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

解码改变的生物转化途径在海湾鳉鱼快速适应遗留污染物中的作用：利用不同的种群敏感性来了解化学脆弱性

• 批准号: 10729757
• 负责人: Ramon Lavado
• 金额: $ 41.87万
• 依托单位: BAYLOR UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-05 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729757
• 关键词: Acclimatization; Analytical Chemistry; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Benzo(a)pyrene; Biochemical; Biological Models; Breeding; Cardiovascular system; Chemical Exposure; Chemicals; Chronic; Dioxins; Disease; Environment; Environmental Health; Environmental Pollutants; Evolution; Excretory function; Exposure to; Fishes; Future; Genes; Genomics; Genotype; Goals; Gulf Killifish; Habitats; Human; Immune response; Immune system; Inflammatory; Killifishes; Laboratories; Literature; Mediating; Metabolic Biotransformation; Metabolic Pathway; Metabolism; Modeling; Molecular; Organism; Pathway interactions; Phase; Phenotype; Physiological; Poison; Pollution; Polychlorinated Biphenyls; Population; Probability; Process; Proteomics; Research; Resistance; Role; Shapes; Stress; Study models; System; Teratogens; Tissues; Toxic Environmental Substances; Toxic effect; Toxicology; Work; Xenobiotics; base; cost; cytokine; environmental toxicology; fitness; graduate student; hands on research; immune activation; insight; interdisciplinary approach; metabolomics; pollutant; pressure; resilience; response; stressor; study population; transcriptomics; undergraduate student

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.

项目摘要/摘要 二恶英类化合物（DLC），如多氯联苯（PCB）和多环芳烃 碳氢化合物（多环芳烃），往往存在于受污染的栖息地，并已被观察到驱动 生物在污染环境中的进化适应。该项目利用以往 描述了适应群体的海湾鳉鱼（底巨）作为一个模型系统，以更好地了解 化学敏感性和生物转化之间的联系。墨西哥湾的鳉鱼已经适应了对多氯联苯的抵抗， 加尔维斯顿湾慢性化学品暴露对PAH相关心血管致畸性的影响 与其他适应性鱼类种群相似，这种适应性种群表型与以下基因的缺失有关： 芳烃受体（AHR）和顽固的AHR途径。这是违反直觉的，因为关键的 AHR途径在生物转化和随后的外源性化学物质排泄中的作用。虽然不 充分阐明，以前的工作表明，适应鱼类生物转化一些多环芳烃， 苯并[a]芘（BaP）。此外，有证据表明，不同的代谢途径受到青睐。 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 或更多的有毒代谢物。换句话说，生物转化的改变是适应性成本的指示，还是 它们是否代表了一种补偿性适应或适应， 成功的生物转化和多环芳烃的排泄？从现有文献中可以清楚地看出， 信号通路对DLC诱导的心血管致畸性提供了强有力的保护， AHR可以提供这种保护。适应群体的基因组研究表明，多个基因 可能与观察到的耐药表型有关。我们的目标是确定AHR缺失对 BaP的生物转化，一种模型PAH，及其对免疫系统的影响，作为一个例子， 生物转化AHR相关途径。我们假设AHR缺失对 生物转化率以及不同组织中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DLCs的关键第二阶段， 他们解释了先前记录的对其他污染物类别的交叉抗性， 行动，并可提供重要的见解，不同人群的脆弱性，以各种化学品 压力源这项拟议中的研究意义重大，因为它将是一系列研究的第一步， 将系统地确定与化学物质相关的生物转化途径的重大改变， 选择压力导致的阻力。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研究机会， 研究，将提供深入了解进化，毒理学，生物转化， 代谢组学和转录组学以及环境健康。