Decoding the role of altered biotransformation pathways in the rapid adaptation of Gulf killifish to legacy pollutants: Using differential population sensitivity to understand chemical vulnerability

项目摘要/摘要 二恶英类化合物(DLC)，如多氯联苯(PCBS)和多环芳烃 碳氢化合物(PAHs)，通常存在于受污染的栖息地，并已被观察到推动 生活在污染环境中的有机体的进化适应。该项目以前利用了 将墨西哥湾剑鱼(Fundulus Grand Is)的适应种群描述为更好地理解 化学敏感性和生物转化之间的联系。海湾剑鱼已经适应了抵抗多氯联苯的能力-和 加尔维斯顿湾慢性化学品暴露下与PAH相关的心血管致畸作用。 与其他适应鱼类种群类似，这种适应种群表型与 芳香烃受体(AHR)和顽固性AHR途径。这是违反直觉的，因为 AHR途径在外来化学物质生物转化和随后排泄中的作用。虽然不是 充分阐明，以前的工作已经表明，适应的鱼生物转化一些多环芳烃的速度更慢，包括 苯并[a]芘(BaP)。此外，有证据表明，不同的代谢途径正受到青睐。 目前尚不清楚的是，在生物转化过程中观察到的变化是否会产生更安全的 或者更多有毒的代谢物。换句话说，生物转化的变化是否表明健康成本，或者 它们是否代表了一种补偿性适应或适应，为 多环芳烃的生物转化和排泄成功？从现有的文献中可以清楚地看出，一个顽固的AHR 通路对DLC诱导的心血管致畸作用提供强大的保护作用，并且 AHR可以提供这种保护。对适应人群的基因组研究表明，多个基因是 可能与观察到的耐药表型有关。我们的目标是确定AHR缺失在 模型多环芳烃BaP的生物转化及其对免疫系统的影响 生物转化AHR相关途径。我们假设AHR基因的缺失对 不同组织的生物转化率以及促炎细胞因子的减少。我们 提出其他自然进化的补偿性变化是适应DLC的关键第二阶段， 它们解释了以前记录的对其他污染物类别的交叉抗性，具有不同的模式 行动，并可以为不同人群对各种化学物质的脆弱性提供重要的见解 压力源。这项拟议的研究意义重大，因为它将是一系列研究的第一步， 将系统地识别与化学物质相关的生物转化途径的重大变化 由选择压力引起的阻力。此外，本提案中概述的工作将提供 为研究生和本科生提供大量的实践研究机会 研究将提供对进化、毒理学、生物转化、 代谢组学和转录组学，以及环境健康。

PROJECT SUMMARY / ABSTRACT Dioxin-like compounds (DLCs), such as polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs), are often present in contaminated habitats and have been observed to drive evolutionary adaptation in organisms inhabiting polluted environments. This project utilizes previously described adapted populations of Gulf killifish (Fundulus grandis) as a model system to better understand the linkages between chemical sensitivity and biotransformation. Gulf killifish have adapted to resist PCB- and PAH-associated cardiovascular teratogenicity in response to chronic chemical exposures in Galveston Bay. Similar to other adapted fish populations, this adapted population phenotype is associated with a deletion in the aryl hydrocarbon receptor (AHR) and a recalcitrant AHR pathway. This is counter-intuitive, given the critical role of the AHR pathway in the biotransformation and subsequent excretion of xenobiotic chemicals. While not fully elucidated, previous work has shown that adapted fish more slowly biotransform some PAHs, including benzo[a]pyrene (BaP). Additionally, there is evidence that different metabolic pathways are being favored. What is not currently known is whether the observed alterations in the biotransformation process produce safer or more toxic metabolites. In other words, are the alterations to biotransformation indicative of a fitness cost, or do they represent a compensatory adaptation or acclimation, providing an alternative solution for the successful biotransformation and excretion of PAHs? It is clear from existing literature that a recalcitrant AHR pathway provides strong protection against DLC-induced cardiovascular teratogenicity and that a deletion in the AHR can provide this protection. Genomic studies of adapted populations suggest that multiple genes are likely involved in observed resistant phenotypes. We aim to determine the role of the AHR deletion on the biotransformation of BaP, a model PAH, and its influence on the immune system as an example of a non- biotransformation AHR-associated pathway. We hypothesize that the AHR deletion has a significant impact on the rate of biotransformation as well as on the decrease of proinflammatory cytokines in different tissues. We propose that other naturally evolved compensatory changes are a critical second stage of adaptation to DLCs, that they explain previously documented cross-resistance to other contaminant classes with different modes of action, and can provide important insights into the vulnerability of different populations to a variety of chemical stressors. The proposed research is significant because it will be the first step in a continuum of research that will systematically identify significant alterations of biotransformation pathways associated with chemical resistance resulting from selection pressure. Furthermore, the work outlined in this proposal will provide substantial research opportunities for both graduate and undergraduate students to engage in hands-on research that will provide insights into the relationships between evolution, toxicology, biotransformation, metabolomics and transcriptomics, and environmental health.