧和城市垃圾焚烧等来源以及烟草成分中共同释放。尽管环境暴露涉及与复杂混合物的共同暴露，但评估混合物潜在风险的方法通常假定反应的可加性，即使可能存在拮抗或协同作用。这项工作的创新之处在于了解环境中常见的重金属和AhR配体之间对AhR调控基因表达的潜在相互作用，以拓宽我们对这些环境污染物毒性的重要后果的理解。

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.