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 二恶英样化合物（DLC），例如多氯联苯（PCB）和多环芳族 碳氢化合物（PAHS）通常存在于受污染的栖息地中，并被观察到驱动 居住在污染环境中的生物中的进化适应。该项目以前使用 描述了墨西哥湾杀戮（turdulus grandis）的适应人群，作为一种模型系统，以更好地了解 化学敏感性与生物转化之间的联系。海湾Killifish已适应抵抗PCB和 PAH相关的心血管致畸性响应加尔维斯顿湾的慢性化学暴露。 与其他适应性鱼类种群类似，这种适应的种群表型与缺失有关 芳基烃受体（AHR）和顽固的AHR途径。考虑到关键，这是违反直觉的 AHR途径在生物转化和随后排泄异种生物化学物质中的作用。虽然没有 完全阐明的，以前的工作表明，适应性鱼类的生物转化更慢一些，包括 苯并[a] pyrene（bap）。此外，有证据表明正在偏爱不同的代谢途径。 目前尚不清楚的是生物转化过程中观察到的改变是否会产生更安全 或更多有毒的代谢产物。换句话说，是对生物转化的改变，指示健身成本，或者 它们是否代表补偿性适应或适应，为 成功的生物转化和PAH的排泄？从现有文献中可以明显看出，顽固的ahr 途径为DLC引起的心血管致畸性提供了强烈的保护，并删除了 AHR可以提供此保护。适应人群的基因组研究表明多个基因是 可能参与观察到的抗性表型。我们旨在确定AHR缺失在 BAP的生物转化，模型PAH及其对免疫系统的影响，作为非 - 生物转化与AHR相关的途径。我们假设AHR缺失对 生物转化的速率以及不同组织中促炎细胞因子的降低。我们 建议其他自然进化的补偿性变化是适应DLC的关键第二阶段， 他们解释了以前记录的以不同模式的其他污染物类别的交叉抵抗 行动，可以提供有关不同人群脆弱性与各种化学物质的脆弱性的重要见解 压力源。拟议的研究很重要，因为它将是连续研究的第一步 将系统地确定与化学相关的生物转化途径的重大变化 选择压力产生的电阻。此外，该提案中概述的工作将提供 研究生和本科生的大量研究机会 将为进化，毒理学，生物转化之间的关系提供见解的研究， 代谢组学和转录组学以及环境健康。