Effect of heavy metals on aryl hyrdocarbon receptor-regulated genes

人类暴露在许多应激源中，包括重金属、燃烧产物、杀虫剂、除草剂和其他环境污染物。为了确保在这些挑战下的生存，哺乳动物细胞进化出了各种可诱导的遗传程序，使它们能够适应有害的外源物质的存在。这些计划需要上调外源生物代谢酶、外源转运体和各种细胞保护蛋白的离散基因组，从而提高外源生物从体内的消除速度，恢复正常的内稳态，并清除受损的大分子。在介导对外来化合物适应的转录因子中，芳香烃受体(AhR)和核因子红系2相关因子(Nrf2)已被广泛研究。从历史上看，AhR与毒性和致癌有关，而Nrf2与细胞保护有关。我的长期目标是：1)了解接触重金属和环境污染物对AhR调节基因表达的潜在影响，以及2)了解AhR在调控Nrf2途径及其下游基因对重金属暴露的反应中所起的作用。我们的假设是氧化还原敏感的转录因子、活化蛋白1(AP-1)和核因子kappaB(NF-kB)，它们的相关蛋白介导了AhR和Nrf2途径之间的交叉相互作用，这些途径参与了重金属对AhR调控基因的调控。这项研究有望对理解金属调控AhR调控基因的细胞和分子机制产生重大影响。更好地认识协调的I期和II期代谢可能会极大地降低由CYP1A1产生的有毒中间体和活性氧物种带来的健康风险。此外，它还将揭示在开发治疗和预防金属中毒的新疗法方面可以利用的新的干预点。

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.