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.

项目概要/摘要 二恶英类化合物 (DLC)，例如多氯联苯 (PCB) 和多环芳香族化合物 碳氢化合物（PAH）通常存在于受污染的栖息地中，并已被观察到会驱动 居住在污染环境中的生物体的进化适应。该项目利用了之前 描述了海湾鳉鱼（Fundulus grandis）的适应性种群作为模型系统，以更好地了解 化学敏感性与生物转化之间的联系。海湾鳉鱼已经适应了抵抗多氯联苯和 加尔维斯顿湾慢性化学暴露引起的与 PAH 相关的心血管致畸性。 与其他适应鱼类种群类似，这种适应种群表型与 芳烃受体 (AHR) 和顽固的 AHR 途径。这是违反直觉的，考虑到关键 AHR 途径在生物转化和随后的异生化学物质排泄中的作用。虽然没有 之前的研究已经充分阐明，已经表明适应的鱼类对某些多环芳烃的生物转化速度更慢，包括 苯并[a]芘（BaP）。此外，有证据表明不同的代谢途径受到青睐。 目前尚不清楚生物转化过程中观察到的变化是否会产生更安全的产品 或更有毒的代谢物。换句话说，生物转化的改变是否表明适应度成本，或者 它们是否代表补偿性适应或驯化，为 PAH 的生物转化和排泄成功吗？从现有文献中可以清楚地看出，顽固的 AHR 通路提供了强有力的保护，防止 DLC 诱导的心血管致畸性，并且缺失 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 可能涉及观察到的耐药表型。我们的目标是确定 AHR 删除对 BaP（一种多环芳烃模型）的生物转化及其对免疫系统的影响（以非-多环芳烃为例） 生物转化AHR相关途径。我们假设 AHR 删除对 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 DLC 的关键第二阶段， 他们解释了先前记录的对具有不同模式的其他污染物类别的交叉耐药性 行动，并可以提供有关不同人群对各种化学品的脆弱性的重要见解 压力源。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相关的生物转化途径的显着改变 选择压力产生的阻力。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实践研究机会 研究将为进化、毒理学、生物转化、 代谢组学和转录组学以及环境健康。