Effect of heavy metals on aryl hyrdocarbon receptor-regulated genes

人类暴露于许多压力源，包括重金属，燃烧产物，杀虫剂，除草剂和其他环境污染物。为了确保在面对这些挑战时的生存，哺乳动物细胞已经进化出各种可诱导的遗传程序，使它们能够适应有害的外源性物质的存在。这些程序需要上调外源性物质代谢酶、外源性物质转运蛋白和各种细胞保护蛋白的离散基因组，这些基因组允许增加外源性物质从体内消除的速率，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的适应的转录因子中，芳烃受体（AhR）和核因子红细胞2相关因子2（Nrf 2）已被广泛研究。历史上，AhR与毒性和致癌作用有关，而Nrf 2与细胞保护作用有关。我的长期目标是：1）了解暴露于重金属和环境污染物（通常共存于环境中）对AhR调控基因表达的潜在影响; 2）了解AhR在Nrf 2途径及其下游基因调控中的作用，以响应重金属暴露。我们的假设是氧化还原敏感的转录因子，激活蛋白1（AP-1）和核因子κ B（NF-kB），以及它们的相关蛋白介导的交叉相互作用之间的AhR和Nrf 2途径参与重金属的调节AhR调控基因。这项研究预计将有很大的影响，负责金属调节AhR调控基因的细胞和分子机制的理解。更好地识别协调的I相和II相代谢可能会大大减轻CYP 1A 1产生的有毒中间体和活性氧物质所带来的健康风险。此外，它还将揭示在开发治疗和预防金属毒性的新疗法时可利用的新干预点。

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.