Effect of heavy metals on aryl hyrdocarbon receptor-regulated genes

重金属对芳烃受体调节基因的影响

• 批准号: RGPIN-2017-03844
• 负责人: ElKadi, Ayman
• 金额: $ 3.64万
• 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: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629471
• 关键词: Effect; heavy; metals; aryl; hyrdocarbon

Humans are exposed to numerous stressors, including heavy metals, products of combustion, pesticides, herbicides, and other environmental pollutants. To ensure survival in the face of such challenges, mammalian cells have evolved a variety of inducible genetic programs that enable them to adapt to the presence of harmful xenobiotics. These programs entail upregulation of discrete batteries of genes for xenobiotic metabolizing enzymes, xenobiotic transporters, and various cytoprotective proteins that allow an increased rate of xenobiotic elimination from the body, restoration of normal homeostasis, and removal of damaged macromolecules. Among transcription factors that mediate adaptation to foreign compounds, the aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) have been widely studied. Historically, the AhR has been associated with toxicity and carcinogenesis, whereas Nrf2 is associated with cytoprotection. My long-term objectives are to: 1) understand the potential outcome upon exposure to heavy metals and environmental pollutants, which commonly co-exist in the environment, on the expression of AhR-regulated genes, and 2) understand the role of AhR in the regulation of Nrf2 pathway and its downstream genes in response to heavy metals exposure. Our hypothesis is redox-sensitive transcription factors, activated protein 1 (AP-1) and nuclear factor kappaB (NF-kB), and their associated proteins mediate the cross-interactions between AhR and Nrf2 pathways that are involved in the modulation of AhR-regulated genes by heavy metals. This research is expected to have a great impact on the understanding of the cellular and molecular mechanisms responsible for the modulation of AhR-regulated genes by metals. Better recognition of coordinate Phase I and II metabolisms may greatly attenuate health risks posed by CYP1A1 generated toxic intermediates and reactive oxygen species. In addition, it will also reveal novel points of intervention to be exploited in the development of new therapies for the treatment and prevention of metals toxicity.

人类面临着许多压力源，包括重金属、燃烧产物、杀虫剂、除草剂和其他环境污染物。为了确保在面对此类挑战时能够生存，哺乳动物细胞进化出了多种诱导性遗传程序，使它们能够适应有害外源物质的存在。这些程序需要上调外源代谢酶、外源转运蛋白和各种细胞保护蛋白的离散基因组，从而提高体内外源消除的速度，恢复正常的体内平衡，并去除受损的大分子。在介导对外来化合物适应的转录因子中，芳基烃受体（AhR）和核因子红细胞2相关因子2（Nrf2）已被广泛研究。从历史上看，AhR 与毒性和致癌作用有关，而 Nrf2 与细胞保护有关。我的长期目标是：1）了解暴露于环境中共存的重金属和环境污染物对 AhR 调节基因表达的潜在结果；2）了解 AhR 在重金属暴露响应中 Nrf2 通路及其下游基因的调节中的作用。我们的假设是氧化还原敏感转录因子、活化蛋白 1 (AP-1) 和核因子 kappaB (NF-kB) 及其相关蛋白介导 AhR 和 Nrf2 途径之间的交叉相互作用，这些途径参与重金属对 AhR 调节基因的调节。这项研究预计将对理解金属调节 AhR 调控基因的细胞和分子机制产生重大影响。更好地识别协调 I 期和 II 期代谢可能会大大减轻 CYP1A1 产生的有毒中间体和活性氧所带来的健康风险。此外，它还将揭示新的干预点，用于开发治疗和预防金属毒性的新疗法。